Christensen Elyse L, Beasley Alexandra, Radchuk Jessica, Mielko Zachery E, Preston Elicia, Stuckett Sidney, Murray John I, Hudson Martin L
Department of Molecular and Cellular Biology, Kennesaw State University, GA 30144.
Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104.
G3 (Bethesda). 2020 Jun 1;10(6):1949-1962. doi: 10.1534/g3.120.401126.
Proper nervous system development is required for an organism's survival and function. Defects in neurogenesis have been linked to neurodevelopmental disorders such as schizophrenia and autism. Understanding the gene regulatory networks that orchestrate neural development, specifically cascades of proneural transcription factors, can better elucidate which genes are most important during early neurogenesis. Neurogenins are a family of deeply conserved factors shown to be both necessary and sufficient for the development of neural subtypes. However, the immediate downstream targets of neurogenin are not well characterized. The objective of this study was to further elucidate the role of /neurogenin in nervous system development and to identify its downstream transcriptional targets, using the nematode as a model for this work. We found that is required for axon outgrowth, nerve ring architecture, and neuronal cell fate specification. We also showed that may have roles in neuroblast migration and epithelial integrity during embryonic development. Using RNA sequencing and comparative transcriptome analysis, we identified eight transcription factors (/NPAS1, /PROP1, /PHOX2A, /LHX6, /NR2E3, /LHX1, /ZNF503, and /RORB) whose transcription is activated, either directly or indirectly, by Our results show that has a role in transcribing known terminal regulators that establish and maintain cell fate of differentiated neural subtypes and confirms that functions as a proneural transcription factor in neurogenesis.
适当的神经系统发育是生物体生存和功能所必需的。神经发生缺陷与精神分裂症和自闭症等神经发育障碍有关。了解协调神经发育的基因调控网络,特别是原神经转录因子级联反应,能够更好地阐明哪些基因在早期神经发生过程中最为重要。神经生成素是一类高度保守的因子,已证明对神经亚型的发育既必要又充分。然而,神经生成素的直接下游靶点尚未得到很好的表征。本研究的目的是利用线虫作为模型,进一步阐明神经生成素在神经系统发育中的作用,并确定其下游转录靶点。我们发现,神经生成素对轴突生长、神经环结构和神经元细胞命运特化是必需的。我们还表明,神经生成素在胚胎发育过程中可能在神经母细胞迁移和上皮完整性方面发挥作用。通过RNA测序和比较转录组分析,我们鉴定出八个转录因子(NPAS1、PROP1、PHOX2A、LHX6、NR2E3、LHX1、ZNF503和RORB),它们的转录直接或间接受神经生成素激活。我们的结果表明,神经生成素在转录已知的终端调节因子方面发挥作用,这些调节因子建立并维持分化神经亚型的细胞命运,并证实神经生成素在神经发生中作为原神经转录因子发挥作用。