| 1. |
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| 2. |
- Boije, Henrik, et al.
(författare)
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Horizontal cell progenitors arrest in G2-phase and undergo terminal mitosis on the vitreal side of the chick retina
- 2009
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Ingår i: Developmental Biology. - : Elsevier. - 0012-1606 .- 1095-564X. ; 330:1, s. 105-113
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Tidskriftsartikel (refereegranskat)abstract
- We have addressed the question when horizontal cells in the chick retina are generated and undergo their terminal mitosis. Horizontal cell progenitors replicate their DNA early and migrate bi-directionally to the horizontal cell layer. It was hypothesized that the cells undergo mitosis directly after replication and migrate as post-mitotic transition cells before differentiating to horizontal cells. However, our results show that cells expressing markers for the axon-bearing and the axon-less subtypes of horizontal cells undergo terminal mitosis while residing on the vitreal side of the retina. By combining horizontal cell transcription factors Lim1, Isl1 and Prox1 labeling with phospho-histone H3, a marker for mitosis, we demonstrate that all or a clear majority of vitreal mitoses are undertaken by the horizontal cell committed progenitors. The pattern of cells that incorporated the thymidine analogue EdU implied that the progenitors replicated their genome while migrating towards the vitreal side. Upon arrival to the vitreal retina they become arrested for about two days prior to mitosis. Hence, cells expressing horizontal cell markers are arrested in G2-phase on the vitreal side of the retina. These results support the existence of committed progenitors that give rise to horizontal cells and that those cells become arrested in G2-phase before undergoing terminal mitosis on the vitreal side of the retina followed by migration to the horizontal cell layer. The results also indicate that the regulation of the transition from G2-phase to mitosis is important for the development of these committed progenitor cells.
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| 3. |
- Burke, R. D., et al.
(författare)
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A genomic view of the sea urchin nervous system
- 2006
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Ingår i: Developmental Biology. - : Elsevier BV. - 0012-1606 .- 1095-564X. ; 300:1, s. 434-460
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Tidskriftsartikel (refereegranskat)abstract
- The sequencing of the Strongylocentrotus purpuratus genome provides a unique opportunity to investigate the function and evolution of neural genes. The neurobiology of sea urchins is of particular interest because they have a close phylogenetic relationship with chordates, yet a distinctive pentaradiate body plan and unusual neural organization. Orthologues of transcription factors that regulate neurogenesis in other animals have been identified and several are expressed in neurogenic domains before gastrulation indicating that they may operate near the top of a conserved neural gene regulatory network. A family of genes encoding voltage-gated ion channels is present but, surprisingly, genes encoding gap junction proteins (connexins and pannexins) appear to be absent. Genes required for synapse formation and function have been identified and genes for synthesis and transport of neurotransmitters are present. There is a large family of G-protein-coupled receptors, including 874 rhodopsin-type receptors, 28 metabotropic glutamate-like receptors and a remarkably expanded group of 161 secretin receptor-like proteins. Absence of cannabinoid, lysophospholipid and melanocortin receptors indicates that this group may be unique to chordates. There are at least 37 putative G-protein-coupled peptide receptors and precursors for several neuropeptides and peptide hormones have been identified, including SALMFamides, NGFFFamide, a vasotocin-like peptide, glycoprotein hormones and insulin/insulin-like growth factors. Identification of a neurotrophin-like gene and Trk receptor in sea urchin indicates that this neural signaling system is not unique to chordates. Several hundred chemoreceptor genes have been predicted using several approaches, a number similar to that for other animals. Intriguingly, genes encoding homologues of rhodopsin, Pax6 and several other key mammalian retinal transcription factors are expressed in tube feet, suggesting tube feet function as photosensory organs. Analysis of the sea urchin genome presents a unique perspective on the evolutionary history of deuterostome nervous systems and reveals new approaches to investigate the development and neurobiology of sea urchins. (c) 2006 Elsevier Inc. All rights reserved.
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| 4. |
- Dudas, Marek, et al.
(författare)
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Epithelial and ectomesenchymal role of the type I TGF-beta receptor ALK5 during facial morphogenesis and palatal fusion
- 2006
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Ingår i: Developmental Biology. - : Elsevier BV. - 1095-564X .- 0012-1606. ; 296:2, s. 298-314
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Tidskriftsartikel (refereegranskat)abstract
- Transforming growth factor beta (TGF-beta) proteins play important roles in morphogenesis of many cramofacial tissues; however, detailed biological mechanisms of TGF-beta action, particularly in vivo, are still poorly understood. Here, we deleted the TGF-beta type I receptor gene Alk5 specifically in the embryonic ectodermal and neural crest cell lineages. Failure in signaling via this receptor, either in the epithelium or in the mesenchyme, caused severe craniofacial defects including cleft palate. Moreover, the facial phenotypes of neural crest-specific Alk5 mutants included devastating facial cleft and appeared significantly more severe than the defects seen in corresponding mutants lacking the TGF-beta type II receptor (TGF beta II), a prototypical binding partner of ALK5. Our data indicate that ALK5 plays unique, non-redundant cell-autonomous roles during facial development. Remarkable divergence between Tgfbr2 and A1k5 phenotypes, together with our biochemical in vitro data, imply that (1) ALK5 mediates signaling of a diverse set of ligands not limited to the three isoforms of TGF-beta, and (2) ALK5 acts also in conjunction with type II receptors other than TGF beta RII. (c) 2006 Elsevier Inc. All rights reserved.
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| 5. |
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| 6. |
- Hao, Limin, et al.
(författare)
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The hedgehog-related gene wrt-5 is essential for hypodermal development in Caenorhabditis elegans
- 2006
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Ingår i: Developmental Biology. - : Elsevier BV. - 0012-1606 .- 1095-564X. ; 290:2, s. 323-336
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Tidskriftsartikel (refereegranskat)abstract
- The Caenorhabditis elegans genome encodes a series of hedgehog-related genes, which are thought to have evolved and diverged from an ancestral Hh gene. They are classified into several families based on their N-terminal domains. Here, we analyze the expression and function of a member of the warthog gene family, wrt-5, that lacks the Hint/Hog domain. wrt-5 is expressed in seam cells, the pharynx, pharyngeal-intestinal valve cells, neurons, neuronal support cells, the excretory cell, and the reproductive system. WRT-5 protein is secreted into the extracelluar space during embryogenesis. Furthermore, during larval development, WRT-5 protein is secreted into the pharyngeal lumen and the pharyngeal expression changes in a cyclical manner in phase with the molting cycle. Deletion mutations in wrt-5 cause embryonic lethality, which are temperature sensitive and more severe at 15 degrees C than at 25 degrees C. Animals that hatch exhibit variable abnormal morphology, for example, bagging worms, blistering, molting defects, or Roller phenotypes. We examined hypodermal cell junctions using the AJM-1: :GFP marker in the wrt-5 mutant background and observed cell boundary abnormalities in the arrested embryos. AJM-1: :GFP protein is also misplaced in pharyngeal muscle cells in the absence of WRT-5. In conclusion, we show that wrt-5 is an essential gene that - despite its lack of a Hint domain - has multiple functions in C. elegans and is implicated in cell shape integrity.
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| 7. |
- Hench, Jürgen, et al.
(författare)
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Spatio-temporal reference model of Caenorhabditis elegans embryogenesis with cell contact maps
- 2009
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Ingår i: Developmental Biology. - : Elsevier BV. - 0012-1606 .- 1095-564X. ; 333:1, s. 1-13
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Tidskriftsartikel (refereegranskat)abstract
- The nematode Caenorhabditis elegans has been used as a model for developmental biology for decades. Still, the few publicly available spatio-temporal (4D) data sets have conflicting information regarding variability of cell positions and are not well-suited for a standard 4D embryonic model, due to compression. We have recorded six uncompressed embryos, and determined their lineage and 4D coordinates, including nuclear radii, until the end of gastrulation. We find a remarkable degree of stability in the cell positions, as well as little rotational movement, which allowed us to combine the data into a single reference model of C. elegans embryogenesis. Using Voronoi decomposition we generated the list of all predicted cell contacts during early embryogenesis and calculated these contacts up to the similar to 150 cell stage, and find that about 1500 contacts last 2.5 min or longer. The cell contact map allows for comparison of multiple 4D data sets, e. g., mutants or related species, at the cellular level. A comparison of our uncompressed 4D model with a compressed embryo shows that up to 40% of the cell contacts can be different. To visualize the 4D model interactively we developed a software utility. Our model provides an anatomical resource and can serve as foundation to display 4D expression data, a basis for developmental systems biology.
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| 8. |
- Hufnagel, Lars, et al.
(författare)
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On the role of glypicans in the process of morphogen gradient formation
- 2006
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Ingår i: Developmental Biology. - : Elsevier BV. - 0012-1606 .- 1095-564X. ; 300:2, s. 512-522
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Tidskriftsartikel (refereegranskat)abstract
- Glypicans are cell surface molecules that influence signaling and gradient formation of secreted morphogens and growth factors. Several distinct functions have been ascribed to glypicans including acting as co-receptors for signaling proteins. Recent data show that glypicans are also necessary for morphogen propagation in the tissue. In the present study, a model describing the interaction of a morphogen with glypicans is formulated, analyzed and compared with measurements of the effect of glypican Dally-like (Dlp) overexpression on Wingless (Wg) morphogen signaling in Drosophila melanogaster wing imaginal discs. The model explains the opposing effect that Dlp overexpression has on Wg signaling in the distal and proximal regions of the disc and makes a number of quantitative predictions for further experiments. In particular, our model suggests that Dlp acts by allowing Wg to diffuse on cell surface while protecting it from loss and degradation, and that Dlp rather than acting as Wg co-receptor competes with receptors for morphogen binding.
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| 9. |
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| 10. |
- Layden, MJ, et al.
(författare)
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Zfh1, a somatic motor neuron transcription factor, regulates axon exit from the CNS
- 2006
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Ingår i: Developmental Biology. - : Elsevier BV. - 0012-1606 .- 1095-564X. ; 291:2, s. 253-263
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Tidskriftsartikel (refereegranskat)abstract
- Motor neurons are defined by their axon projections, which exit the CNS to innervate somatic or visceral musculature, yet remarkably little is known about how motor axons are programmed to exit the CNS. Here, we describe the role of the Drosophila Zfh1 transcription factor in promoting axon exit from the CNS. Zfh1 is detected in all embryonic somatic motor neurons, glia associated with the CNS surface and motor axons, and one identified interneuron. In zfh1 mutants, ventral projecting motor axons often stall at the edge of the CNS, failing to enter the muscle field, despite having normal motor neuron identity. Conversely, ectopic Zfh1 induces a subset of interneurons-all normally expressing two or more "ventral motor neuron transcription factors" (e.g. Islet, Hb9, Nkx6, Lim3)-to project laterally and exit the CNS. We conclude that Zfh1 is required for ventral motor axon exit from the CNS. © 2005 Elsevier Inc. All rights reserved.
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| 11. |
- Lilja, Tobias, et al.
(författare)
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The acetyltransferase activity of Drosophila CBP is dispensable for regulation of the Dpp pathway in the early embryo
- 2007
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Ingår i: Developmental Biology. - : Elsevier BV. - 0012-1606 .- 1095-564X. ; 305:2, s. 650-658
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Tidskriftsartikel (refereegranskat)abstract
- The CBP protein is a transcriptional co-activator and histone acetyltransferase. Reduced expression of Drosophila CBP (dCBP) in the early embryo specifically impairs signaling by the TGF-β molecules Dpp and Screw (Scw). This occurs by a failure to activate transcription of the tolloid (tld) gene, which codes for a protease that generates active Dpp and Scw ligands. We show that dCBP directly regulates this gene by binding to the tld enhancer, and that tld expression can be partially rescued with a dCBP transgene. At a slightly later stage of development, Dpp/Scw signaling recovers in mutant embryos, but is unable to turn on expression of the Dpp/Scw-target gene rhomboid (rho). Interestingly, an acetyltransferase (AT)-defective dCBP transgene rescued tld and rho gene expression to an extent comparable to the wild-type transgene, whereas a transgene containing a 130 amino acid deletion rescued tld but not late rho expression. A tracheal phenotype caused by the reduced dCBP levels was also rescued more efficiently with the wild-type dCBP transgene than with this mutant transgene. Our results indicate that separate parts of the dCBP protein are required on different promoters, and that the AT activity of dCBP is dispensable for certain aspects of Dpp signaling. We discuss the similarity of these results to the role of p300/CBP in TGF-β signaling in the mouse.
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| 12. |
- Liu, Kui, et al.
(författare)
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Successful ovulation in plasminogen-deficient mice treated with the broad-spectrum matrix metalloproteinase inhibitor galardin.
- 2006
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Ingår i: Developmental Biology. - New York : Academic P.. - 0012-1606 .- 1095-564X. ; 295:2, s. 615-622
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Tidskriftsartikel (refereegranskat)abstract
- Many studies have suggested the hypothesis that the plasminogen activator (PA) system and the matrix metalloproteinase (MMP) system, either separately or in combination, may provide the proteolytic activity that is required for rupture of the follicular wall at the time of ovulation. Our recent studies on ovulation in plasminogen (plg)-deficient mice have, however, shown that plasmin is not required for normal ovulation, leading us to the hypothesis that MMPs may be a more important source of proteolysis for this process. To investigate the role of MMPs and also the possibility of a functional overlap or synergy between the MMP and PA systems during ovulation, we have studied ovulation efficiency in wild-type and plg-deficient mice treated with the broad-spectrum MMP inhibitor galardin. We found that in both wild-type mice and heterozygous plg-deficient (plg(+/-)) mice that had been treated with galardin prior to ovulation, there was a mild (18-20%) reduction in ovulation efficiency. Surprisingly, galardin treatment of plg-deficient (plg(-/-)) mice only caused an additional 14% reduction in ovulation efficiency as compared to vehicle-treated plg(-/-) mice. Our data therefore suggest that although MMPs may play a role in degradation of the follicular wall, they may not be obligatory for ovulation. In contrast to previous studies on tissue remodeling during wound heating and placental development, we have demonstrated that there is no obvious functional overlap or synergy between the PA and MMP systems, which has previously been thought to be essential for the ovulatory process.
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| 13. |
- Lopes, S M C D, et al.
(författare)
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Altered primordial germ cell migration in the absence of transforming growth factor beta signaling via ALK5
- 2005
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Ingår i: Developmental Biology. - : Elsevier BV. - 1095-564X .- 0012-1606. ; 284:1, s. 194-203
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Tidskriftsartikel (refereegranskat)abstract
- Transforming growth factor beta (TGF beta) inhibits proliferation and promotes the migration of primordial germ cells (PGCs) towards explants of gonadal ridges in vitro. However, its effects in vivo are still unclear. Here, we analyzed the behavior of PGCs in embryos lacking TGF beta signaling via the type I receptor ALK5. TGF beta in vivo was neither a chemoattractant for PGCs, nor did it affect their proliferation during migration towards the gonadal ridges up to embryonic day (E) 10. Unexpectedly, the absence of TGF beta signaling in fact resulted in significant facilitation of PGC migration out of the hindgut, due to the reduced deposition of collagen type I surrounding the gut of Alk5-deficient mutant embryos. Migratory PGCs adhere strongly to collagen; therefore, reduced collagen type I along the gut may result in reduced adhesion, facilitating migration into the dorsal mesenterium and gonadal ridges. Our results provide new evidence for the role of TGF beta signaling in migration of PGCs in vivo distinct from that described previously.
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| 14. |
- Mörck, Catarina, 1972, et al.
(författare)
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Misexpression of acetylcholinesterases in the C. elegans pha-2 mutant accompanies ultrastructural defects in pharyngeal muscle cells
- 2006
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Ingår i: Developmental Biology. - : Elsevier BV. - 0012-1606 .- 1095-564X. ; 297:2, s. 446-460
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Tidskriftsartikel (refereegranskat)abstract
- pha-2 is the Caenorhabditis elegans homolog of the vertebrate homeobox gene Hex. Embryonic expression of pha-2 is mostly pharyngeal and the only described mutant allele of pha-2 results in a severe pharyngeal defect in which certain muscle cells (pm5 cells) and neurons are grossly deformed. Here, we performed a detailed characterization of the pha-2 phenotype using cell-type-specific reporters, physical manipulation of the nuclei in pharyngeal muscle cells using optical "tweezers", electron microscopy, staining of the actin cytoskeleton as well as phenotypic rescue and ectopic expression experiments. The main findings of the present study are (i) the pha-2 (ad472) mutation specifically impairs the pharyngeal expression of pha-2; (ii) in the pha-2 mutant, the cytoskeleton of the pm5 cells is measurably weaker than in normal cells and is severely disrupted by large tubular structures and organelles; (iii) the pm5 cells of the pha-2 mutant fail to express the acetylcholinesterase genes ace-1 and ace-2; (iv) ectopic expression of pha-2 can induce ectopic expression of ace-1 and ace-2; and (v) the anc-1 mutant with mislocalized pm5 cell nuclei occasionally shows an isthmus phenotype similar to that of pha-2 worms.
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| 15. |
- Oblander, S A, et al.
(författare)
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Distinctive functions of membrane type 1 matrix-metalloprotease (MT1-MMP or MMP-14) in lung and submandibular gland development are independent of its role in pro-MMP-2 activation
- 2005
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Ingår i: Developmental Biology. - : Elsevier BV. - 1095-564X .- 0012-1606. ; 277:1, s. 255-269
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Tidskriftsartikel (refereegranskat)abstract
- Membrane type 1-matrix metalloprotease (MT1-MMP or MMP-14) is a major activator of pro-MMP-2 and is essential for skeletal development. We show here that it is required for branching morphogenesis of the submandibular gland but not the lung. Instead, in the lung, it is essential for postnatal development of alveolar septae. Lung development in Mmp14-/- mice is arrested at the prealveolar stage with compensatory hyperinflation of immature saccules. Mmp2-/- mice lacked comparable defects in the lung and submandibular gland, suggesting that NIT1-MMP acts via mechanisms independent of pro-MMP-2 activation. Since the developmental defects in the lung are first manifest around the time of initial vascularization (E16.5), we investigated the behavior of pulmonary endothelial cells from Mmp14+/+ and Mmp14-/- mice. Endothelial cells from lungs of 1-week-old Mmp14-/- mice show reduced migration and formation of three-dimensional structures on Matrigel. Since pulmonary septal development requires capillary growth, the underlying mechanism of pulmonary hypoplasia in Mmp14-/- mice may be defective angiogenesis, supporting a model in which angiogenesis is a critical rate-limiting step for acquisition of pulmonary parenchymal mass.
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| 16. |
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| 17. |
- Rauthan, Manish, et al.
(författare)
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The C-elegans M3 neuron guides the growth cone of its sister cell M2 via the Kruppel-like zinc finger protein MNM-2
- 2007
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Ingår i: Developmental Biology. - : Elsevier BV. - 1095-564X .- 0012-1606. ; 311:1, s. 185-199
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Tidskriftsartikel (refereegranskat)abstract
- The invariant cell-cell interactions occurring during C. elegans development offer unique opportunities to discover how growing axons may receive guidance cues from neighboring cells. The mnm-2 mutant was isolated because of its defects in the axon trajectory of the bilateral M2 pharyngeal neurons in C. elegans. We found that mnm-2 enhances the effects of many growth cone guidance mutations on these axons, suggesting that it performs a novel function during axon guidance. We cloned mnm-2 and found that it encodes a protein with three C2H2 zinc finger domains related to the Kruppel-like Factor protein family. mnm-2 is expressed only transiently in the M2 neuron, but exhibits a sustained expression in its sister cell, the M3 neuron. Strikingly, the expression of mnm-2 is not sustained in the M3 cell of the mnm-2 mutant, indicating that this gene positively regulates itself in that cell. Electropharyngeograms also indicate that the M3 cell is functionally impaired in the mnm-2 mutant. We used an M3-specific promoter to show that the M2 axon defect can be rescued by expression of mnm-2 in its sister cell M3. The same promoter was used to express the pro-apoptotic gene egl-1 to kill the M3 cell, which resulted in an M2 axon guidance defect similar to that found in the mnm-2 mutant. Our results suggest an M2 axon guidance model in which the M3 cell provides an important signal to the growth cone of its sister M2 and that this signal and the proper differentiation of M3 both depend on mnm-2 expression. This mechanism of axon guidance regulation allows fine-tuning of trajectories between sister cells. (C) 2007 Elsevier Inc. All rights reserved.
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| 18. |
- Scherfer, Christoph, et al.
(författare)
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The Toll immune-regulated Drosophila protein Fondue is involved in hemolymph clotting and puparium formation
- 2006
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Ingår i: Developmental Biology. - : Elsevier BV. - 0012-1606 .- 1095-564X. ; 295, s. 156-163
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Tidskriftsartikel (refereegranskat)abstract
- Clotting is critical in limiting hemolymph loss and initiating wound healing in insects as in vertebrates. It is also an important immune defense, quickly forming a secondary barrier to infection, immobilizing bacteria and thereby promoting their killing. However, hemolymph clotting is one of the least understood immune responses in insects. Here, we characterize fondue (fon; CG15825), an immune-responsive gene of Drosophila melanogaster that encodes an abundant hemolymph protein containing multiple repeat blocks. After knockdown of fon by RNAi, bead aggregation activity of larval hemolymph is strongly reduced, and wound closure is affected. Jon is thus the second Drosophila gene after hemolectin (hml), for which a knockdown causes a clotting phenotype. In contrast to hml-RNAi larvae, clot fibers are still observed in samples from fon-RNAi larvae. However, clot fibers from fon-RNAi larvae are more ductile and longer than in wt hemolymph samples, indicating that Fondue might be involved in cross-linking of fiber proteins. In addition, fon-RNAi larvae exhibit melanotic tumors and constitutive expression of the antifungal peptide gene Drosomycin (Drs), while fon-RNAi pupae display an aberrant pupal phenotype. Altogether, our studies indicate that Fondue is a major hemolymph protein required for efficient clotting in Drosophila.
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| 19. |
- Schnabel, R., et al.
(författare)
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Global cell sorting in the C. elegans embryo defines a new mechanism for pattern formation
- 2006
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Ingår i: Developmental Biology. - : Academic Press Inc.. - 0012-1606 .- 1095-564X. ; 294:2, s. 418-431
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Tidskriftsartikel (refereegranskat)abstract
- 4D microscopic observations of Caenorhabditis elegans development show that the nematode uses an unprecedented strategy for development. The embryo achieves pattern formation by sorting cells, through far-ranging movements, into coherent regions before morphogenesis is initiated. This sorting of cells is coupled to their particular fate. If cell identity is altered by experiment, cells are rerouted to positions appropriate to their new fates even across the whole embryo. This cell behavior defines a new mechanism of pattern formation, a mechanism that is also found in other animals. We call this new mechanism "cell focusing". When the fate of cells is changed, they move to new positions which also affect the shape of the body. Thus, this process is also important for morphogenesis. © 2006 Elsevier Inc. All rights reserved.
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| 20. |
- Smith, Joel, et al.
(författare)
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A spatially dynamic cohort of regulatory genes in the endomesodermal gene network of the sea urchin embryo
- 2008
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Ingår i: Developmental Biology. - : Elsevier BV. - 0012-1606 .- 1095-564X. ; 313:2, s. 863-875
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Tidskriftsartikel (refereegranskat)abstract
- A gene regulatory network subcircuit comprising the otx, wnt8, and blimp1 genes accounts for a moving torus of gene expression that sweeps concentrically across the vegetal domain of the sea urchin embryo. Here we confirm by mutation the inputs into the blimp1 cis-regulatory module predicted by network analysis. Its essential design feature is that it includes both activation and autorepression sites. The wnt8 gene is functionally linked into the subcircuit in that cells receiving this ligand generate a beta-catenin/Tcf input required for blimp1 expression, while the wnt8 gene in turn requires a Blimp1 input. Their torus-like spatial expression patterns and gene regulatory analysis indicate that the genes even-skipped and hox11/13b are also entrained by this subcircuit. We verify the cis-regulatory inputs of even-skipped predicted by network analysis. These include activation by beta-catenin/Tcf and Blimp1, repression within the torus by Hox11/13b, and repression outside the torus by Tcf in the absence of Wnt8 signal input. Thus even-skipped and hox11/13b, along with blimp1 and wnt8, are members of a cohort of torus genes with similar regulatory inputs and similar, though slightly out-of-phase, expression patterns, which reflect differences in eis-regulatory design.
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| 21. |
- Sridurongrit, Somyoth, et al.
(författare)
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Signaling via the Tgf-beta type I receptor Alk5 in heart development
- 2008
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Ingår i: Developmental Biology. - : Elsevier BV. - 1095-564X .- 0012-1606. ; 322:1, s. 208-218
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Tidskriftsartikel (refereegranskat)abstract
- Trophic factors secreted both from the endocardium and epicardium regulate appropriate growth of the myocardium during cardiac development. Epicardially-derived cells play also a key role in development of the coronary vasculature. This process involves transformation of epithelia] (epicardial) cells to mesenchymal cells (EMT). Similarly, a subset of endocardial cells undergoes EMT to form the mesenchyme of endocardial cushions, which function as primordia for developing valves and septa. While it has been suggested that transforming growth factor-beta s (Tgf-beta) play an important role in induction of EMT in the avian epi- and endocardium, the function of Tgf-beta s in corresponding mammalian tissues is still poorly understood. In this study, we have ablated the Tgf-beta type I receptor Alk5 in endo-, myo- and epicardial lineages using the Tie2-Cre, Nkx2.5-Cre, and Gata5-Cre driver lines, respectively. We show that while Alk5-mediated signaling does not play a major role in the myocardium during mouse cardiac development, it is critically important in the endocardium for induction of EMT both in vitro and fit vivo. Moreover, loss of epicardial Alk5-mediated signaling leads to disruption of cell-cell interactions between the epicardium and myocardium resulting in a thinned myocardium. Furthermore, epicardial cells lacking Alk5 fail to undergo Tgf-beta-inducecl EMT in vitro, Late term mutant embryos lacking epicardial Alk5 display defective formation of a smooth Muscle cell layer around coronary arteries, and aberrant formation of capillary vessels in the myocardium suggesting that AIk5 is controlling vascular homeostasis during cardiogenesis. To conclude, Tgf-beta signaling via AIk5 is not required in myocardial cells during mammalian cardiac development, but plays an irreplaceable cell-autonomous role regulating cellular communication, differentiation and proliferation in endocardial and epicardial cells. (c) 2008 Elsevier Inc, All rights reserved.
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| 22. |
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| 23. |
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| 24. |
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| 25. |
- Blixt, Åsa, 1960, et al.
(författare)
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Foxe3 is required for morphogenesis and differentiation of the anterior segment of the eye and is sensitive to Pax6 gene dosage.
- 2007
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Ingår i: Developmental biology. - : Elsevier BV. - 0012-1606. ; 302:1, s. 218-29
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Tidskriftsartikel (refereegranskat)abstract
- The dysgenetic lens (dyl) mouse mutant has mutations in Foxe3, which inactivate DNA binding by the encoded forkhead transcription factor. Here we confirm, by targeted inactivation, that Foxe3 mutations are responsible for the dyl phenotype, which include loss of lens epithelium; a small, cataractic lens; and failure of the lens to detach from the surface ectoderm. In contrast to a recent report of targeted Foxe3, we found no phenotypic difference between dyl and Foxe3(-/-) mutants when congenic strains were compared, and thus nothing that argues against Foxe3(dyl) being a null allele. In addition to the lens, most tissues of the anterior segment-iris, cornea, ciliary body and trabecular meshwork-are malformed or show differentiation defects. Many of these abnormalities, such as irido-corneal and irido-lenticular adherences, are present in a less severe form in mice heterozygous for the Foxe3 mutation, in spite of these having an intact lens epithelium. Early Foxe3 expression is highly sensitive to a halved Pax6 gene dosage and there is a striking phenotypic similarity between Pax6 and Foxe3 mutants. We therefore propose that many of the ocular malformations associated with Pax6 haploinsufficiency are consequences of a reduced expression of Foxe3.
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