| 1. |
- Janssen, Ralf, 1975-, et al.
(författare)
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Expression of netrin and its receptors uncoordinated-5 and frazzled in arthropods and onychophorans suggests conserved and diverged functions in neuronal pathfinding and synaptogenesis
- 2023
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Ingår i: Developmental Dynamics. - : John Wiley & Sons. - 1058-8388 .- 1097-0177. ; 252:1, s. 172-185
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Tidskriftsartikel (refereegranskat)abstract
- Background Development of the nervous system and the correct connection of nerve cells require coordinated axonal pathfinding through an extracellular matrix. Outgrowing axons exhibit directional growth toward or away from external guidance cues such as Netrin. Guidance cues can be detected by growth cones that are located at the end of growing axons through membrane-bound receptors such as Uncoordianted-5 and Frazzled. Binding of Netrin causes reformation of the cytoskeleton and growth of the axon toward (or away from) the source of Netrin production. Results Here, we investigate the embryonic mRNA expression patterns of netrin genes and their potential receptors, uncoordinated-5 and frazzled in arthropod species that cover all main branches of Arthropoda, that is, Pancrustacea, Myriapoda, and Chelicerata. We also studied the expression patterns in a closely related outgroup species, the onychophoran Euperipatoides kanangrensis, and provide data on expression profiles of these genes in larval tissues of the fly Drosophila melanogaster including the brain and the imaginal disks. Conclusion Our data reveal conserved and diverged aspects of neuronal guidance in Drosophila with respect to the other investigated species and suggest a conserved function in nervous system patterning of the developing appendages.
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| 2. |
- Jones, Iwan, et al.
(författare)
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Reduced mTORC1-signaling in retinal ganglion cells leads to vascular retinopathy
- 2022
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Ingår i: Developmental Dynamics. - : John Wiley & Sons. - 1058-8388 .- 1097-0177. ; 251:2, s. 321-335
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Tidskriftsartikel (refereegranskat)abstract
- Background: The coordinated wiring of neurons, glia and endothelial cells into neurovascular units is critical for central nervous system development. This is best exemplified in the mammalian retina where interneurons, astrocytes and retinal ganglion cells sculpt their vascular environment to meet the metabolic demands of visual function. Identifying the molecular networks that underlie neurovascular unit formation is an important step towards a deeper understanding of nervous system development and function.Results: Here, we report that cell-to-cell mTORC1-signaling is essential for neurovascular unit formation during mouse retinal development. Using a conditional knockout approach we demonstrate that reduced mTORC1 activity in asymmetrically positioned retinal ganglion cells induces a delay in postnatal vascular network formation in addition to the production of rudimentary and tortuous vessel networks in adult animals. The severity of this vascular phenotype is directly correlated to the degree of mTORC1 down regulation within the neighboring retinal ganglion cell population.Conclusions: This study establishes a cell nonautonomous role for mTORC1-signaling during retinal development. These findings contribute to our current understanding of neurovascular unit formation and demonstrate how ganglion cells actively sculpt their local environment to ensure that the retina is perfused with an appropriate supply of oxygen and nutrients.
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| 3. |
- Leigh, Nicholas D, et al.
(författare)
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Rebuilding limbs, one cell at a time
- 2022
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Ingår i: Developmental Dynamics. - : Wiley. - 1097-0177 .- 1058-8388. ; 251:9, s. 1389-1403
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Tidskriftsartikel (refereegranskat)abstract
- The regeneration of salamander limbs has been a special fascination among scientists and keen observers for centuries. Perhaps due to how closely the salamander's limb anatomically mirrors our own, a grand aspiration of regenerative medicine has been to provoke such a process following injury or loss of human limbs. Research in the last century has focused on understanding the blastema, a proliferative cell mass that develops after limb amputation (see Box 1 “A primer on limb regeneration” and reviews for discussion of foundational knowledge1-3). The first micrographs of limb blastemas (examples in Thornton4 and Hay5) brought limb regeneration to a cellular level and ushered in a new era of questions centered around the origin, potency, and processes of regenerative cells that has occupied the field ever since. Within this commentary, we will outline some of these persistent questions underlying limb regeneration, and how new technologies and approaches are paving the way toward a cellular understanding of complex tissue regeneration.
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| 4. |
- Niklasson, Camilla U., et al.
(författare)
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Hypoxia inducible factor-2 alpha importance for migration, proliferation, and self-renewal of trunk neural crest cells
- 2021
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Ingår i: Developmental Dynamics. - : Wiley. - 1058-8388 .- 1097-0177. ; 250:2, s. 191-236
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Tidskriftsartikel (refereegranskat)abstract
- Background: The neural crest is a transient embryonic stem cell population. Hypoxia inducible factor (HIF)-2 α is associated with neural crest stem cell appearance and aggressiveness in tumors. However, little is known about its role in normal neural crest development.Results: Here, we show that HIF-2 α is expressed in trunk neural crest cells of human, murine, and avian embryos. Knockdown as well as overexpression of HIF-2 α in vivo causes developmental delays, induces proliferation, and self-renewal capacity of neural crest cells while decreasing the proportion of neural crest cells that migrate ventrally to sympathoadrenal sites. Reflecting the in vivo phenotype, transcriptome changes after loss of HIF-2 α reveal enrichment of genes associated with cancer, invasion, epithelial-to-mesenchymal transition, and growth arrest.Conclusions: Taken together, these results suggest that expression levels of HIF-2 α must be strictly controlled during normal trunk neural crest development and that dysregulated levels affects several important features connected to stemness, migration, and development.
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| 5. |
- Nord, Christoffer, et al.
(författare)
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Reduced mTORC1-signaling in progenitor cells leads to retinal lamination deficits
- 2024
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Ingår i: Developmental Dynamics. - : John Wiley & Sons. - 1058-8388 .- 1097-0177.
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Tidskriftsartikel (refereegranskat)abstract
- Background: Neuronal lamination is a hallmark of the mammalian central nervous system (CNS) and underlies connectivity and function. Initial formation of this tissue architecture involves the integration of various signaling pathways that regulate the differentiation and migration of neural progenitor cells.Results: Here, we demonstrate that mTORC1 mediates critical roles during neuronal lamination using the mouse retina as a model system. Down-regulation of mTORC1-signaling in retinal progenitor cells by conditional deletion of Rptor led to decreases in proliferation and increased apoptosis during embryogenesis. These developmental deficits preceded aberrant lamination in adult animals which was best exemplified by the fusion of the outer and inner nuclear layer and the absence of an outer plexiform layer. Moreover, ganglion cell axons originating from each Rptor-ablated retina appeared to segregate to an equal degree at the optic chiasm with both contralateral and ipsilateral projections displaying overlapping termination topographies within several retinorecipient nuclei. In combination, these visual pathway defects led to visually mediated behavioral deficits.Conclusions: This study establishes a critical role for mTORC1-signaling during retinal lamination and demonstrates that this pathway regulates diverse developmental mechanisms involved in driving the stratified arrangement of neurons during CNS development.
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| 6. |
- Nord, Hanna, et al.
(författare)
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Genetic compensation between Pax3 and Pax7 in zebrafish appendicular muscle formation
- 2022
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Ingår i: Developmental Dynamics. - : John Wiley & Sons. - 1058-8388 .- 1097-0177. ; 251:9, s. 1423-1438
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Tidskriftsartikel (refereegranskat)abstract
- Background: Migrating muscle progenitors delaminate from the somite and subsequently form muscle tissue in distant anatomical regions such as the paired appendages, or limbs. In amniotes, this process requires a signaling cascade including the transcription factor paired box 3 (Pax3).Results: In this study, we found that, unlike in mammals, pax3a/3b double mutant zebrafish develop near to normal appendicular muscle. By analyzing numerous mutant combinations of pax3a, pax3b and pax7a, and pax7b, we determined that there is a feedback system and a compensatory mechanism between Pax3 and Pax7 in this developmental process, even though Pax7 alone is not required for appendicular myogenesis. pax3a/3b/7a/7b quadruple mutant developed muscle-less pectoral fins.Conclusions: We found that Pax3 and Pax7 are redundantly required during appendicular myogenesis in zebrafish, where Pax7 is able to activate the same developmental programs as Pax3 in the premigratory progenitor cells.
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| 7. |
- Rondon-Galeano, Maria, et al.
(författare)
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MAFBmodulates the maturation of lymphatic vascular networks in mice
- 2020
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Ingår i: Developmental Dynamics. - : WILEY. - 1058-8388 .- 1097-0177. ; 249:10, s. 1201-1216
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Tidskriftsartikel (refereegranskat)abstract
- Background Lymphatic vessels play key roles in tissue fluid homeostasis, immune cell trafficking and in diverse disease settings. Lymphangiogenesis requires lymphatic endothelial cell (LEC) differentiation, proliferation, migration, and co-ordinated network formation, yet the transcriptional regulators underpinning these processes remain to be fully understood. The transcription factor MAFB was recently identified as essential for lymphangiogenesis in zebrafish and in cultured human LECs. MAFB is activated in response to VEGFC-VEGFR3 signaling and acts as a downstream effector. However, it remains unclear if the role of MAFB in lymphatic development is conserved in the mammalian embryo. Results We generated aMafbloss-of-function mouse using CRISPR/Cas9 gene editing.Mafbmutant mice presented with perinatal lethality associated with cyanosis. We identify a role for MAFB in modifying lymphatic network morphogenesis in the developing dermis, as well as developing and postnatal diaphragm. Furthermore, mutant vessels displayed excessive smooth muscle cell coverage, suggestive of a defect in the maturation of lymphatic networks. Conclusions This work confirms a conserved role for MAFB in murine lymphatics that is subtle and modulatory and may suggest redundancy in MAF family transcription factors during lymphangiogenesis.
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| 8. |
- Waldmann, Laura, et al.
(författare)
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The Role of Gdf5 in the Development of the Zebrafish Fin Endoskeleton
- 2022
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Ingår i: Developmental Dynamics. - : John Wiley & Sons. - 1058-8388 .- 1097-0177. ; 251:9, s. 1535-1549
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Tidskriftsartikel (refereegranskat)abstract
- The development of the vertebrate skeleton requires a complex interaction of multiple factors to facilitate correct shaping and positioning of bones and joints. Growth and differentiation factor 5 (Gdf5), a member of the transforming growth factor-beta family (TGF-beta) is involved in patterning appendicular skeletal elements including joints. Expression of gdf5 in zebrafish has been detected within the first pharyngeal arch jaw joint, fin mesenchyme condensations and segmentation zones in median fins, however little is known about the functional role of Gdf5 outside of Amniota. We generated CRISPR/Cas9 knockout of gdf5 in zebrafish and analysed the resulting phenotype at different developmental stages. Homozygous gdf5 mutant zebrafish display truncated median fin endoskeletal elements and loss of posterior radials in the pectoral fins. These findings are consistent with phenotypes observed in human and mouse appendicular skeleton in response to Gdf5 knockout, suggesting a broadly conserved role for Gdf5 in Osteichthyes.
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| 9. |
- Wheaton, Benjamin Joel, et al.
(författare)
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Alternative LIM homeodomain splice variants are dynamically regulated at key developmental steps in vertebrates
- 2022
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Ingår i: Developmental Dynamics. - : American Association for Anatomy. - 1058-8388 .- 1097-0177. ; 251:7, s. 1223-1243
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Tidskriftsartikel (refereegranskat)abstract
- Background: Alternative splicing provides a broad strategy to amplify the genome. Yet how alternative splicing influences neurodevelopment or indeed which variants are translated at developmental choice points remains poorly explored. Here we focused on a gene important for neurodevelopment, the Lim homeodomain transcription factor, Lhx9. Lhx9 has two noncanonical splice variants, Lhx9a and Lhx9b which compared with the canonical variant Lhx9c have a truncated homeodomain and an alternative C-terminal sequence, suggesting that, if translated, these variants could differently impact on cellular function.Results: We created a unique antibody tool designed to selectively detect noncanonical Lhx9 variants (Lhx9ab) and used this to examine the protein expression dynamics in embryos. Lhx9ab variants were translated and dynamically expressed similarly between mouse and chicken at key developmental choice points in the spinal cord, limbs and urogenital ridge. Within the spinal cord, enrichment of Lhx9c vs Lhx9ab expression was observed during key migration and axonal projection choice points.Conclusions: These data support the notion that the expression dynamics between canonical and noncanonical Lhx9 variants could play an important role in spinal neuron maturation. More broadly, determining the temporal dynamics of alternative protein variants is a key entry point to understand how splicing influences developmental processes.
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