Zeb2 Recruits HDAC-NuRD to Inhibit Notch and Controls Schwann Cell Differentiation and Remyelination

The mechanisms that coordinate and balance a complex network of opposing regulators to control Schwann cell (SC) differentiation remain elusive. Here we demonstrate that zinc-finger E-box binding-homeobox 2 (Zeb2/Sip1) transcription factor is a critical intrinsic timer that controls the onset of Schwann cell (SC) differentiation by recruiting HDAC1/2-NuRD co-repressor complexes. Zeb2 deletion arrests SCs at an undifferentiated state during peripheral nerve development and inhibits remyelination after injury. Zeb2 antagonizes inhibitory effectors including Notch and Sox2. Importantly, genome-wide transcriptome analysis reveals a Zeb2 target gene, encoding the Notch effector Hey2, as a potent inhibitor for SC differentiation. Strikingly, a genetic Zeb2 variant, which is associated with Mowat-Wilson syndrome, disrupts the interaction with HDAC1/2-NuRD and abolishes Zeb2 activity for SC differentiation. Therefore, Zeb2 controls SC maturation by recruiting HDAC1/2-NuRD complexes and inhibiting a novel Notch-Hey2 signaling axis, pointing to the critical role of HDAC1/2-NuRD activity in peripheral neuropathies caused by ZEB2 mutations.