Sertm2 is a conserved micropeptide that promotes GDNF-mediated motor neuron subtype specification

Area of Science:

• Molecular Biology
• Neuroscience
• Genetics

Background:

• Small open-reading frame-encoded micropeptides within long noncoding RNAs (lncRNAs) are often overlooked.
• Their roles in neural development and neurodegeneration are not well understood.
• Emerging evidence suggests micropeptides participate in various biological pathways.

Purpose of the Study:

• Investigate the function of murine micropeptide Sertm2, encoded by lncRNA A730046J19Rik, in spinal motor neuron development.
• Determine Sertm2's evolutionary conservation and subcellular localization.
• Elucidate Sertm2's role in motor neuron subtype specification and motor function.

Main Methods:

• Subcellular localization analysis of Sertm2.
• Generation of C-terminally Flag-tagged Sertm2 expressed from the A730046J19Rik locus in mice.
• Generation and analysis of Sertm2 knockout mice and human induced pluripotent stem cell (iPSC)-derived motor neurons.

Main Results:

• Sertm2 is a conserved transmembrane protein enriched in the cytoplasm and neurites of spinal motor neurons.
• Sertm2 knockout mice exhibit impaired GDNF signaling-induced Etv4+ motor pools, motor nerve arborization defects, and motor deficits.
• Human SERTM2 knockout iPSC-derived motor neurons also show reduced ETV4+ motor pools.

Conclusions:

• Sertm2 is a novel, evolutionarily conserved micropeptide crucial for spinal motor neuron development.
• Sertm2 plays a critical role in maintaining GDNF-induced motor neuron subtype identity.
• Defects in Sertm2 function lead to motor coordination and muscle weakness, suggesting its importance in preventing neurodegenerative conditions.