Unexpected Kif4a functions in adult regeneration encompass a dual role in neurons and in proliferative repair Schwann cells

Abstract

Contrary to the adult central nervous system (CNS), the peripheral nervous system (PNS) has an intrinsic ability to regenerate that, among others, passes by expressing regeneration-associated genes such as kinesin family members. We here show that Kinesin family motor protein 4a (KIF4A), associated to neurodevelopmental disorders and thought for long to be only embryonically expressed, is highly abundant in axons and Schwann cells of adult rat CNS and rat and human PNS. Moreover, Kif4a is up-regulated in injured PNS neurons, being detected in their nuclei and regrowing axons, consistent with its functions as a chromokinesin and in the axonal transport of e.g. β1-integrin and L1CAM. Interestingly, Kif4a is also highly up-regulated in Schwann cells transdifferentiating into a proliferative repair phenotype at the injured distal nerve stumps. A role for Kif4a in cultured Schwann cells proliferation was confirmed, with Kif4a mRNA expression being ≈6-fold higher in proliferating versus growth-arrested Schwann cells, and Kif4a knockdown impairing Schwann cells proliferation. To our knowledge, this is the first description of KIF4A expression in adult nervous systems, up-regulation in neuroregeneration and pro-neuroregenerative roles, including promoting Schwann cells proliferation. KIF4A dual role in axonal regeneration, through neurons and glia, places as an attractive target for future neuroregeneration therapies.