Setd5 Coordinates Motor Neuron Development and Locomotor Function

Notably, late-stage Setd5 deletion with Isl1-Cre revealed a cell-context-specific requirement for Setd5 in maintaining Foxp1 expression selectively within thoracic preganglionic motor column neurons. These developmental defects resulted in aberrant axonogenesis, impaired neuromuscular junction formation, and severe locomotor phenotypes, including reduced spontaneous movement, poor motor coordination, and abnormal gait.

Transcriptomic profiling of Setd5-deficient pMNs identified downregulation of cell-cycle genes and upregulation of neural differentiation programs, mechanistically linking Setd5 loss to the observed cellular phenotypes. Heterozygous animals displayed intermediate defects, confirming a dose-sensitive requirement. Collectively, our findings establish Setd5 as a critical epigenetic coordinator of MN proliferation and differentiation, and provide a mechanistic framework for understanding the motor abnormalities associated with SETD5 syndrome.