Fbxo9 functions downstream of Sox10 to determine neuron-glial fate choice in the dorsal root ganglia through Neurog2 destabilization
| العنوان: | Fbxo9 functions downstream of Sox10 to determine neuron-glial fate choice in the dorsal root ganglia through Neurog2 destabilization |
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| المؤلفون: | Mai Har Sham, Martin Cheung, Jialin Hong, Jessica Aijia Liu, Andrew Tai, Kathryn S.E. Cheah, May Pui Lai Cheung, Chi Wai Cheung |
| المصدر: | Proceedings of the National Academy of Sciences of the United States of America |
| بيانات النشر: | National Academy of Sciences, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Male, Neurogenesis, SOX10, Sox10, Amino Acid Motifs, Nerve Tissue Proteins, Neurog2, Chick Embryo, Mice, Ubiquitin, medicine, Basic Helix-Loop-Helix Transcription Factors, Animals, Neurogenin-2, Transcription factor, Mice, Knockout, Neurons, Multidisciplinary, biology, Protein Stability, SOXE Transcription Factors, F-Box Proteins, Neural crest, Gene Expression Regulation, Developmental, neural crest progenitors, Biological Sciences, Fbxo9, Ubiquitin ligase, Cell biology, medicine.anatomical_structure, nervous system, Neural Crest, embryonic structures, biology.protein, Female, Neuron, Spinal Nerve Roots, Glial cell fate commitment, Neuroglia, Developmental Biology, Protein Binding |
| الوصف: | Significance The neuron–glial lineage segregation of NC progenitors forming the DRG is essential for peripheral nervous system development. However, hierarchical transcriptional control does not explain how this lineage bifurcation occurs. Here, we provide in vivo evidence that a glial lineage specifier, Sox10, inhibits neurogenesis via a degradation mechanism. A ubiquitin-ligase, Fbxo9, acting downstream of Sox10 destabilizes the proneural Neurog2 protein, leading to the loss of neurogenic capacity in NC progenitors while leaving their glial potential intact. Functional inhibition of Fbxo9 and possibly other members of the F-box family lead to prolonged expression of Neurog2 protein that causes both the expansion of NC progenitors and precocious neuronal differentiation. Our results unravel a previously unrecognized mechanism in neuron–glial cell fate decision. The transcription factor Sox10 is a key regulator in the fate determination of a subpopulation of multipotent trunk neural crest (NC) progenitors toward glial cells instead of sensory neurons in the dorsal root ganglia (DRG). However, the mechanism by which Sox10 regulates glial cell fate commitment during lineage segregation remains poorly understood. In our study, we showed that the neurogenic determinant Neurogenin 2 (Neurog2) exhibited transient overlapping expression with Sox10 in avian trunk NC progenitors, which progressively underwent lineage segregation during migration toward the forming DRG. Gain- and loss-of-function studies revealed that the temporary expression of Neurog2 was due to Sox10 regulation of its protein stability. Transcriptional profiling identified Sox10-regulated F-box only protein (Fbxo9), which is an SCF (Skp1-Cul-F-box)-type ubiquitin ligase for Neurog2. Consistently, overexpression of Fbxo9 in NC progenitors down-regulated Neurog2 protein expression through ubiquitination and promoted the glial lineage at the expense of neuronal differentiation, whereas Fbxo9 knockdown resulted in the opposite phenomenon. Mechanistically, we found that Fbxo9 interacted with Neurog2 to promote its destabilization through the F-box motif. Finally, epistasis analysis further demonstrated that Fbxo9 and probably other F-box members mediated the role of Sox10 in destabilizing Neurog2 protein and directing the lineage of NC progenitors toward glial cells rather than sensory neurons. Altogether, these findings unravel a Sox10–Fbxo9 regulatory axis in promoting the glial fate of NC progenitors through Neurog2 destabilization. |
| اللغة: | English |
| تدمد: | 1091-6490 0027-8424 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9b439227c030512a78261d3b652e608c http://europepmc.org/articles/PMC7049171 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....9b439227c030512a78261d3b652e608c |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10916490 00278424 |
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