Abstract
Long noncoding RNAs (lncRNAs) play pivotal roles in modulating gene expression during development and disease. Despite their high expression in the central nervous system (CNS), understanding the precise physiological functions of CNS-associated lncRNAs has been challenging, largely due to the in vitro-centric nature of studies in this field. Here, utilizing mouse embryonic stem cell (ESC)-derived motor neurons (MNs), we identified an unexplored MN-specific lncRNA, Litchi (Long Intergenic RNAs in Chat Intron). By employing an "exon-only" deletion strategy in ESCs and a mouse model, we reveal that Litchi deletion profoundly impacts MN dendritic complexity, axonal growth, and altered action potential patterns. Mechanistically, voltage-gated channels and neurite growth-related genes exhibited heightened sensitivity to Litchi deletion. Our Litchi-knockout mouse model displayed compromised motor behaviors and reduced muscle strength, highlighting Litchi's critical role in motor function. This study unveils an underappreciated function of lncRNAs in orchestrating MN maturation and maintaining robust electrophysiological properties.