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

Neural bHLH transcription factors play a key role in the early steps of neuronal specification in many animals. We have previously observed that the Achaete-Scute HLH-3, the Olig HLH-16 and their binding partner the E protein HLH-2 activate the terminal differentiation program of a specific class of cholinergic neurons, AIY, in C. elegans. Here we identify a role for a fourth bHLH, the Neurogenin NGN-1, in this process, raising the question of why so many neural bHLHs are required for a single neuronal specification event. Using quantitative imaging we show that the combined action of different bHLHs is needed to activate the correct level of expression of the terminal selector transcription factors TTX-3 and CEH-10 that subsequently initiate and maintain the expression of a large battery of terminal differentiation genes. Surprisingly, the different bHLHs have an antagonistic effect on another target, the proapoptotic BH3-only factor EGL-1, normally not expressed in AIY and otherwise detrimental for its specification. We propose that the use of multiple neural bHLHs allows robust neuronal specification while, at the same time, preventing spurious activation of deleterious genes.

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Piecemeal regulation of convergent neuronal lineages by bHLH transcription factors in Caenorhabditis elegans

Development ◽

10.1242/dev.199224 ◽

2021 ◽

Vol 148 (11) ◽

Author(s):

Neda Masoudi ◽

Eviatar Yemini ◽

Ralf Schnabel ◽

Oliver Hobert

Keyword(s):

Transcription Factors ◽

Caenorhabditis Elegans ◽

Contralateral Side ◽

Mirror Image ◽

Neuronal Markers ◽

C Elegans ◽

Helix Loop Helix ◽

Distinct Lineage ◽

Bhlh Transcription Factors ◽

Identity Transformations

ABSTRACT Cells of the same type can be generated by distinct cellular lineages that originate in different parts of the developing embryo (‘lineage convergence’). Several Caenorhabditis elegans neuron classes composed of left/right or radially symmetric class members display such lineage convergence. We show here that the C. elegans Atonal homolog lin-32 is differentially expressed in neuronal lineages that give rise to left/right or radially symmetric class members. Loss of lin-32 results in the selective loss of the expression of pan-neuronal markers and terminal selector-type transcription factors that confer neuron class-specific features. Another basic helix-loop-helix (bHLH) gene, the Achaete-Scute homolog hlh-14, is expressed in a mirror image pattern relative to lin-32 and is required to induce neuronal identity and terminal selector expression on the contralateral side of the animal. These findings demonstrate that distinct lineage histories converge via different bHLH factors at the level of induction of terminal selector identity determinants, which thus serve as integrators of distinct lineage histories. We also describe neuron-to-neuron identity transformations in lin-32 mutants, which we propose to also be the result of misregulation of terminal selector gene expression.

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Faculty Opinions recommendation of A multiparameter network reveals extensive divergence between C. elegans bHLH transcription factors.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1162875.624504 ◽

2009 ◽

Author(s):

Andy Pereira ◽

Arjun Krishnan

Keyword(s):

Transcription Factors ◽

C Elegans ◽

Bhlh Transcription Factors

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Faculty Opinions recommendation of A multiparameter network reveals extensive divergence between C. elegans bHLH transcription factors.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1162875.793496403 ◽

2014 ◽

Author(s):

Rosa Puertollano

Keyword(s):

Transcription Factors ◽

C Elegans ◽

Bhlh Transcription Factors

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Transcription factors from multiple families ensure enhancer selectivity and robust neuron terminal differentiation

10.1101/2020.09.04.283036 ◽

2020 ◽

Author(s):

Angela Jimeno-Martín ◽

Erick Sousa ◽

Noemi Daroqui ◽

Rebeca Brocal-Ruiz ◽

Miren Maicas ◽

...

Keyword(s):

Transcription Factors ◽

Rna Interference ◽

Terminal Differentiation ◽

Specific Gene ◽

Neuron Type ◽

C Elegans ◽

Effector Genes ◽

Genetic Robustness ◽

Gene Regulatory ◽

Dopaminergic Terminal

SUMMARYTo search for general principles underlying neuronal regulatory programs we built an RNA interference library against all transcription factors (TFs) encoded in C. elegans genome and systematically screened for specification defects in ten different neuron types of the monoaminergic (MA) superclass.We identified over 90 TFs involved in MA specification, with at least ten different TFs controlling differentiation of each individual neuron type. These TFs belong predominantly to five TF families (HD, bHLH, ZF, bZIP and NHR). Next, focusing on the complexity of terminal differentiation, we identified and functionally characterized the dopaminergic terminal regulatory program. We found that seven TFs from four different families act in a TF collective to provide genetic robustness and to impose a specific gene regulatory signature enriched in the regulatory regions of dopamine effector genes. Our results provide new insights on neuron-type regulatory programs that could help better understand specification and evolution of neuron types.

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Control of spinal motor neuron terminal differentiation through sustained Hoxc8 gene activity

10.1101/2021.05.26.445841 ◽

2021 ◽

Author(s):

Catarina Catela ◽

Yifei Weng ◽

Kailong Wen ◽

Weidong Feng ◽

Paschalis Kratsios

Keyword(s):

Transcription Factors ◽

Motor Neurons ◽

Terminal Differentiation ◽

Differentiation Markers ◽

Spinal Motor Neuron ◽

C Elegans ◽

Spinal Motor Neurons ◽

Spinal Motor ◽

Evolutionarily Conserved ◽

Genes Encoding

Spinal motor neurons (MNs) constitute cellular substrates for several movement disorders. Although their early development has received much attention, how spinal MNs become and remain terminally differentiated is poorly understood. Here, we determined the transcriptome of mouse brachial MNs at embryonic and postnatal stages. We found that genes encoding homeodomain (HOX, LIM) transcription factors (TFs), previously implicated in early MN development, continue to be expressed postnatally, suggesting later functions. To test this, we inactivated Hoxc8 at successive stages of MN development. We found that Hoxc8 is not only required to establish but also maintain expression of several MN terminal differentiation markers. Furthermore, we uncovered novel TFs with continuous MN expression, a Hoxc8 dependency for maintained expression of Iroquois (Irx) homeodomain TFs, and a new role for Irx2 in MN development. Our findings dovetail recent observations in C. elegans MNs, pointing toward an evolutionarily conserved role for Hox in neuronal terminal differentiation.

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