A map of terminal regulators of neuronal identity in Caenorhabditis elegans

Abstract

Our present day understanding of nervous system development is an amalgam of insights gained from studying different aspects and stages of nervous system development in a variety of invertebrate and vertebrate model systems, with each model system making its own distinctive set of contributions. One aspect of nervous system development that has been among the most extensively studied in the nematode C. elegans is the nature of the gene regulatory programs that specify hardwired, terminal cellular identities. I will first summarize a number of maps (anatomical, functional, molecular) that describe the terminal identity of individual neurons in the C. elegans nervous system. I then provide a comprehensive summary of regulatory factors that specify terminal identities in the nervous system, synthesizing these past studies into a regulatory map of cellular identities in the C. elegans nervous system. This map shows that for three quarters of all neurons in the C. elegans nervous system, regulatory factors that control terminal identity features are known. In-depth studies of specific neuron types have revealed that regulatory factors rarely act alone, but rather act cooperatively in neuron-type specific combinations. In most cases examined so far, distinct, biochemically-unlinked terminal identity features are co-regulated via cooperatively acting transcription factors, termed terminal selectors, but there are also cases in which distinct identity features are controlled in a piecemeal fashion by independent regulatory inputs. The regulatory map also illustrates that identity-defining transcription factors are re-employed in distinct combinations in different neuron types. However, the same transcription factor can drive terminal differentiation in neurons that are unrelated by lineage, unrelated by function, connectivity and neurotransmitter deployment. Lastly, the regulatory map illustrates the preponderance of homeodomain transcription factors in the control of terminal identities, suggesting that these factors have ancient, phylogenetically conserved roles in controlling terminal neuronal differentiation in the nervous system.

The Role of Epigenetic Mechanisms in the Regulation of Gene Expression in the Nervous System

“…Accompanying the rediscovery of another DNA modification, 5-hydroxylmethylation (5hmC), in adult mouse neurons (Kriaucionis and Heintz, 2009), Tet proteins were identified to oxidize 5mC to 5hmC (Tahiliani et al, 2009;Ito et al, 2010). These findings immediately raised the possibility that Tet proteins initiate the active DNA demethylation process via the 5hmC intermediate step.…”

“…Neuronal specification is governed by transcriptional programs that are established during the early stages of neuronal development (Molyneaux et al, 2007;Hobert, 2011) and remain in place in the adult brain (Deneris and Hobert, 2014). Programs of gene activation by transcription factors are combined with systems that suppress genes whose expression might enforce the differentiation of neurons of other types (Cobos et al, 2006;Molyneaux et al, 2007;Hobert, 2011Hobert, , 2016Greig et al, 2013;Deneris and Hobert, 2014).…”

“…Programs of gene activation by transcription factors are combined with systems that suppress genes whose expression might enforce the differentiation of neurons of other types (Cobos et al, 2006;Molyneaux et al, 2007;Hobert, 2011Hobert, , 2016Greig et al, 2013;Deneris and Hobert, 2014). Gene regulatory processes that play a pivotal role in neuronal specification include the epigenetic silencing of non-neuronal/other neuron fatedetermining genes.…”

An Expanded Role for the RFX Transcription Factor DAF-19, with Dual Functions in Ciliated and Nonciliated Neurons

“…Mutations in transcription factor genes often phenocopy neuronal ablation by causing 611 misregulation of target genes, thereby affecting specific neuron function (Hobert, 2016a). 612 daf-19 null mutants are dauer formation constitutive, thus one might expect to see differential 613 gene regulation in neurons that inhibit dauer entry.…”

Programming and reprogramming the brain: a meeting of minds in neural fate

“…In an impressive large-scale effort, his team identified the specific combinations of transcription factors needed for terminal differentiation of most neuronal classes of C. elegans (Hobert, 2016). Termed 'terminal selectors', these factors endow neuronal cells with a specific neuronal subtype identity, rather than initially establishing a neuronal fate and gross morphology.…”