Shaikh, N. M.; Thulabandu, V.; Inoue, A.; Pare, J.; Norrie, J.; Zhang, Q.; Xu, B.; Cao, X.

Cell fate commitment is commonly thought to entail progressive restriction of developmental potential, enforced by passive, heterochromatin-based silencing of alternative lineage programs. Here we show that maintenance of neural identity during cerebellum development instead requires active repression of a starkly divergent fate by the TEAD-INSM1 transcriptional complex. Loss of TEAD1/2 or INSM1 activates the myogenic master regulator Myod1, resulting in neural cells acquiring transcriptional, structural, and metabolic features of skeletal muscle cells. Deletion of Myod1 fully suppresses neural-to-muscle conversion while partially rescuing neural developmental defects. Our results uncover a latent alternative lineage during neurodevelopment and a surprising role for sequence-specific transcription factors in enforcing lineage boundaries, including those previously thought essentially unbreachable, with implications for understanding aberrant differentiation in disease contexts and cell-type evolution.