Nuclear proteome reveals microtubule-associated protein regulating fate and disease

Cellular differentiation and morphogenesis require the coordination between cytoskeletal remodeling and transcriptional programs, raising the question of how cytoskeletal information is conveyed to the nucleus. Here, we profile the nuclear and cytosolic proteome of human and murine neural stem cells (NSCs) and uncover abundant cytoskeletal proteins in the nucleus, including the microtubule-associated protein 1B (MAP1B), implicated in disease. We find that MAP1B shuttles to the nucleus where it interacts with the BRG1-containing chromatin remodeling complex. MAP1B's nuclear enrichment promotes NSC fate, as opposed to its cytosolic function promoting neuronal differentiation. In vivo, increasing the nuclear/cytosol ratio disrupts neuronal positioning, reminiscent of patients with MAP1B mutations. Mutant human brain organoids show aberrant MAP1B nuclear enrichment, enhanced BRG1 chromatin binding, and neuronal ectopia formation. Our study uncovers a nuclear pool of cytoskeleton-associated proteins, revealing their role in fate regulation during brain development and reshaping our understanding of neurodevelopmental disease etiology.