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Intrinsic and non-cell autonomous roles for a neurodevelopmental syndrome-linked transcription factor

ABSTRACT: Transcription factors (TFs) are essential for neuronal identity, yet their potential non–cell-autonomous functions remain largely unexplored. Here, we uncover both cell- and non–cell-autonomous roles for the conserved terminal selector UNC-3 in C. elegans motor neurons (MNs). UNC-3 is an ortholog of human EBF3, mutations in which cause a severe neurodevelopmental syndrome. Single-cell RNA sequencing of cholinergic MNs, which express unc-3, and downstream GABA MNs, which do not, revealed that unc-3 loss disrupts neuronal identity in distinct ways across MN classes. Four cholinergic MN classes lose their molecular identity entirely, whereas the AS class retains it partially, illuminating terminal selector–driven neuronal diversification processes. Integrated transcriptomic and genomic analyses uncovered a dual cell-autonomous role for UNC-3 as both a direct activator and repressor of neuron-type–specific genes in cholinergic MNs, including repression of alternate neurotransmitter programs. Unexpectedly, unc-3 loss also caused widespread transcriptional, morphological, and connectivity defects in downstream GABA MNs. Mechanistically, these non-cell-autonomous effects are mediated by cholinergic neurotransmission and include activation of the pro-regenerative bZIP TF CEBP-1 (C/EBP) and dysregulation of UNC-6/Netrin signaling. These findings redefine terminal selectors as both intrinsic and extrinsic regulators of neuronal identity and circuit assembly, offering a mechanistic framework for understanding EBF3 syndrome pathogenesis.

ORGANISM(S): Caenorhabditis elegans

PROVIDER: GSE314726 | GEO | 2026/02/01

REPOSITORIES: GEO

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Project description:Motor neuron (MN), together with interneuron, are the two major neuronal types in spinal cord. MNs control muscle movement and are essential for breathing, walking and fine motor skills. Malfunction of MNs is frequently associated with neuronal diseases such as spinal muscular atrophy and amyotrophic lateral sclerosis. To establish normal function, MNs need to be differentiated properly from neural progenitor cells. Thus, it is of great importance to study the mechanism for MN specification. This study focuses on Mnx1 - a conserved homeobox transcription factor gets expressed during MN specification. Mnx1 is also the most widely used MN marker. Previous studies reported that Mnx1 mutation in mouse causes early lethality - probably by affecting the controlling over respiratory system. However, the exact role of Mnx1 for MN identity remains poorly understood. Taking advantage of a recently developed in vitro model for efficient MN induction from mouse ES cells, we combined experimental and OMICs techniques to systematically investigate the molecular function of Mnx1. We identified thousands of Mnx1 binding sites - many are co-bound by core MN factor Lhx3 and Isl1 and lack active histone marks. Disruption of Mnx1 causes increased expression of 85 genes - while only 14 genes get down-regulated. Up-regulated genes are enriched with neuronal functions, usually get expressed during MN differentiation, and tend to have higher expression in motor neurons and brain compared with other tissues – indicating Mnx1 may fine tune neuronal genes to desired level. However, only a dozen of regions with increased H3K27ac marks are bound by Mnx1, and only two up-regulated genes (Pbx3 and Pou6f2) are identified as putative direct targets of Mnx1 - both are core neuronal factors with the potential to regulate other differential neuronal genes. These results suggest that Mnx1 may contribute to MN identity by fine-tuning the expression of many neuronal genes through direct regulation of a few core neuronal transcription factors. In summary, this study represents the first systematic investigation about the molecular function of the core MN factor Mnx1. It clarifies the mechanism of Mnx1 for MN identity, and also improves the understanding about the regulation mode of homeobox transcription factors.

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Intrinsic and non-cell autonomous roles for a neurodevelopmental syndrome-linked transcription factor

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