Pinch-mediated signaling controls myelination and remyelination in the peripheral nervous system

ABSTRACT During the development of the peripheral nervous system, Schwann cells rely on intricate interactions among extracellular matrix proteins, integrins, and growth factor signaling pathways to ensure survival, axonal sorting, and the myelination of axons. Central to these interactions is the IPP complex, a heterotrimeric assembly of Pinch (‘particularly interesting new cysteine-histidine-rich’) proteins, integrin-linked kinase (Ilk) and parvins, which serves as a crucial signaling hub linking integrins to diverse cellular pathways. Through Schwann cell-specific conditional gene ablation in mice, we reveal distinct and essential roles for Pinch1 and Pinch2 in Schwann cell function. While Pinch1 is primarily required for proper radial sorting of axons and maturation of Remak bundles, Pinch2 modulates myelin thickness and is crucial for effective remyelination following sciatic nerve injury. Our data suggest that Pinch1-mediated specific modulation of Rho GTPase signaling is essential for sorting of axon bundles, and that Pinch2 likely modulates RhoA to relieve its inhibitory effect on myelination and remyelination. These findings support a dual intrinsic function of the IPP complex regulating active Rho GTPase signaling, shedding light on the molecular mechanisms underlying developmental peripheral nervous system myelination and repair.