| 1. |
- Lundquist, Patrik, 1969, et al.
(författare)
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Na+/Ca2+ exchanger isoforms of rat odontoblasts and osteoblasts.
- 2000
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Ingår i: Calcified Tissue International. - 0171-967X. ; 67:1, s. 60-7
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Tidskriftsartikel (refereegranskat)abstract
- In odontoblasts as well as osteoblasts, a number of mechanisms for the inflow and extrusion of Ca2+ have been demonstrated. The entrance of Ca2+ ions into odontoblasts occurs mainly through voltage-gated calcium channels. Extrusion of Ca2+ is found to be an ATP-dependent process and, in addition, Na+/Ca2+-antiports exist, which are provoked by extracellular Na+. The aim of this study was to identify the Na+/Ca2+-antiport isoforms expressed in dentinogenically active rat incisor odontoblasts and to make a comparison with different osteoblastic cells. Using RT-PCR and RNAse protection assay, we demonstrated the expression of three different isoforms, NaCa 3, 7, and 10, of the NCX1-encoded antiport in odontoblasts and osteoblastic cells. When incubated in the presence of Na+, dissected rat incisor odontoblasts as well as the osteoblastic cells extruded Ca2+ ions, as detected by chlorotetracycline and Fura-2 fluorometry, thus supporting a physiological role for the detected isoform expression. Odontoblasts and rat calvarial osteoblasts, as well as osteoblast-like cell lines UMR-106.01 and Saos-2, were shown to exhibit identical phenotypes of Na+/Ca2+-antiport isoform expression, different from the expression patterns of other tissues. The significance of this specific expression pattern is unknown, but there is a possibility that it is in some way related to the unique demands on these cell types to produce mineralized connective tissue.
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| 2. |
- Bohlooly-Yeganeh, Mohammad, 1966, et al.
(författare)
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Enhanced spontaneous locomotor activity in bovine GH transgenic mice involves peripheral mechanisms
- 2001
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Ingår i: Endocrinology. ; 142:10, s. 4560-4567
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Tidskriftsartikel (refereegranskat)abstract
- Clinical and experimental studies indicate a role for GH in mechanisms related to anhedonia/hedonia, psychic energy, and reward. Recently we showed that transgenic mice with general overexpression of bovine GH display increased spontaneous locomotor activity. In the present study, we investigated whether this behavioral change is owing to a direct action of GH in the central nervous system or to peripheral GH actions. A transgenic construct, containing the glial fibrillary acidic protein promoter directing specific expression of bovine GH to the central nervous system, was designed. The central nervous system-specific expression of bovine GH in the glial fibrillary acidic protein-bovine GH transgenic mice was confirmed, but no effect on spontaneous locomotor activity was observed. Serum bovine GH levels were increased in glial fibrillary acidic protein-bovine GH transgenic mice but clearly lower than in transgenic mice with general overexpression of bovine GH. In contrast to the transgenic mice with general overexpression of bovine GH, glial fibrillary acidic protein-bovine GH mice did not display any difference in serum IGF-I levels. The levels of free T(3) and the conversion of the free T(4) to free T(3) were only increased in transgenic mice with general overexpression of bovine GH, but serum corticosterone levels were similarly increased in both transgenic models. These results suggest that free T(3) and/or IGF-I, affecting dopamine and serotonin systems in the central nervous system, may mediate the enhanced locomotor activity observed in transgenic mice with general overexpression of bovine GH.
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| 3. |
- Boström, Hans, et al.
(författare)
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PDGF-A/PDGF alpha-receptor signaling is required for lung growth and the formation of alveoli but not for early lung branching morphogenesis
- 2002
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Ingår i: Developmental Dynamics. - : Wiley. - 1058-8388 .- 1097-0177. ; 223:1, s. 155-162
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Tidskriftsartikel (refereegranskat)abstract
- Platelet-derived growth factors (PDGF) constitute a family of four gene products (PDGF-A-D) acting by means of two receptor tyrosine kinases, PDGFR alpha and beta. Three of the ligands (PDGF-A, -B, and -C) bind to PDGFR alpha with high affinity. Knockout of pdgf-a in mice has demonstrated a role for PDGF-A in the recruitment of smooth muscle cells to the alveolar sacs and their further compartmentalization into alveoli. Although this is a late, postnatal step in lung development, pdgf-a antisense oligonucleotides were previously shown to inhibit epithelial branching in rat lung explants in vitro, which reflects an early embryonic process. These conflicting results may be explained by substitution of genetic loss of pdgf-a by maternal transfer of PDGF-A to the knockout embryo or the presence of other PDGFR alpha agonists (PDGF-B and -C) in vivo, potentially masking an effect of PDGF-A on branching morphogenesis. Alternatively, the administration of pdgf-a antisense oligonucleotides affected other processes than the intended. To discriminate between these opposing possibilities, we have analyzed lung development in pdgfr alpha -/- embryos and lung primordia grown in vitro. Our analysis shows that, while the pdgfr alpha -/- lungs and explanted lung rudiments were smaller than normal, branching morphogenesis appears qualitatively intact and proceeds until at least embryonic day 15.5, generating both prospective conducting and respiratory airways. We conclude that, although PDGF-AA signaling over PDGFR alpha may have direct or indirect roles in overall lung growth, it does not specifically control early branching of the lung epithelium.
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| 4. |
- El Shahawy, Maha, et al.
(författare)
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Cell fate specification in the lingual epithelium is controlled by antagonistic activities of Sonic hedgehog and retinoic acid
- 2017
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Ingår i: Plos Genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 13:7
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Tidskriftsartikel (refereegranskat)abstract
- The interaction between signaling pathways is a central question in the study of organogenesis. Using the developing murine tongue as a model, we uncovered unknown relationships between Sonic hedgehog (SHH) and retinoic acid (RA) signaling. Genetic loss of SHH signaling leads to enhanced RA activity subsequent to loss of SHH-dependent expression of Cyp26a1 and Cyp26c1. This causes a cell identity switch, prompting the epithelium of the tongue to form heterotopic minor salivary glands and to overproduce oversized taste buds. At developmental stages during which Wnt10b expression normally ceases and Shh becomes confined to taste bud cells, loss of SHH inputs causes the lingual epithelium to undergo an ectopic and anachronic expression of Shh and Wnt10b in the basal layer, specifying de novo taste placode induction. Surprisingly, in the absence of SHH signaling, lingual epithelial cells adopted a Merkel cell fate, but this was not caused by enhanced RA signaling. We show that RA promotes, whereas SHH, acting strictly within the lingual epithelium, inhibits taste placode and lingual gland formation by thwarting RA activity. These findings reveal key functions for SHH and RA in cell fate specification in the lingual epithelium and aid in deciphering the molecular mechanisms that assign cell identity.
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| 5. |
- El Shahawy, Maha, et al.
(författare)
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Sonic Hedgehog Signaling Is Required for Cyp26 Expression during Embryonic Development
- 2019
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Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1422-0067. ; 20:9
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Tidskriftsartikel (refereegranskat)abstract
- Deciphering how signaling pathways interact during development is necessary for understanding the etiopathogenesis of congenital malformations and disease. In several embryonic structures, components of the Hedgehog and retinoic acid pathways, two potent players in development and disease are expressed and operate in the same or adjacent tissues and cells. Yet whether and, if so, how these pathways interact during organogenesis is, to a large extent, unclear. Using genetic and experimental approaches in the mouse, we show that during development of ontogenetically different organs, including the tail, genital tubercle, and secondary palate, Sonic hedgehog (SHH) loss-of-function causes anomalies phenocopying those induced by enhanced retinoic acid signaling and that SHH is required to prevent supraphysiological activation of retinoic signaling through maintenance and reinforcement of expression of the Cyp26 genes. Furthermore, in other tissues and organs, disruptions of the Hedgehog or the retinoic acid pathways during development generate similar phenotypes. These findings reveal that rigidly calibrated Hedgehog and retinoic acid activities are required for normal organogenesis and tissue patterning.
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| 6. |
- Gritli Linde, Amel, 1959, et al.
(författare)
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Abnormal hair development and apparent follicular transformation to mammary gland in the absence of Hedgehog signaling
- 2007
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Ingår i: Developmental Cell. - : Elsevier BV. - 1534-5807. ; 12:1, s. 99-112
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Tidskriftsartikel (refereegranskat)abstract
- Here, we show that removing the Shh receptor Smoothened from the skin epithelium results in a seemingly contradictory constellation of phenotypes including cellular disorganization, altered proliferation, and loss of hair follicle (HF) progenitors. We provide evidence that the lack of Smoothened in the epithelium results in excess Shh levels in the mesenchyme. Thus, the observed defects can be attributed not only to decreased epithelial Shh signaling, but increased mesenchymal Shh signalling. The latter contributes to exuberant HF induction, while the former depletes the resulting follicular stem cell niches. Two additional, unanticipated epithelial requirements for Shh relate to the robust acquisition of appropriate cell type identities: In the mutant mice, follicular outer root sheath takes on an epidermal character, and certain HF disappear altogether, having adopted a strikingly mammary gland-like fate. Our study uncovers a multifaceted function for Shh in sculpting and maintaining the integrity and identity of the developing HF.
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| 7. |
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| 8. |
- Gritli Linde, Amel, 1959, et al.
(författare)
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Effects of suramin on polyamine metabolism in B16 murine melanoma cells
- 1998
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Ingår i: Anticancer Res. - 0250-7005. ; 18:2A, s. 855-62
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Tidskriftsartikel (refereegranskat)abstract
- Polyamines and their biosynthetic enzymes, such as ornithine decarboxylase (ODC) and S-adenosylmethionine decarboxylase (AdoMetDC), are crucial for normal and neoplastic cell growth and differentiation. Suramin inhibits the growth of several tumor cells by affecting various intracellular targets, but its effects on polyamines are not known. In this study, the effects of suramin on some parameters of polyamine metabolism in B16 melanoma cells were investigated in vitro. Suramin increased cellular ODC activity and ODC mRNA levels, whereas the drug was directly inhibitory to the enzyme. AdoMetDC was not affected. Cellular putrescine levels were enhanced by suramin, whereas spermidine and spermine pools were unaltered. Cells cultured in the presence of suramin showed decreased cellular polyamine transport, but no direct inhibitory effect on the polyamine transporter could be found. Fluorescence spectroscopy demonstrated a direct interaction between suramin and spermine. It may be concluded that suramin affects polyamine metabolism, and that its effects in some respects are opposite to those of alpha-difluoromethylomithine (DFMO), a specific inhibitor of ODC.
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| 9. |
- Gritli Linde, Amel, 1959, et al.
(författare)
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Expression patterns of the Tmem16 gene family during cephalic development in the mouse
- 2009
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Ingår i: Gene Expression Patterns. - : Elsevier BV. - 1567-133X. ; 9:3, s. 178-191
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Tidskriftsartikel (refereegranskat)abstract
- Tmem16a, Tmem16c, Tmem16f, Tmem16h and Tmem16k belong to the newly identified Tmem16 gene family encoding eight-pass transmembrane proteins. We have analyzed the expression patterns of these genes during mouse cephalic development. In the central nervous system, Tmem16a transcripts were abundant in the ventricular neuroepithelium, whereas the other Tmem16 family members were readily detectable in the subventricular zone and differentiating fields. In the rostral spinal cord, Tmem16f expression was highest in the motor neuron area. In the developing eye, the highest amounts of Tmem16a transcripts were detected in the lens epithelium, hyaloid plexus and outer layer of the retina, while the other family members were abundant in the retinal ganglionic cell layer. Interestingly, throughout development, Tmem16a expression in the inner ear was robust and restricted to a subset of cells within the epithelium, which at later stages formed the organ of Corti. The stria vascularis was particularly rich in Tmem16a and Tmem16f mRNA. Other sites of Tmem16 expression included cranial nerve and dorsal root ganglia, meningeal precursors and the pituitary. Tmem16c and Tmem16f transcripts were also patent in the submandibular autonomic ganglia. A conspicuous feature of Tmem16a was its expression along the walls of blood vessels as well as in cells surrounding the trigeminal and olfactory nerve axons. In organs developing through epithelial-mesenchymal interactions, such as the palate, tooth and tongue, the above five Tmem16 family members showed interesting dynamic expression patterns as development proceeded. Finally and remarkably, osteoblasts and chondrocytes were particularly loaded with Tmem16a, Tmem16c and Tmem16f transcripts.
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| 10. |
- Gritli Linde, Amel, 1959, et al.
(författare)
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Nuclear translocation of antizyme and expression of ornithine decarboxylase and antizyme are developmentally regulated
- 2001
-
Ingår i: Developmental Dynamics. ; 220:3, s. 259-275
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Tidskriftsartikel (refereegranskat)abstract
- The polyamines are important regulators of cell growth and differentiation. Cells acquire polyamines by energy-dependent transport and by synthesis where the highly regulated ornithine decarboxylase (ODC) catalyzes the first and rate-controlling step. Inactivation of ODC is mainly exerted by antizyme (AZ), a 20--25 kDa polyamine-induced protein that binds to ODC, inactivates it, and targets it for degradation by the 26S proteasome without ubiquitination. In the present study, we have performed a systematic analysis of the expression of ODC and AZ, at the mRNA and protein levels, during mouse development. The expression patterns for ODC and AZ were found to be developmentally regulated, suggesting important functions for the polyamines in early embryogenesis, axonogenesis, epithelial-mesenchymal interaction, and in apoptosis. In addition, AZ protein was found to translocate to the nucleus in a developmentally regulated manner. The nuclear localization is consistent with the fact that the amino acid sequence of AZ exhibits features that characterize nuclear proteins. Interestingly, we found that cultivation of mandibular components of the first branchial arch in the presence of a selective proteasome inhibitor caused ODC accumulation in the nucleus of a subset of cells, suggesting that the observed nuclear translocation of AZ is linked to proteasome-mediated ODC degradation in the nucleus. The presence of AZ in the nucleus may suggest that nuclear ODC activity is under tight control, and that polyamine production can be rapidly interrupted when those developmental events, which depend on access to nuclear polyamines, have been completed.
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| 11. |
- Gritli Linde, Amel, 1959, et al.
(författare)
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Opposing effects of suramin and DL-alpha-difluoromethylornithine on polyamine metabolism contribute to a synergistic action on B16 melanoma cell growth in vitro
- 1998
-
Ingår i: Anticancer Res. - 0250-7005. ; 18:2A, s. 863-70
-
Tidskriftsartikel (refereegranskat)abstract
- Polyamines are crucial for normal and neoplastic cell growth. Treatment with the polyanionic drug suramin has pronounced antigrowth activity in several tumor cell lines, but its clinical use has been hampered by its toxicity. We have earlier shown that suramin affects cellular polyamine metabolism and transport, and that these effects were, in some respects, opposite to those of alpha-difluoromethylomithine (DFMO), a specific inhibitor to ornithine decarboxylase, a key metabolic enzyme for polyamines. DFMO has been used in anticancer trials, although with limited success. Combinations of suramin and DFMO were, hence, evaluated in vitro and were found to strongly inhibit B16 melanoma cell proliferation. DFMO alone induced melanoma cell differentiation, and suramin used in combination with DFMO did not abrogate this DFMO-induced differentiation. Synergy analysis demonstrated a pronounced growth-inhibitory synergism between suramin and DFMO. The results suggest that the efficacy of combinations of DFMO with suramin or its analogues should be further explored, especially in cells requiring high levels of polyamines for their growth.
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| 12. |
- Gritli Linde, Amel, 1959, et al.
(författare)
-
Shh signaling within the dental epithelium is necessary for cell proliferation, growth and polarization
- 2002
-
Ingår i: Development. ; 129:23, s. 5323-5337
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Tidskriftsartikel (refereegranskat)abstract
- Sonic hedgehog (Shh), a member of the mammalian hedgehog (Hh) family, plays a key role during embryogenesis and organogenesis. Tooth development, odontogenesis, is governed by sequential and reciprocal epithelial-mesenchymal interactions. Genetic removal of Shh activity from the dental epithelium, the sole source of Shh during tooth development, alters tooth growth and cytological organization within both the dental epithelium and mesenchyme of the tooth. In this model it is not clear which aspects of the phenotype represent the direct action of Shh on a target tissue or indirect effects due to deficiencies in reciprocal signalings between the epithelial and mesenchymal components. To distinguish between these two alternatives and extend our understanding of Shh’s actions in odontogenesis, we have used the Cre-loxP system to remove Smoothened (Smo) activity in the dental epithelium. Smo, a seven-pass membrane protein is essential for the transduction of all Hh signals. Hence, removal of Smo activity from the dental epithelium should block Shh signaling within dental epithelial derivatives while preserving normal mesenchymal signaling. Here we show that Shh-dependent interactions occur within the dental epithelium itself. The dental mesenchyme develops normally up until birth. In contrast, dental epithelial derivatives show altered proliferation, growth, differentiation and polarization. Our approach uncovers roles for Shh in controlling epithelial cell size, organelle development and polarization. Further, we provide evidence that Shh signaling between ameloblasts and the overlying stratum intermedium may involve subcellular localization of Ptc2 and Gli1 mRNAs, both of which are targets of Shh signaling in these cells.
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| 13. |
- Gritli Linde, Amel, 1959, et al.
(författare)
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The whereabouts of a morphogen: direct evidence for short- and graded long-range activity of hedgehog signaling peptides
- 2001
-
Ingår i: Developmental Biology. ; 236:2, s. 364-386
-
Tidskriftsartikel (refereegranskat)abstract
- Sonic Hedgehog (Shh) and Indian Hedgehog (Ihh) are members of the Hedgehog (Hh) family of signaling molecules known to be involved in embryonic patterning and morphogenesis. The Hh proteins undergo an autocatalytic cleavage to yield an N-terminal and a C-terminal peptide, with the signaling capacities confined to the N peptide. Drosophila Hh-N has been shown to act via both short- and long-range signaling. In vertebrates, however, attempts to directly demonstrate Shh (SHH) or Ihh (IHH) proteins at a distance from producing cells have been largely unsuccessful. Furthermore, the fact that the Hh N peptides occur in a cholesterol-modified, membrane-tethered form is not easily reconciled with long-range signaling. This study used optimized immunohistochemistry combined with tissue separation and biochemical analyses in vivo and in vitro to determine the range of action of SHH and IHH in the mouse embryo. In all embryonic structures studied, we detect signaling peptides in producing cells, but we also find that ligands move over considerable distances depending on the tissue. These data provide direct evidence for the presence of Hedgehog signaling peptides in target compartments, suggesting a direct long-range action without a need for secondary mediators. Visualization of Hedgehog proteins in target tissues was achieved only under conditions that allowed proteoglycan/glycosaminoglycan (PG/GAG) preservation. Furthermore, we show that induced changes of the composition of PG/GAG in the tooth alter SHH signaling. These data suggest a crucial role for PG/GAGs in Hedgehog movement.
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| 14. |
- Larsson, Birgitta, et al.
(författare)
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Extracts of ECL-cell granules/vesicles and of isolated ECL cells from rat oxyntic mucosa evoke a Ca2+ second messenger response in osteoblastic cells
- 2001
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Ingår i: Regulatory Peptides. ; 97:2-3, s. 153-161
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Tidskriftsartikel (refereegranskat)abstract
- Surgical removal of the acid-producing part of the stomach (oxyntic mucosa) reduces bone mass through mechanisms not yet fully understood. The existence of an osteotropic hormone produced by the so-called ECL cells has been suggested. These cells, which are numerous in the oxyntic mucosa, operate under the control of circulating gastrin. Both gastrin and an extract of the oxyntic mucosa decrease blood calcium and stimulate Ca2+ uptake into bone. Conceivably, gastrin lowers blood calcium indirectly by releasing a hypothetical hormone from the ECL cells. The present study investigated, by means of fura-2 fluorometry, the effect of extracts of preparations enriched in ECL cell granules/vesicles from rat oxyntic mucosa on mobilization of intracellular Ca2+ in three osteoblast-like cell lines, UMR-106.01, MC3T3-E1 and Saos-2, and of extracts of isolated ECL cells in UMR-106.01 cells. The extracts were found to induce a dose-related rapid increase in intracellular Ca2+ concentrations in the osteoblast-like cells. The response was not due to histamine or pancreastatin, known ECL cell constituents, and could be abolished by pre-digesting the extracts with exo-aminopeptidase. The results show that the increase in [Ca2+](i) reflects a mobilization of Ca2+ from the endoplasmic reticulum. The observation of an increase in [Ca2+](i) also in murine embryonic fibroblasts show that the response is not limited to osteoblastic cells. The finding that the extracts evoked a typical Ca2+ -mediated second messenger response in osteoblastic cells provides evidence for the existence of a novel osteotropic peptide hormone (gastrocalcin), produced in the ECL cells, and supports the view that gastrectomy-induced osteopathy may reflect a lack of this hormone.
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| 15. |
- Reibring, Claes-Göran, 1955, et al.
(författare)
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Distinct and Overlapping Expression Patterns of the Homer Family of Scaffolding Proteins and Their Encoding Genes in Developing Murine Cephalic Tissues.
- 2020
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Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1422-0067. ; 21:4
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Tidskriftsartikel (refereegranskat)abstract
- In mammals Homer1, Homer2 and Homer3 constitute a family of scaffolding proteins with key roles in Ca2+ signaling and Ca2+ transport. In rodents, Homer proteins and mRNAs have been shown to be expressed in various postnatal tissues and to be enriched in brain. However, whether the Homers are expressed in developing tissues is hitherto largely unknown. In this work, we used immunohistochemistry and in situ hybridization to analyze the expression patterns of Homer1, Homer2 and Homer3 in developing cephalic structures. Our study revealed that the three Homer proteins and their encoding genes are expressed in a wide range of developing tissues and organs, including the brain, tooth, eye, cochlea, salivary glands, olfactory and respiratory mucosae, bone and taste buds. We show that although overall the three Homers exhibit overlapping distribution patterns, the proteins localize at distinct subcellular domains in several cell types, that in both undifferentiated and differentiated cells Homer proteins are concentrated in puncta and that the vascular endothelium is enriched with Homer3 mRNA and protein. Our findings suggest that Homer proteins may have differential and overlapping functions and are expected to be of value for future research aiming at deciphering the roles of Homer proteins during embryonic development.
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| 16. |
- Reibring, Claes-Göran, 1955, et al.
(författare)
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Expression Patterns and Subcellular Localization of Carbonic Anhydrases Are Developmentally Regulated during Tooth Formation.
- 2014
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 9:5
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Tidskriftsartikel (refereegranskat)abstract
- Carbonic anhydrases (CAs) play fundamental roles in several physiological events, and emerging evidence points at their involvement in an array of disorders, including cancer. The expression of CAs in the different cells of teeth is unknown, let alone their expression patterns during odontogenesis. As a first step towards understanding the role of CAs during odontogenesis, we used immunohistochemistry, histochemistry and in situ hybridization to reveal hitherto unknown dynamic distribution patterns of eight CAs in mice. The most salient findings include expression of CAII/Car2 not only in maturation-stage ameloblasts (MA) but also in the papillary layer, dental papilla mesenchyme, odontoblasts and the epithelial rests of Malassez. We uncovered that the latter form lace-like networks around incisors; hitherto these have been known to occur only in molars. All CAs studied were produced by MA, however CAIV, CAIX and CARPXI proteins were distinctly enriched in the ruffled membrane of the ruffled MA but exhibited a homogeneous distribution in smooth-ended MA. While CAIV, CAVI/Car6, CAIX, CARPXI and CAXIV were produced by all odontoblasts, CAIII distribution displayed a striking asymmetry, in that it was virtually confined to odontoblasts in the root of molars and root analog of incisors. Remarkably, from initiation until near completion of odontogenesis and in several other tissues, CAXIII localized mainly in intracellular punctae/vesicles that we show to overlap with LAMP-1- and LAMP-2-positive vesicles, suggesting that CAXIII localizes within lysosomes. We showed that expression of CAs in developing teeth is not confined to cells involved in biomineralization, pointing at their participation in other biological events. Finally, we uncovered novel sites of CA expression, including the developing brain and eye, the olfactory epithelium, melanoblasts, tongue, notochord, nucleus pulposus and sebaceous glands. Our study provides important information for future single or multiple gene targeting strategies aiming at deciphering the function of CAs during odontogenesis.
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| 17. |
- Reibring, Claes-Göran, 1955, et al.
(författare)
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Loss of BMP2 and BMP4 Signaling in the Dental Epithelium Causes Defective Enamel Maturation and Aberrant Development of Ameloblasts
- 2022
-
Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1422-0067. ; 23:11
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Tidskriftsartikel (refereegranskat)abstract
- BMP signaling is crucial for differentiation of secretory ameloblasts, the cells that secrete enamel matrix. However, whether BMP signaling is required for differentiation of maturation-stage ameloblasts (MA), which are instrumental for enamel maturation into hard tissue, is hitherto unknown. To address this, we used an in vivo genetic approach which revealed that combined deactivation of the Bmp2 and Bmp4 genes in the murine dental epithelium causes development of dysmorphic and dysfunctional MA. These fail to exhibit a ruffled apical plasma membrane and to reabsorb enamel matrix proteins, leading to enamel defects mimicking hypomaturation amelogenesis imperfecta. Furthermore, subsets of mutant MA underwent pathological single or collective cell migration away from the ameloblast layer, forming cysts and/or exuberant tumor-like and gland-like structures. Massive apoptosis in the adjacent stratum intermedium and the abnormal cell-cell contacts and cell-matrix adhesion of MA may contribute to this aberrant behavior. The mutant MA also exhibited severely diminished tissue non-specific alkaline phosphatase activity, revealing that this enzyme's activity in MA crucially depends on BMP2 and BMP4 inputs. Our findings show that combined BMP2 and BMP4 signaling is crucial for survival of the stratum intermedium and for proper development and function of MA to ensure normal enamel maturation.
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| 18. |
- Reyahi, Azadeh, et al.
(författare)
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Foxf2 Is Required for Brain Pericyte Differentiation and Development and Maintenance of the Blood-Brain Barrier
- 2015
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Ingår i: Developmental Cell. - : Elsevier BV. - 1534-5807 .- 1878-1551. ; 34:1, s. 19-32
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Tidskriftsartikel (refereegranskat)abstract
- Pericytes are critical for cerebrovascular maturation and development of the blood-brain barrier (BBB), but their role in maintenance of the adult BBB, and how CNS pericytes differ from those of other tissues, is less well understood. We show that the forkhead transcription factor Foxf2 is specifically expressed in pericytes of the brain and that Foxf2(-/-) embryos develop intracranial hemorrhage, perivascular edema, thinning of the vascular basal lamina, an increase of luminal endothelial caveolae, and a leaky BBB. Foxf2(-/-) brain pericytes were more numerous, proliferated faster, and expressed significantly less Pdgfr beta. Tgf beta-Smad2/3 signaling was attenuated, whereas phosphorylation of Smad1/5 and p38 were enhanced. Tgf beta pathway components, including Tgf beta 2, Tgf beta r2, Alk5, and integrins alpha(V)beta(8), were reduced. Foxf2 inactivation in adults resulted in BBB breakdown, endothelial thickening, and increased trans-endothelial vesicular transport. On the basis of these results, FOXF2 emerges as an interesting candidate locus for stroke susceptibility in humans.
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| 19. |
- Vazirisani, Forugh, 1967, et al.
(författare)
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Developmental changes in cellular and extracellular structural macromolecules in the secondary palate and nasal cavity of the mouse
- 2010
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Ingår i: European Journal of Oral Sciences. - 1600-0722. ; 118:3, s. 221-236
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to analyse the hitherto largely unknown expression patterns of some specific cellular and extracellular molecules during palate and nasal cavity development. We show that epithelia of the developing palate and the vomerine epithelium express similar sets of structural proteins. With the exception of keratin 15, which becomes barely detectable in the elevated palatal shelves, nearly all of these become upregulated at the presumptive areas of fusion and in the adhering epithelia of the palate and nasal septum. In vivo and in vitro analyses indicated that keratin 15 protein reduction is independent of Tgfβ-Alk5 signaling. Foxa1 expression also highlighted the regionalization of the palatal and nasal epithelia. Due to lack of reliable markers of the palatal periderm, the fate of peridermal cells has been controversial. We identified LewisX/SSEA1 as a specific peridermal marker, and showed that numerous peridermal cells remain trapped in the medial epithelial seam (MES). The fate of these cells is likely apoptosis together with the rest of MES cells, as we provided further strong evidence for this event. Heparan sulphate, chondroitin-6-sulphate and versican displayed dynamically changing distribution patterns. The hitherto unknown innervation pattern of the developing palate was revealed. These findings may be of value for unravelling the pathogenesis of palatal clefting.
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| 20. |
- Vazirisani, Forugh, 1967, et al.
(författare)
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Fate-mapping of the epithelial seam during palatal fusion rules out epithelial-mesenchymal transformation.
- 2005
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Ingår i: Developmental Biology. - : Elsevier BV. - 0012-1606. ; 285:2, s. 490-495
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Tidskriftsartikel (refereegranskat)abstract
- During palatogenesis, fusion of the palatine shelves is a crucial event, the failure of which results in the birth defect, cleft palate. The fate of the midline epithelial seam (MES), which develops transiently upon contact of the two palatine shelves, is still strongly debated. Three major mechanisms underlying the regression of the MES upon palatal fusion have been proposed: (1) apoptosis has been evidenced by morphological and molecular criteria; (2) epithelial-mesenchymal transformation has been suggested based on ultrastructural and lipophilic dye cell labeling observations; and (3) migration of MES cells toward the oral and nasal areas has been proposed following lipophilic dye cell labeling. To verify whether epithelial-mesenchymal transformation of MES cells takes place during murine palatal fusion, we used the Cre/lox system to genetically mark Sonic hedgehog- and Keratin-14-expressing palatal epithelial cells and to identify their fate in vivo. Our analyses provide conclusive evidence that rules out the occurrence of epithelial-mesenchymal transformation of MES cells.
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| 21. |
- Zhao, Dawei, 1963, et al.
(författare)
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Expression of Pit2 sodium-phosphate cotransporter during murine odontogenesis is developmentally regulated
- 2006
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Ingår i: European Journal of Oral Sciences. ; 114:6, s. 517-523
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Tidskriftsartikel (refereegranskat)abstract
- Different sodium-dependent inorganic phosphate (Pi) uptake mechanisms play a major role in cellular Pi homeostasis. The function and detailed distribution patterns of the type III Na+-phosphate cotransporter PiT-2 in different organs during development are still largely unknown. We therefore examined the temporospatial expression patterns of Pit2 during murine odontogenesis. Odontoblasts were always devoid of Pit2 expression, whereas only a transient but strong expression was detected in young secretory ameloblasts. However, the stratum intermedium and, later on, the papillary layer and cells of the subodontoblastic layer exhibited high amounts of Pit2 mRNA, which increased gradually as the tooth matured. Hormonal treatment or Pi starvation of tooth germs in vitro did not alter Pit2 levels or patterns of expression, indicating mechanisms of regulation different from those of PiT-1 or other cell types. PiT-2 also functions as a retroviral receptor, and functional membrane-localized protein was confirmed throughout the dental papilla/pulp by demonstrating cellular permissiveness to infection by a gammaretrovirus that uses PiT-2 as a receptor. The distinct pattern of Pit2 expression during odontogenesis suggests that its Pi-transporter function may be important for homeostasis of dental cells and not specifically for mineralization of the dental extracellular matrices. The expression of viral receptors in enamel-forming cells and the dental pulp may be of pathological significance.
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| 22. |
- Bouldin, Courtney M., et al.
(författare)
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Shh pathway activation is present and required within the vertebrate limb bud apical ectodermal ridge for normal autopod patterning
- 2010
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Ingår i: Proceedings of the National Academy of Sciences USA. - 0027-8424. ; 107:12, s. 5489-5494
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Tidskriftsartikel (refereegranskat)abstract
- Expression of Sonic Hedgehog (Shh) in the posterior mesenchyme of the developing limb bud regulates patterning and growth of the developing limb by activation of the Hedgehog (Hh) signaling pathway. Through the analysis of Shh and Hh signaling target genes, it has been shown that activation in the limb bud mesoderm is required for normal limb development to occur. In contrast, it has been stated that Hh signaling in the limb bud ectoderm cannot occur because components of the Hh signaling pathway and Hh target genes have not been found in this tissue. However, recent array-based data identified both the components necessary to activate the Hh signaling pathway and targets of this pathway in the limb bud ectoderm. Using immunohistochemistry and various methods of detection for targets of Hh signaling, we found that SHH protein and targets of Hh signaling are present in the limb bud ectoderm including the apex of the bud. To directly test whether ectodermal Hh signaling was required for normal limb patterning, we removed Smo, an essential component of the Hh signaling pathway, from the apical ectodermal ridge (AER). Loss of functional Hh signaling in the AER resulted in disruption of the normal digit pattern and formation of additional postaxial cartilaginous condensations. These data indicate that contrary to previous accounts, the Hh signaling pathway is present and required in the developing limb AER for normal autopod development.
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| 23. |
- Economou, Andrew D, et al.
(författare)
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Periodic stripe formation by a Turing-mechanism operating at growth zones in the mammalian palate
- 2012
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 44:3, s. 348-352
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Tidskriftsartikel (refereegranskat)abstract
- We present direct evidence of an activator-inhibitor system in the generation of the regularly spaced transverse ridges of the palate. We show that new ridges, called rugae, that are marked by stripes of expression of Shh (encoding Sonic hedgehog), appear at two growth zones where the space between previously laid rugae increases. However, inter-rugal growth is not absolutely required: new stripes of Shh expression still appeared when growth was inhibited. Furthermore, when a ruga was excised, new Shh expression appeared not at the cut edge but as bifurcating stripes branching from the neighboring stripe of Shh expression, diagnostic of a Turing-type reaction-diffusion mechanism. Genetic and inhibitor experiments identified fibroblast growth factor (FGF) and Shh as components of an activator-inhibitor pair in this system. These findings demonstrate a reaction-diffusion mechanism that is likely to be widely relevant in vertebrate development.
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| 24. |
- Fagman, Henrik, 1975, et al.
(författare)
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Genetic deletion of sonic hedgehog causes hemiagenesis and ectopic development of the thyroid in mouse.
- 2004
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Ingår i: American Journal of Pathology. - 0002-9440. ; 164:5, s. 1865-72
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Tidskriftsartikel (refereegranskat)abstract
- Thyroid dysgenesis encountered in 85% of patients with congenital hypothyroidism is a morphologically heterogeneous condition with primarily unknown pathogenesis. Here we identify sonic hedgehog (Shh) as a novel regulator of thyroid development. In Shh knockout mice the thyroid primordium is correctly specified in the pharyngeal endoderm, but budding and dislocation are slightly delayed. In late development the thyroid fails to form a bilobed gland. Instead a single thyroid mass is found unilaterally and mostly to the left of the midline. Thyroid-specific transcription factors (TTF-1 and TTF-2) and thyroglobulin are expressed indicating terminal differentiation. Strikingly, TTF-1- and TTF-2-positive cells aberrantly develop in the presumptive trachea of Shh-/- embryos. The ectopic tissue buds ventrolaterally into the adjacent mesenchyme, and less extensively into the tracheal lumen, forming follicle-like structures that accumulate thyroglobulin. Shh mRNA is not expressed in the thyroid precursor cells at any developmental stage. The results indicate that Shh signaling indirectly governs the symmetric bilobation of the thyroid during late organogenesis. Shh also seems to repress inappropriate thyroid differentiation in nonthyroid embryonic tissues. This study provides clues to the molecular mechanisms that might be dysregulated in thyroid hemiagenesis and development of ectopic thyroid tissue outside the thyroglossal duct.
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| 25. |
- Gritli Linde, Amel, 1959
(författare)
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Molecular control of secondary palate development
- 2007
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Ingår i: Developmental Biology. - : Elsevier BV. - 0012-1606. ; 301:2, s. 309-326
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Forskningsöversikt (refereegranskat)abstract
- Compared with the embryonic development of other organs, development of the secondary palate is seemingly simple. However, each step of palatogenesis, from initiation until completion, is subject to a tight molecular control that is governed by epithelial-mesenchymal interactions. The importance of a rigorous molecular regulation of palatogenesis is reflected when loss of-function of a single protein generates cleft palate, a frequent malformation with a complex etiology. Genetic studies in humans and targeted mutations in mice have identified numerous factors that play key roles during palatogenesis. This review highlights the current understanding of the molecular and cellular mechanisms involved in normal and abnormal palate development with special respect to recent advances derived from studies of mouse models.
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| 26. |
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| 27. |
- Gritli Linde, Amel, 1959, et al.
(författare)
-
Skin fibroblasts from spermine synthase-deficient hemizygous gyro male (Gy/Y) mice overproduce spermidine and exhibit increased resistance to oxidative stress but decreased resistance to UV irradiation
- 2001
-
Ingår i: Biochemical Journal. ; 352, s. 381-367
-
Tidskriftsartikel (refereegranskat)abstract
- Hemizygous gyro male (Gy/Y) mice are a model for X-linked hypophosphataemic rickets. As in humans, the disease is caused by deletions in the Phex gene, a phosphate-regulating gene having homologies with endopeptidases on the X chromosome. Some phenotypic abnormalities in Gy/Y mice have recently been attributed to the fact that the Gy deletion also includes the neighbouring spermine synthase gene, resulting in spermine deficiency. Spermine and its precursors spermidine and putrescine are essential for cell growth and differentiation. As a novel method for studying the function of spermine, we established primary cultures of skin fibroblasts from hemizygous Gy/Y mice. The Gy/Y cells contained no detectable spermine. In view of the fact that spermine is a free-radical scavenger in vitro, we were surprised to find that Gy/Y cells were more resistant to oxidative stress than their normal (X/Y) counterparts. However, our finding that spermidine accumulates markedly in the spermine-deficient Gy/Y cells can probably explain this increased resistance. It is the first indication that spermidine can serve as a free-radical scavenger in vivo and not only in vitro. When subjecting the Gy/Y cells to UV-C irradiation we made another interesting finding: the mutant cells were more sensitive than the normal X/Y cells. This finding indicates that spermine, probably because of its high-affinity binding to DNA, is important in protection against chromatin damage.
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| 28. |
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| 29. |
- Gritli Linde, Amel, 1959
(författare)
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The Etiopathogenesis of Cleft Lip and Cleft Palate: Usefulness and Caveats of Mouse Models : In: Mouse Models of Developmental Genetic Disease (R Krauss, Ed.)
- 2008
-
Ingår i: Current Topics in Developmental Biology. - 0070-2153. ; 84, s. 37-138
-
Forskningsöversikt (refereegranskat)abstract
- Cleft lip and cleft palate are frequent human congenital malformations with a complex multifactorial etiology. These orofacial clefts can occur as part of a syndrome involving multiple organs or as isolated clefts without other detectable defects. Both forms of clefting constitute a heavy burden to the affected individuals and their next of kin. Human and mouse facial traits are utterly dissimilar. However, embryonic development of the lip and palate are strikingly similar in both species, making the mouse a model of choice to study their normal and abnormal development. Human epidemiological and genetic studies are clearly important for understanding the etiology of lip and palate clefting. However, our current knowledge about the etiopathogenesis of these malformations has mainly been gathered throughout the years from mouse models, including those with mutagen-, teratogen- and targeted mutation-induced clefts as well as from mice with spontaneous clefts. This review provides a comprehensive description of the numerous mouse models for cleft lip and/or cleft palate. Despite a few weak points, those models have revealed the high order of molecular complexity as well as the stringent spatiotemporal regulations and interactions between key factors which govern the development of these orofacial structures.
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| 30. |
- Gritli Linde, Amel, 1959
(författare)
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The Mouse as a Developmental Model for Cleft Lip and Palate Research
- 2012
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Ingår i: Frontiers of Oral Biology. - 1420-2433. ; 16, s. 32-51
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Forskningsöversikt (refereegranskat)abstract
- Vertebrate and invertebrate model organisms are essential for deciphering biological processes. One of these, the mouse, proved to be a valuable model for understanding the etiopathogenesis of a vast array of human diseases, including congenital malformations such as orofacial clefting conditions. This small mammal’s usefulness in cleft lip and palate research stems not only from the striking anatomical and molecular similarities of lip and palate development between human and mouse embryos, but also from its amenability to experimental and genetic manipulation. Using some recent studies as illustrative examples, this review describes different ways of generating and exploiting mouse models to study normal and abnormal development of the lip and palate. Despite a few surmountable disadvantages of using the mouse, numerous mutants have revealed a growing number of molecular key players and have pointed at a tight and complex molecular control during each step of lip and palate development.
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| 31. |
- Johansson, Eva M., 1900, et al.
(författare)
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Nuclear factor 1-C2 is regulated by prolactin and shows a distinct expression pattern in the mouse mammary epithelial cells during development
- 2005
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Ingår i: Molecular Endocrinology. - : The Endocrine Society. - 0888-8809 .- 1944-9917. ; 19:4, s. 992-1003
-
Tidskriftsartikel (refereegranskat)abstract
- We have previously demonstrated that the transcription factor nuclear factor (NF)1-C2 plays an important role in the mammary gland for the activation of the tumor suppressor gene p53. It also activates the milk genes carboxyl ester lipase and whey acidic protein, implying that NF1-C2 participates both in the establishment of a functional gland and in protection of the gland against tumorigenesis during proliferation. In this study, we have developed a new sensitive NF1-C2-specific antiserum for immunohistochemical analyses of the NF1-C2 distribution during mammary gland development. We show that the NF1-C2 protein is present in the epithelial compartment at the virgin stage and throughout mammary gland development. However, in the lactation stage the NF1-C2 protein levels strongly decreased, and many epithelial nuclei stained negative. In situ hybridization shows that NF1-C2 transcripts are expressed in the whole epithelium at pregnancy as well as the lactation stage, indicating that the reduction in protein levels is posttranscriptionally regulated. At involution, the NF1-C2 proteins are back to high levels. Based on studies using NMuMG cells and mammary tissue from heterozygous prolactin receptor knockout mice, we also demonstrate that prolactin has a direct effect in the maintenance of the NF1-C2 protein levels in the mammary epithelial nuclei at the virgin stage and during pregnancy. Hence, we have identified another transcription factor in the mammary gland, besides signal transducer and activator of transcription 5, through which prolactin may control mammary gland development. Furthermore, our data suggest a link between prolactin and p53 in the mammary gland, through NF1-C2.
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| 32. |
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| 33. |
- Lewis, Paula M, et al.
(författare)
-
Sonic hedgehog signaling is required for expansion of granule neuron precursors and patterning of the mouse cerebellum.
- 2004
-
Ingår i: Developmental Biology. - : Elsevier BV. - 0012-1606. ; 270:2, s. 393-410
-
Tidskriftsartikel (refereegranskat)abstract
- The signals that promote regional growth and development of the brain are not well understood. Sonic hedgehog (Shh) is produced by Purkinje cells of the cerebellum and is a potent inducer of granule cell proliferation. Here, we demonstrate that Shh protein is present in the murine cerebellum during late stages of embryogenesis and is associated with Purkinje cell bodies and their processes. To better determine the role of Shh during cerebellar development, we genetically removed Shh activity specifically from Purkinje cells and the cerebellar anlage of the mouse embryo. We show that Shh is required for expansion of the granule neuron precursor population, but not for the subsequent differentiation of these cells. In addition, the loss of Shh activity influences Purkinje cell development and the formation of folia in the cerebellum. A role for Shh in compartmentalization of the cerebellum is also suggested by the more severe rostral defects observed in the absence of Hedgehog signaling. Together, these findings provide additional evidence for Shh's key regulatory role in controlling growth of the cerebellar primordium.
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| 34. |
- Machold, Robert, et al.
(författare)
-
Sonic hedgehog is required for progenitor cell maintenance in telencephalic stem cell niches
- 2003
-
Ingår i: Neuron. ; 39:6, s. 937-950
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Tidskriftsartikel (refereegranskat)abstract
- To directly test the requirement for hedgehog signaling in the telencephalon from early neurogenesis, we examined conditional null alleles of both the Sonic hedgehog and Smoothened genes. While the removal of Shh signaling in these animals resulted in only minor patterning abnormalities, the number of neural progenitors in both the postnatal subventricular zone and hippocampus was dramatically reduced. In the subventricular zone, this was partially attributable to a marked increase in programmed cell death. Consistent with Hedgehog signaling being required for the maintenance of stem cell niches in the adult brain, progenitors from the subventricular zone of floxed Smo animals formed significantly fewer neurospheres. The loss of hedgehog signaling also resulted in abnormalities in the dentate gyrus and olfactory bulb. Furthermore, stimulation of the hedgehog pathway in the mature brain resulted in elevated proliferation in telencephalic progenitors. These results suggest that hedgehog signaling is required to maintain progenitor cells in the postnatal telencephalon.
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| 35. |
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| 36. |
- Newton, P. T., et al.
(författare)
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A radical switch in clonality reveals a stem cell niche in the epiphyseal growth plate
- 2019
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 567:7747
-
Tidskriftsartikel (refereegranskat)abstract
- Longitudinal bone growth in children is sustained by growth plates, narrow discs of cartilage that provide a continuous supply of chondrocytes for endochondral ossification(1). However, it remains unknown how this supply is maintained throughout childhood growth. Chondroprogenitors in the resting zone are thought to be gradually consumed as they supply cells for longitudinal growth(1,2), but this model has never been proved. Here, using clonal genetic tracing with multicolour reporters and functional perturbations, we demonstrate that longitudinal growth during the fetal and neonatal periods involves depletion of chondroprogenitors, whereas later in life, coinciding with the formation of the secondary ossification centre, chondroprogenitors acquire the capacity for self-renewal, resulting in the formation of large, stable monoclonal columns of chondrocytes. Simultaneously, chondroprogenitors begin to express stem cell markers and undergo symmetric cell division. Regulation of the pool of self-renewing progenitors involves the hedgehog and mammalian target of rapamycin complex 1 (mTORC1) signalling pathways. Our findings indicate that a stem cell niche develops postnatally in the epiphyseal growth plate, which provides a continuous supply of chondrocytes over a prolonged period.
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| 37. |
- Ohazama, A, et al.
(författare)
-
Lrp4 modulates extracellular integration of cell signaling pathways in development
- 2008
-
Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 3:12
-
Tidskriftsartikel (refereegranskat)abstract
- The extent to which cell signaling is integrated outside the cell is not currently appreciated. We show that a member of the low-density receptor-related protein family, Lrp4 modulates and integrates Bmp and canonical Wnt signalling during tooth morphogenesis by binding the secreted Bmp antagonist protein Wise. Mouse mutants of Lrp4 and Wise exhibit identical tooth phenotypes that include supernumerary incisors and molars, and fused molars. We propose that the Lrp4/Wise interaction acts as an extracellular integrator of epithelial-mesenchymal cell signaling. Wise, secreted from mesenchyme cells binds to BMP's and also to Lrp4 that is expressed on epithelial cells. This binding then results in the modulation of Wnt activity in the epithelial cells. Thus in this context Wise acts as an extracellular signaling molecule linking two signaling pathways. We further show that a downstream mediator of this integration is the Shh signaling pathway.
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| 38. |
- Rice, Ritva, et al.
(författare)
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Disruption of Fgf10/Fgfr2b-coordinated epithelial-mesenchymal interactions causes cleft palate.
- 2004
-
Ingår i: Journal of Clinical Investigation. - 0021-9738. ; 113:12, s. 1692-1700
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Tidskriftsartikel (refereegranskat)abstract
- Classical research has suggested that early palate formation develops via epithelial-mesenchymal interactions, and in this study we reveal which signals control this process. Using Fgf10-/-, FGF receptor 2b-/- (Fgfr2b-/-), and Sonic hedgehog (Shh) mutant mice, which all exhibit cleft palate, we show that Shh is a downstream target of Fgf10/Fgfr2b signaling. Our results demonstrate that mesenchymal Fgf10 regulates the epithelial expression of Shh, which in turn signals back to the mesenchyme. This was confirmed by demonstrating that cell proliferation is decreased not only in the palatal epithelium but also in the mesenchyme of Fgfr2b-/- mice. These results reveal a new role for Fgf signaling in mammalian palate development. We show that coordinated epithelial-mesenchymal interactions are essential during the initial stages of palate development and require an Fgf-Shh signaling network.
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| 39. |
- Wennbo, H, et al.
(författare)
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Activation of the prolactin receptor but not the growth hormone receptor is important for induction of mammary tumors in transgenic mice.
- 1997
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Ingår i: The Journal of clinical investigation. - 0021-9738 .- 1558-8238. ; 100:11, s. 2744-51
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Tidskriftsartikel (refereegranskat)abstract
- Transgenic mice overexpressing the human growth hormone gene develop mammary carcinomas. Since human growth hormone gene can activate both the growth hormone receptor (GHR) and the prolactin (PRL) receptor (PRLR), it is not clear which receptor system is responsible for the malignant transformation. To clarify the receptor specificity, we created transgenic mice with two different genes: (a) transgenic mice overexpressing the bovine growth hormone (bGH) gene having high levels of bGH only activating the GHR and also high serum levels of IGF-I; and (b) transgenic mice overexpressing the rat PRL (rPRL) gene that have elevated levels of PRL (one line 150 ng/ml and one line 13 ng/ml) only binding to the PRLR and with normal IGF-I levels. When analyzed histologically, all of the PRL transgenic female mice developed mammary carcinomas at 11-15 mo of age. Only normal mammary tissue was observed among the bGH transgenic animals and the controls. Cell lines established from a tumor produced rPRL and expressed PRLR. In organ culture experiments, an auto/paracrine effect of rPRL was demonstrated. In conclusion, activation of the PRLR is sufficient for induction of mammary carcinomas in mice, while activation of the GHR is not sufficient for mammary tumor formation.
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| 40. |
- Yeh, Brian K., et al.
(författare)
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Structural basis for activation of fibroblast growth factor signaling by sucrose octasulfate
- 2002
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Ingår i: Molecular and Cellular Biology. ; 22:20, s. 7184-7192
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Tidskriftsartikel (refereegranskat)abstract
- Sucrose octasulfate (SOS) is believed to stimulate fibroblast growth factor (FGF) signaling by binding and stabilizing FGFs. In this report, we show that SOS induces FGF-dependent dimerization of FGF receptors (FGFRs). The crystal structure of the dimeric FGF2-FGFR1-SOS complex at 2.6-A resolution reveals a symmetric assemblage of two 1:1:1 FGF2-FGFR1-SOS ternary complexes. Within each ternary complex SOS binds to FGF and FGFR and thereby increases FGF-FGFR affinity. SOS also interacts with the adjoining FGFR and thereby promotes protein-protein interactions that stabilize dimerization. This structural finding is supported by the inability of selectively desulfated SOS molecules to promote receptor dimerization. Thus, we propose that SOS potentiates FGF signaling by imitating the dual role of heparin in increasing FGF-FGFR affinity and promoting receptor dimerization. Hence, the dimeric FGF-FGFR-SOS structure substantiates the recently proposed "two-end" model, by which heparin induces FGF-FGFR dimerization. Moreover, the FGF-FGFR-SOS structure provides an attractive template for the development of easily synthesized SOS-related heparin agonists and antagonists that may hold therapeutic potential.
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