biostudies-otherUnknownNational Health Research Institutes Academia SinicaNational Science and Technology CouncilHomo sapiens (human)Mus musculus (mouse)https://www.ebi.ac.uk/biostudies/studies/S-BSST1750biostudies-otherNHRI-EX113-11330NI113-2326-B-001-001AS-GCP-113-L02 & AS-BRPT-113-01falseSertm2 is a Conserved Micropeptide that Modulates GDNF-mediated Motor Neuron Subtype SpecificationSmall open reading frame-encoded micropeptides within long non-coding RNAs (lncRNAs) are often overlooked due to their small size and low abundance. However, emerging evidence links these micropeptides to various biological pathways, though their roles in neural development and neurodegeneration remain unclear. Here, we investigate the function of murine micropeptide Sertm2, encoded by the lncRNA A730046J19Rik, during spinal motor neuron (MN) development. Sertm2 is predicted to be a conserved transmembrane protein found in both murine and human and subcellular analysis revealed that Sertm2 is enriched in the cytoplasm and neurites. By generating insert C terminal Flag tag of Sertm2 in the A730046J19Rik locus, we demonstrate that Sertm2 micropeptide is localized the spinal MNs. In Sertm2 knockout mice, GDNF signaling-induced Etv4+ motor pool is impaired with its motor nerve arborization defects, culminating with impaired motor coordination and muscle weakness. Similarly, human SERTM2 knockout iPSC-derived MNs also lead to a reduction of ETV4+ motor pools, highlighting that Sertm2 is a novel, evolutionarily-conserved micropeptide essential for maintaining GDNF induced MN subtype identity. 2025-05-31T00:00:00Z2024-12-09T11:28:26.656Z2024-12-09T11:28:26.656ZS-BSST1750