Loss of prohibitin 2 in Schwann cells dysregulates key transcription factors controlling developmental myelination

Schwann cells are critical for the proper development and function of the peripheral nervous system (PNS), where they form a collaborative relationship with axons. Past studies highlighted that a pair of proteins called the prohibitins play major roles in Schwann cell biology. Prohibitins are ubiquitously expressed and versatile proteins. We have previously shown that while prohibitins play a crucial role in Schwann cell mitochondria for long‐term myelin maintenance and axon health, they may also be present at the Schwann cell‐axon interface during development. Here, we expand on this, showing that drug‐mediated modulation of prohibitins in vitro disrupts myelination and confirming that Schwann cell‐specific ablation of prohibitin 2 (Phb2) in vivo results in severe defects in radial sorting and myelination. We show in vivo that Phb2‐null Schwann cells cannot effectively proliferate and the transcription factors EGR2 (KROX20), POU3F1 (OCT6), and POU3F2 (BRN2), necessary for proper Schwann cell maturation, are dysregulated. Schwann cell‐specific deletion of Jun, a transcription factor associated with negative regulation of myelination, confers partial rescue of the developmental defect seen in mice lacking Schwann cell Phb2. Finally, we identify a pool of candidate PHB2 interactors that change their interaction with PHB2 depending on neuronal signals, and thus are potential mediators of PHB2‐associated developmental defects. This work develops our understanding of Schwann cell biology, revealing that Phb2 may modulate the timely expression of transcription factors necessary for proper PNS development, and proposing candidates that may play a role in PHB2‐mediated integration of axon signals in the Schwann cell. Main Points Loss of Schwann cell (SC) PHB2 causes severe radial sorting and myelination defects. PHB2‐null SCs exhibit poor proliferation and transcription factor dysregulation. PHB2 may play a role in formation of SC‐axon contacts and cytoskeletal remodeling required for radial sorting.