SERTM2: a neuroactive player in the world of micropeptides

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Long noncoding RNAs (lncRNAs) are increasingly recognized for roles beyond basic transcription regulation.
• Some lncRNAs possess unannotated open reading frames, suggesting potential for protein-coding capacity.
• Motor neuron function is critical for movement, and its dysregulation underlies various neurological disorders.

Purpose of the Study:

• To investigate the functional role of the lncMN3 long noncoding RNA in motor neurons.
• To characterize the protein product derived from lncMN3 and its physiological impact.
• To elucidate the molecular mechanisms underlying lncMN3-derived peptide function in neuronal excitability.

Main Methods:

• Analysis of lncMN3 expression in motor neurons.
• Generation of custom antibodies to detect the lncMN3-derived micropeptide, SERTM2.
• In vitro differentiation of mouse embryonic stem cells into motor neurons for patch-clamp electrophysiology.
• Creation and characterization of SERTM2 knockout motor neurons.
• In vivo assessment of motor function using treadmill tests.
• Identification of interacting proteins using biochemical assays.

Main Results:

• Demonstrated production of the type I transmembrane micropeptide SERTM2 from lncMN3.
• SERTM2 depletion in motor neurons led to altered resting membrane potential and reduced excitability.
• Absence of SERTM2 impaired motor performance in vivo.
• Identified TASK1, a potassium channel, as a direct interactor of SERTM2.

Conclusions:

• lncMN3 encodes the micropeptide SERTM2, which plays a significant role in motor neuron physiology.
• SERTM2 influences neuronal excitability by interacting with the TASK1 potassium channel.
• This study highlights a novel class of functional micropeptides derived from lncRNAs with implications for neuronal function and disease.