Role of Periaxin dimerization in peripheral myelination

Abstract

In the peripheral nervous system (PNS), Schwann cells ensheathe and myelinate axons to promote saltatory conduction of nerve impulses. Close interactions between Schwann cells and axons, and Schwann cells and the basal lamina are essential for the regulation of Schwann cell development and function. Myelinating Schwann cells are highly polarized radially and longitudinally for specifying distinct domains in the axon, which is required for fast action potential propagation. In addition, the Schwann cell cytoplasm is organized into discrete compartments, called Cajal bands, which contain different dystrophin-glycoprotein complexes that are believed to segregate the Schwann cell plasma membrane into appositions between the outer surface of the myelin sheath and the cytoplasmic face of the Schwann cell plasma membrane.

Periaxin is expressed in myelinating Schwann cells, and homodimerizes at its PDZ domain to form a transmembrane complex with dystrophin-related protein 2 (DRP2) and dystroglycan. This PDG complex is concentrated at the appositions, and is essential for myelin sheath maintenance and stability in the mature PNS. In mice lacking Periaxin, an intact myelin sheath is formed but subsequently becomes unstable. Periaxin-null Schwann cells are also shorter, which has been proposed to result in a reduction in nerve conduction velocity.

This thesis is a study of how Periaxin PDZ domain dimerization contributes to the regulation of PDG complex stability, apposition maintenance, Schwann cell internodal distance and myelin stability. I have studied the function of Periaxin by generating a conditional mutant mouse that lacks the PDZ domain, which is predicted to abrogate dimerization. In these mutants, DRP2 is severely depleted and appositions containing DRP2 fail to form. Mutant Schwann cells also have disrupted Cajal bands and shorter internodal lengths. In the mature peripheral nerves, mutant mice display a peripheral neuropathy characterized by hypermyelination with focally folded myelin. Nerve conduction velocity, motor coordination and sensory function were also studied in these mutant mice. Taken together, these data suggest that dimerization of the Periaxin PDZ domain is required for the stabilization of the PDG and appositions, and regulation of Schwann cell elongation and myelin maintenance.

By analyzing a tamoxifen-inducible conditional mouse lacking Periaxin’s PDZ domain in mature myelinating Schwann cells, this work also shows that Periaxin dimerization is essential for maintaining Schwann cell compartmentalization and myelin stability in adult nerves.

Finally, studies of single amino acid mutations of the Periaxin PDZ reveal that subtle changes in the structure of the PDZ domain can abrogate dimerization,and a possible mechanism for PDZ-PDZ homodimerization of Periaxin is proposed.