Intrinsic and non-cell autonomous roles for a neurodevelopmental syndrome-linked transcription factor
Year: 2025
Type: preprint
Abstract: 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.
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Awards: Molecular mechanisms for neuron-specific assembly of electrical synapses, Molecular mechanisms of motor neuron terminal identity, Identification of the transcriptional targets of three conserved regulatory factors necessary for motor neuron subtype function - Resubmission 01, Hox-dependent mechanisms for establishment and maintenance of motor neuron terminal identity, Vanderbilt Mouse Metabolic Phenotyping Center, The Vanderbilt Institute for Clinical and Translational Research (VICTR) UL1, Molecular Genetics of Synaptic Plasticity, VANTAGE:Consolidation to create the Vanderbilt Technologies for Advanced Genomics, Molecular and Cellular Basis for Digestive Diseases, Caenorhabditis Genetics Center, Cancer Center Support Grant, Discovery and analysis of the C. elegans neuronal gene expression network (CeNGEN), Core Grant in Vision Research, Deciphering terminal selector functions in motor neurons: from worms to humans
OpenAlex ID: W7117320463