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bioRxiv · 10.64898/2026.05.13.725001

Active repression of muscle fate preserves neural lineage identity during cerebellum development

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

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.

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Shaikh, N. M., Thulabandu, V., Inoue, A., Pare, J., Norrie, J., Zhang, Q., Xu, B., Cao, X.. 2026-05-15. Active repression of muscle fate preserves neural lineage identity during cerebellum development. https://doi.org/10.64898/2026.05.13.725001

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