The enteric nervous system of the C. elegans pharynx is specified by the Sine oculis-like homeobox gene ceh-34

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    Evaluation Summary:

    This paper will be of interest to developmental neurobiologists working on the transcriptional control of neural cell fate and connectivity. The data largely support the authors' finding that a single homeodomain transcription factor is a circuit-wide specifier of cell fate that functions combinatorially with other factors in the development of the C. elegans pharyngeal nervous system. The authors speculate about intriguing similarities between the nematode pharyngeal nervous system and vertebrate enteric nervous systems.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #3 agreed to share their name with the authors.)

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Abstract

Overarching themes in the terminal differentiation of the enteric nervous system, an autonomously acting unit of animal nervous systems, have so far eluded discovery. We describe here the overall regulatory logic of enteric nervous system differentiation of the nematode Caenorhabditis elegans that resides within the foregut (pharynx) of the worm. A C. elegans homolog of the Drosophila Sine oculis homeobox gene, ceh-34 , is expressed in all 14 classes of interconnected pharyngeal neurons from their birth throughout their life time, but in no other neuron type of the entire animal. Constitutive and temporally controlled ceh-34 removal shows that ceh-34 is required to initiate and maintain the neuron type-specific terminal differentiation program of all pharyngeal neuron classes, including their circuit assembly. Through additional genetic loss of function analysis, we show that within each pharyngeal neuron class, ceh-34 cooperates with different homeodomain transcription factors to individuate distinct pharyngeal neuron classes. Our analysis underscores the critical role of homeobox genes in neuronal identity specification and links them to the control of neuronal circuit assembly of the enteric nervous system. Together with the pharyngeal nervous system simplicity as well as its specification by a Sine oculis homolog, our findings invite speculations about the early evolution of nervous systems.

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  1. Author Response:

    Reviewer #1 (Public Review):

    In this tour-de-force analysis of transcriptional regulation and cell fate specification in C. elegans, Vidal et al. explore the role of the Sine Oculis/Six1/Six2 ortholog ceh-34 in the pharyngeal nervous system. Previous work demonstrated that ceh-34 is exclusively expressed in all pharyngeal neuron types. The current work data shows that ceh-34 function is required for the diverse differentiated features of all pharyngeal neuron subtypes, as well as their interconnectivity, but, interestingly, not for their basal "pan-neuronal" features. ceh-34 is also required to maintain these features, at least into larval stages. Convincing evidence is presented indicating that subtype-specificity emerges through the cooperation of ceh-34 with various individual homeodomain factors, consistent with …

  2. Evaluation Summary:

    This paper will be of interest to developmental neurobiologists working on the transcriptional control of neural cell fate and connectivity. The data largely support the authors' finding that a single homeodomain transcription factor is a circuit-wide specifier of cell fate that functions combinatorially with other factors in the development of the C. elegans pharyngeal nervous system. The authors speculate about intriguing similarities between the nematode pharyngeal nervous system and vertebrate enteric nervous systems.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #3 agreed to share their name with the authors.)

  3. Reviewer #1 (Public Review):

    In this tour-de-force analysis of transcriptional regulation and cell fate specification in C. elegans, Vidal et al. explore the role of the Sine Oculis/Six1/Six2 ortholog ceh-34 in the pharyngeal nervous system. Previous work demonstrated that ceh-34 is exclusively expressed in all pharyngeal neuron types. The current work data shows that ceh-34 function is required for the diverse differentiated features of all pharyngeal neuron subtypes, as well as their interconnectivity, but, interestingly, not for their basal "pan-neuronal" features. ceh-34 is also required to maintain these features, at least into larval stages. Convincing evidence is presented indicating that subtype-specificity emerges through the cooperation of ceh-34 with various individual homeodomain factors, consistent with the homeodomain …

  4. Reviewer #2 (Public Review):

    Vidal et al. describe the role of the SIX-family transcription factor CEH-34 in the development of the pharyngeal nervous system. The manuscript is strong in several ways. The study is comprehensive and elegantly presented. The authors' conclusions are, with only a few minor exceptions, clearly supported by the presented data. And the study uses sophisticated genetic approaches to determine gene expression in vivo and manipulate gene function.

    The manuscript has some weaknesses. First, some of the manuscript is redundant with published data. The authors could better consolidate and synthesize what is known about the pharyngeal nervous system and CEH-34. The authors could also relegate data that support a point already made to supplementary figures. Second, the study does not address functional consequences …

  5. Reviewer #3 (Public Review):

    This study addresses the development of the enteric nervous system in C. elegans. The authors find that the homeobox gene ceh-34 is specifically expressed in all 14 classes of pharyngeal neurons, but no other neurons in the animal. Mutant analysis reveals that ceh-34 is necessary for the differentiation of all 14 neuron classes. ceh-34 acts with several other homeodomain TFs to specify the different neuron classes. The authors speculate that the selective role for ceh-34 in specifying the entire enteric nervous system supports the notion of this system as perhaps the primordial origin of the nervous system.

    The study is overall of high quality and the conclusions balanced. While the combinatorial coding of neuronal subtype cell fate by TFs dates back at least two decades, this concept has not hitherto been …