MBNL1-dependent alternative splicing of NUMA1 shapes neuronal identity during fibroblast-to-neuron reprogramming

However, the post-transcriptional mechanisms that refine neuronal identity downstream of fate induction remain poorly understood. Here, we identify alternative splicing as a critical regulator of neuronal identity during fibroblast-to-neuron reprogramming.

Knockdown of the RNA-binding protein MBNL1 establishes a distinct reprogramming state (AMmnp) that enhances neuronal maturation and strongly biases induced neurons toward an inhibitory, GABAergic identity, without markedly altering overall conversion efficiency. Transcriptomic analyses revealed coordinated repression of extracellular matrix-associated gene programs together with widespread remodeling of alternative splicing.