Abstract
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.
Highlights
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)
At HH18/19, when most NC cells (NCCs) had colonized at the prospective DRG [24], only a small portion of Sox10+/Neurogenin 2 (Neurog2)+ cells appeared in the dorsal pole, and the majority of cells expressing Sox10 alone were detected in the developing DRG, where expression of pan-neuronal marker TuJ1 became prominent in a subset of neuronal precursors with nuclear and cytoplasmic localization of Neurog2 (Fig. 1 E, G, and H and SI Appendix, Fig. S1)
These expression studies revealed an initial coexpression of Sox10 and nuclear Neurog2 in bipotent neuroglial NC progenitors followed by relocalization of Neurog2 from the nucleus to cytoplasm at the point of lineage segregation
Summary
The transcription factor Sox 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). Epistasis analysis further demonstrated that Fbxo and probably other F-box members mediated the role of Sox in destabilizing Neurog protein and directing the lineage of NC progenitors toward glial cells rather than sensory neurons. These findings unravel a Sox10–Fbxo regulatory axis in promoting the glial fate of NC progenitors through Neurog destabilization. Data deposition: The RNA sequencing data and list of up- and down-regulated genes by Sox overexpression have been deposited in Figshare (11378727)
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