Sertm2 is a conserved micropeptide that promotes GDNF-mediated motor neuron subtype specification
Dr. Chen, Jun-An - April, 2025
Small open-reading frame-encoded micropeptides within long noncoding 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 mouse and human, with subcellular analysis revealing that it is enriched in the cytoplasm and neurites. By generating C terminally Flag-tagged Sertm2 and expressing it from the A730046J19Rik locus, we demonstrate that the Sertm2 micropeptide localizes in spinal MNs in mice. The GDNF signaling-induced Etv4+ motor pool is impaired in Sertm2 knockout mice, which display motor nerve arborization defects that culminate in impaired motor coordination and muscle weakness. Similarly, human SERTM2 knockout iPSC-derived MNs also display reduced ETV4+ motor pools, highlighting that Sertm2 is a novel, evolutionarily conserved micropeptide essential for maintaining GDNF-induced MN subtype identity.
Tiny Peptide, Big Impact: A Hidden Regulator of Motor Neuron Development
A study led by Dr. Jun-An Chen’s group at the Institute of Molecular Biology (IMB) uncovered a surprising discovery—a misannotated long noncoding RNA (lncRNA) that actually encodes a micropeptide named Sertm2. This finding challenges the traditional view of noncoding RNAs and highlights the critical role of micropeptides in spinal motor neuron development.