MBNL2 dysfunction in outer radial glial cells is associated with disrupted corticogenesis in congenital myotonic dystrophy.

Abstract

Myotonic dystrophy type 1 (DM1) arises from toxic CUG-expanded DMPK transcripts that sequester Muscleblind-like (MBNL) proteins, yet how this molecular lesion perturbs brain development in congenital DM1 (CDM) remains unknown. Here, we identify an unanticipated developmental role for MBNL2 in outer radial glial cells, a progenitor population critical for cortical expansion. We demonstrate that MBNL2 is expressed in these cells both in vivo and in forebrain organoids derived from patient-specific human induced pluripotent stem cells (hiPSCs), rendering them particularly sensitive to MBNL2 titration. Using genome editing to excise the CTG repeats in the DMPK gene, we provide evidence that the expanded trinucleotide tract directly contributes to defective neuronal migration and impaired differentiation of late-born cortical neurons in CDM organoids. These findings redefine MBNL2 as a potential regulator of human corticogenesis and uncover a developmental mechanism by which RNA toxicity drives this severe form of DM1. By revealing a prenatal origin for CDM neuropathology linked to MBNL2 dysfunction, this work opens avenues for therapeutic strategies targeting early developmental windows.