Abstract
Oligodendrocytes are the myelinating glial cells of the central nervous system. In the course of brain development, oligodendrocyte precursor cells migrate, scan the environment and differentiate into mature oligodendrocytes with multiple cellular processes which recognize and ensheath neuronal axons. During differentiation, oligodendrocytes undergo dramatic morphological changes requiring cytoskeletal rearrangements which need to be tightly regulated. The non-receptor tyrosine kinase Fyn plays a central role in oligodendrocyte differentiation and myelination. In order to improve our understanding of the role of oligodendroglial Fyn kinase, we have identified Fyn targets in these cells. Purification and mass-spectrometric analysis of tyrosine-phosphorylated proteins in response to overexpressed active Fyn in the oligodendrocyte precursor cell line Oli-neu, yielded the adaptor molecule p130Cas. We analyzed the function of this Fyn target in oligodendroglial cells and observed that reduction of p130Cas levels by siRNA affects process outgrowth, the thickness of cellular processes and migration behavior of Oli-neu cells. Furthermore, long term p130Cas reduction results in decreased cell numbers as a result of increased apoptosis in cultured primary oligodendrocytes. Our data contribute to understanding the molecular events taking place during oligodendrocyte migration and morphological differentiation and have implications for myelin formation.
Highlights
Oligodendrocytes play a key role in central nervous system (CNS) homeostasis
oligodendrocyte precursor cells (OPCs) migrate through the developing CNS and appear to scan the environment for appropriate axonal targets which are recognized and myelinated if certain prerequisites are met [30,31]
A number of signals have been identified which seem to determine the movement of OPCs and the place, timing and rate of myelin formation, a detailed understanding of these mechanisms is still lacking
Summary
Oligodendrocytes play a key role in central nervous system (CNS) homeostasis. They myelinate neuronal axons and thereby facilitate saltatory conduction of action potentials and provide trophic support for neurons [1]. During CNS development, oligodendrocyte precursor cells (OPCs) migrate from the subventricular zone towards the white matter where they differentiate into myelin-forming oligodendrocytes. This maturation process is accompanied by increasing complexity of cellular process branching as well as an increased expression of several myelin genes [2]. The Src family non-receptor tyrosine kinase Fyn is a key molecule in the oligodendroglial differentiation and myelination process integrating neuronal signals into oligodendrocyte responses [4] and loss of Fyn activity results in hypomyelination in the CNS [5]. Our results demonstrate that oligodendroglial p130Cas contributes to the Fyn signalling pathway and affects morphological changes important for oligodendrocyte differentiation and the myelination process
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