Diversification of C. elegans Motor Neuron Identity via Selective Effector Gene Repression

Kerk, Sze Yen; Kratsios, Paschalis; Hart, Michael P.; Mourao, Romulo; Hobert, Oliver

doi:10.1016/j.neuron.2016.11.036

Cited by 80 publications

(143 citation statements)

References 49 publications

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“…We note that hypomorphic effects in the ethanol treated group have been previously reported for other AID-tagged TFs in C. elegans [47]. Such effects appear to be target genespecific, as they were observed for glr-5 and flp-11, but not ser-2 ( Fig.…”

Section: D-f)supporting

confidence: 78%

“…These findings reveal a simple and economical mechanism that secures neuronal terminal identity features: the same TF is continuously required -from development throughout life -to not only activate neuron type-specific identity genes, but also prevent expression of "unwanted" terminal features. A continuous requirement for repression of terminal identity genes has been previously reported for three other TFs, bnc-1/BNC and mab-9/Tbx20 in C. elegans MNs and ewg/NRF1 in the Drosophila eye [47,54]. However, it is currently unknown whether these factors exert a dual and continuous function like UNC-3.…”

Section: During Development Individual Neuron Types Must Select Theimentioning

confidence: 93%

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A terminal selector prevents a Hox transcriptional switch to safeguard motor neuron identity throughout life

Feng

Dao

et al. 2019

Preprint

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149/150 words)Nervous system function critically relies on continuous expression of neuron type-specific terminal identity features, such as neurotransmitter receptors, ion channels and neuropeptides. How individual neuron types select such features during development and maintain them throughout life is poorly understood. Here, we report an unconventional mechanism that enables cholinergic motor neurons (MNs) in the C. elegans ventral nerve cord to select and maintain their distinct terminal identity features. The conserved terminal selector UNC-3 (Collier/Ebf) UNC-3 is continuously required not only to promote cholinergic MN features, but also to prevent expression of "unwanted" terminal identity features normally reserved for other neuron types. Mechanistically, this dual function is achieved by the ability of UNC-3 to prevent a switch in the transcriptional targets of the Hox protein LIN-39 (Scr/Dfd/Hox4-5). The strategy of a terminal selector preventing a Hox transcriptional switch may constitute a general principle for safeguarding neuronal terminal identity features throughout life. 18]. Because they are present in both C. elegans sexes (males and hermaphrodites), we will refer to them as "sex-shared" MNs. In addition, there are two subtypes of "sex-specific" cholinergic MNs; the hermaphrodite-specific VC neurons control egg laying [19,20], whereas the male-specific CA neurons are required for mating [21] (Fig. 1A). Apart from distinct morphology and connectivity, each subtype can be molecularly defined based on the combinatorial expression of known terminal identity genes, such as ion channels, NT receptors, and neuropeptides ( Fig. 1B). An extensive collection of transgenic reporter animals for MN subtype-specific terminal identity genes is available, thereby providing a unique opportunity to investigate, at single-cell resolution, the effects of TF gene removal on 5 developing and adult MNs. UNC-3, the sole C. elegans ortholog of the Collier/Olf/Ebf (COE) family of TFs, is selectively expressed in all sex-shared cholinergic MNs of the nerve cord ( Fig. 1B) [22][23][24][25][26].Animals lacking unc-3 display striking locomotion defects [27]. UNC-3 is known to directly activate a large battery of terminal identity genes expressed either in all sex-shared cholinergic MNs (e.g., the NT identity genes unc-17/ VAChT and cha-1/ ChAT), or in certain subtypes (e.g., ion channels, NT receptors, signaling molecules) [23] ( Fig. 1B-C). Based on its ability to broadly co-regulate many distinct terminal identity features, unc-3 has been classified as a terminal selector gene [2]. Besides its well-established function as activator of terminal identity genes in cholinergic MNs, whether and how UNC-3 can prevent expression of "unwanted" terminal features remains unclear.Here, we identify a dual role for UNC-3 and describe an unconventional mechanism through which sex-shared cholinergic MNs select and maintain their terminal identity features. We find that UNC-3 is continuously required, from development through adulthood...

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Section: D-f)supporting

confidence: 78%

Section: During Development Individual Neuron Types Must Select Theimentioning

confidence: 93%

A terminal selector prevents a Hox transcriptional switch to safeguard motor neuron identity throughout life

Feng

Dao

et al. 2019

Preprint

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“…The left panel shows known mechanisms for interclass-specification. Class-specific repressor proteins counteract unc-3 ’s activity, thereby generating ‘inter’-class diversity in C. elegans MNs (example of DA and VA class is shown) (Kerk et al, 2017). The right panel illustrates the problem of subclass diversification: Within a given class, the mechanisms controlling the expression of subclass-specific genes and thereby generate ‘intra’-class diversity are not known (example of DA class is shown). DOI: http://dx.doi.org/10.7554/eLife.25751.00210.7554/eLife.25751.003Summary of synaptic wiring data.(extracted from www.wormwiring.org).…”

Section: Introductionmentioning

confidence: 99%

An intersectional gene regulatory strategy defines subclass diversity of C. elegans motor neurons

Kratsios

Kerk

Catela

et al. 2017

eLife

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A core principle of nervous system organization is the diversification of neuron classes into subclasses that share large sets of features but differ in select traits. We describe here a molecular mechanism necessary for motor neurons to acquire subclass-specific traits in the nematode Caenorhabditis elegans. Cholinergic motor neuron classes of the ventral nerve cord can be subdivided into subclasses along the anterior-posterior (A-P) axis based on synaptic connectivity patterns and molecular features. The conserved COE-type terminal selector UNC-3 not only controls the expression of traits shared by all members of a neuron class, but is also required for subclass-specific traits expressed along the A-P axis. UNC-3, which is not regionally restricted, requires region-specific cofactors in the form of Hox proteins to co-activate subclass-specific effector genes in post-mitotic motor neurons. This intersectional gene regulatory principle for neuronal subclass diversification may be conserved from nematodes to mice.DOI: http://dx.doi.org/10.7554/eLife.25751.001

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“…This poses the question of how the same shared transcription factor can differentially activate and/or repress gene sets in specific subtypes of Sst + neurons. In the nematode C. elegans, unc-3 is a transcription factor with a similar role: all six subtypes of ventral cholinergic motor (VCM) neurons express unc-3, which is able to initiate and maintain the distinct neuronal features of each neuronal type, by co-acting with complementary, class-specific repressing transcription factors (Kerk et al, 2017;Kratsios et al, 2011). Similar to the effect of Sox6 ablation in cortical Sst + neurons, loss of unc-3 disrupts VCM neuronal class diversity and generates a "hybrid" motor neuron (Kerk et al, 2017;Kratsios et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Transcriptional maintenance of cortical somatostatin interneuron subtype identity during migration

Munguba

Nikouei

Hochgerner

et al. 2019

Preprint

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Recent work suggests that cortical interneuron diversity arises from genetic mechanisms guided by the interplay of intrinsic developmental patterning and local extrinsic cues. Individual genetic programs underlying subtype identity are at least partly established in postmitotic neural precursors, prior to their tangential migration and integration in the cortical circuitry. Nevertheless, it is unclear how distinct interneuron identities are maintained during their migration and maturation. Sox6 is a transcription factor with an established role in MGEderived interneuron maturation and positional identity. To determine its role in maintaining somatostatin (Sst)-expressing interneurons' subtype identity, we conditionally removed Sox6 in migrating Sst interneurons and assessed the effects on their mature identity using singlecell RNA-sequencing (scRNAseq), in situ hybridization and electrophysiology. Sox6 removal prior to migration in Sst-expressing neurons reduced subtype diversity without affecting overall number of neurons. Seven out of nine Sst-expressing molecular subtypes were absent in the mature primary somatosensory cortex of Sox6-cKO mice, including the Chodl-Nos1expressing type which has been shown to be specified at, or shortly after, cell cycle exit. The remaining Sst-expressing subtypes in the Sox6-cKO cortex comprised three molecular subtypes, Crh-C1ql3 and Hpse-Cbln4, and a third subtype that seemed to be a molecular hybrid of these subtypes. Moreover, Sox6-cKO cells still expressed genes enriched within the entire class of Sst-expressing neurons, such as Sst, Lhx6, Satb1, Elfn1 and Mafb. Removal of Sox6 at P7, after cells have reached their final destination and begin integration into the network, did not disrupt Chodl-Nos1 marker expression. Our findings suggest that expression 2 of Sox6 during the migratory phase of cortical interneurons is necessary for maintenance of Sst + subtype identity, indicating that subtype maintenance during migration requires active transcriptional programs.

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Diversification of C. elegans Motor Neuron Identity via Selective Effector Gene Repression

Cited by 80 publications

References 49 publications

A terminal selector prevents a Hox transcriptional switch to safeguard motor neuron identity throughout life

A terminal selector prevents a Hox transcriptional switch to safeguard motor neuron identity throughout life

An intersectional gene regulatory strategy defines subclass diversity of C. elegans motor neurons

Transcriptional maintenance of cortical somatostatin interneuron subtype identity during migration

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