ngn-1/neurogenin Activates Transcription of Multiple Terminal Selector Transcription Factors in theCaenorhabditis elegansNervous System

Abstract

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 ngn-1/neurogenin in nervous system development and to identify its downstream transcriptional targets, using the nematode Caenorhabditis elegans as a model for this work. We found that ngn-1 is required for axon outgrowth, nerve ring architecture, and neuronal cell fate specification. We also showed that ngn-1 may have roles in neuroblast migration and epithelial integrity during embryonic development. Using RNA sequencing and comparative transcriptome analysis, we identified eight transcription factors (hlh-34/NPAS1, unc-42/PROP1, ceh-17/PHOX2A, lim-4/LHX6, fax-1/NR2E3, lin-11/LHX1, tlp-1/ZNF503, and nhr-23/RORB) whose transcription is activated, either directly or indirectly, by ngn-1. Our results show that ngn-1 has a role in transcribing known terminal regulators that establish and maintain cell fate of differentiated neural subtypes and confirms that ngn-1 functions as a proneural transcription factor in C. elegans neurogenesis.

Multiple neural bHLHs ensure the precision of a neuronal specification event in Caenorhabditis elegans

“…These data suggest that ngn-1 affects the fate, axonal projection and position of the AIY neuron. Similar observations in ngn-1 mutants have been recently reported ( Christensen et al, 2020 ), however, in this study, the origin of these AIY neuron defects was not further analyzed.…”

“…Another possibility is that NGN-1 binds egl-1 cis -regulatory regions and that the presence of a specific cofactor on egl-1 cis -regulatory regions turns NGN-1 into a repressor. Interestingly, a recent RNA sequencing study showed that the majority of differentially expressed genes in ngn-1 mutants are upregulated supporting the idea that NGN-1 may indeed be able to act as a repressor ( Christensen et al, 2020 ).…”

Piecemeal regulation of convergent neuronal lineages by bHLH transcription factors inCaenorhabditis elegans

“…Our analysis of basic helix-loop-helix (bHLH) transcription factors was originally motivated by our quest to understand how the expression of terminal selector transcription factors is controlled. Terminal selectors have emerged as key regulators of neuronal identity throughout the entire nervous system (Hobert, 2016), yet we understand little about how their expression is induced in the embryo (Baumeister et al, 1996;Bertrand and Hobert, 2009;Christensen et al, 2020;Mitani et al, 1993;Murgan et al, 2015). Based on a previously reported effect of lin-32 on the expression of the terminal selectors unc-86/Brn3 (Baumeister et al, 1996) and mec-3 (Mitani et al, 1993), we sought to investigate the role of lin-32 further.…”

cnd-1/NeuroD1 Functions with the Homeobox Geneceh-5/Vax2 and Hox Geneceh-13/labial To Specify Aspects of RME and DD Neuron Fate inCaenorhabditis elegans

“…This suggests that cnd-1 functions close to the end of a transcriptional regulatory cascade during C. elegans embryogenesis. This is in contrast to ngn-1 /neurogenin, which controls expression of at least eight downstream transcription factors ( Christensen et al 2020 ).…”