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Establishment and maintenance of motor neuron identity via temporal modularity in terminal selector function.

ABSTRACT: Terminal selectors are transcription factors (TFs) that establish during development and maintain throughout life post-mitotic neuronal identity. We previously showed that UNC-3/Ebf, the terminal selector of C. elegans cholinergic motor neurons (MNs), acts indirectly to prevent alternative neuronal identities (Feng et al., 2020). Here, we globally identify the direct targets of UNC-3. Unexpectedly, we find that the suite of UNC-3 targets in MNs is modified across different life stages, revealing 'temporal modularity' in terminal selector function. In all larval and adult stages examined, UNC-3 is required for continuous expression of various protein classes (e.g. receptors, transporters) critical for MN function. However, only in late larvae and adults, UNC-3 is required to maintain expression of MN-specific TFs. Minimal disruption of UNC-3's temporal modularity via genome engineering affects locomotion. Another C. elegans terminal selector (UNC-30/Pitx) also exhibits temporal modularity, supporting the potential generality of this mechanism for the control of neuronal identity.

SUBMITTER: Li Y

PROVIDER: S-EPMC7529460 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Establishment and maintenance of motor neuron identity via temporal modularity in terminal selector function.

Li Yinan Y Osuma Anthony A Correa Edgar E Okebalama Munachiso A MA Dao Pauline P Gaylord Olivia O Aburas Jihad J Islam Priota P Brown André Ex AE Kratsios Paschalis P

eLife 20201001

Terminal selectors are transcription factors (TFs) that establish during development and maintain throughout life post-mitotic neuronal identity. We previously showed that UNC-3/Ebf, the terminal selector of <i>C. elegans</i> cholinergic motor neurons (MNs), acts indirectly to prevent alternative neuronal identities (Feng et al., 2020). Here, we globally identify the direct targets of UNC-3. Unexpectedly, we find that the suite of UNC-3 targets in MNs is modified across different life stages, re ...[more]

PMID: 33001031

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Project description:BACKGROUND:Spatial patterning specifies neural progenitor identity, with further diversity generated by temporal patterning within individual progenitor lineages. In vertebrates, these mechanisms generate "cardinal classes" of neurons that share a transcription factor identity and common morphology. In Drosophila, two cardinal classes are Even-skipped (Eve)+ motor neurons projecting to dorsal longitudinal muscles, and Nkx6+ motor neurons projecting to ventral oblique muscles. Cross-repressive interactions prevent stable double-positive motor neurons. The Drosophila neuroblast 7-1 (NB7-1) lineage uses a temporal transcription factor cascade to generate five distinct Eve+ motor neurons; the origin and development of Nkx6+ motor neurons remains unclear. METHODS:We use a neuroblast specific Gal4 line, sparse labelling and molecular markers to identify an Nkx6+ VO motor neuron produced by the NB7-1 lineage. We use lineage analysis to birth-date the VO motor neuron to the Kr+ Pdm+ neuroblast temporal identity window. We use gain- and loss-of-function strategies to test the role of Kr+ Pdm+ temporal identity and the Nkx6 transcription factor in specifying VO neuron identity. RESULTS:Lineage analysis identifies an Nkx6+ neuron born from the Kr+ Pdm+ temporal identity window in the NB7-1 lineage, resulting in alternation of cardinal motor neuron subtypes within this lineage (Eve>Nkx6?>?Eve). Co-overexpression of Kr/Pdm generates ectopic VO motor neurons within the NB7-1 lineage - the first evidence that this TTF combination specifies neuronal identity. Moreover, the Kr/Pdm combination promotes Nkx6 expression, which itself is necessary and sufficient for motor neuron targeting to ventral oblique muscles, thereby revealing a molecular specification pathway from temporal patterning to cardinal transcription factor expression to motor neuron target selection. CONCLUSIONS:We show that one neuroblast lineage generates interleaved cardinal motor neurons fates; that the Kr/Pdm TTFs form a novel temporal identity window that promotes expression of Nkx6; and that the Kr/Pdm?>?Nkx6 pathway is necessary and sufficient to promote VO motor neuron targeting to the correct ventral muscle group.

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Establishment and maintenance of motor neuron identity via temporal modularity in terminal selector function.

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Establishment and maintenance of motor neuron identity via temporal modularity in terminal selector function.

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