Zeb2 recruits HDAC–NuRD to inhibit Notch and controls Schwann cell differentiation and remyelination

Abstract

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.

A histone deacetylase 3–dependent pathway delimits peripheral myelin growth and functional regeneration

“…After peripheral nerve transection in mice, denervated SCs resume proliferation, which is followed by differentiation and remyelination of regenerated axons 11 . We focused our analysis on the regenerating site, defined as a tissue bridge consisting of the SC–axon growth tip proximal to the injury 11,12 . At 6 days post injury (d.p.i.…”

“…SCs from the sciatic nerves of newborn rats (1–2 d old) were isolated as described previously 12 . SCs were grown in DMEM with 10% FBS (Life Technologies), supplemented with 10 ng/ml neuregulin 1 (NRG1 type III; 396-HB-050, R&D Systems) and 5 μM forskolin (Sigma, F6886) plus -glutamine and penicillin–streptomycin; this is hereafter denoted as SC proliferation medium.…”

“…The morphometric measurements were performed in toluidine blue–stained semithin sections. The number of myelinated axons per nerve was analyzed in ultrathin sections using a JEOL 1200 EXII electron microscope, as previously described 12 .…”

“…cDNA was synthesized from 1 μg RNA using iScript Reverse Transcription Supermix (Bio-Rad) according to the manufacturer’s instructions. Real-time qPCR was performed using the StepOnePlus Real-time PCR System (Applied Biosystems) with quantitative SYBR green PCR mix (Bio-Rad, 170-8880), as previously described 12 . PCR primer sequences are available upon request.…”

Toward a better understanding of enteric gliogenesis

“…47 Furthermore, the ZEB2 transcription factor has been shown to be a critical regulator of Schwann cell maturation through HDAC/NuRD-mediated repression of genes that inhibit maturation such as Hey2, Sox2 and Ednrb. 48,49 When focusing on the regulation of Nr2f1 only, a role for its antisense long non-coding RNA A830082k12Rik is also likely. Indeed, based on their co-regulation in Spot Tg/Tg enteric NCCs (Table 1), 39 A830082k12Rik is expected to activate Nr2f1 transcription in cis as described previously for several similar cases.…”