Integrin-Linked Kinase (ILK) Deletion Disrupts Oligodendrocyte Development by Altering Cell Cycle

Abstract

During development, oligodendrocytes are initially specified, after which oligodendrocyte precursor cells (OPCs) migrate and proliferate before differentiating into myelinating cells. Lineage-specific programming of oligodendrocytes results from sensing environmental cues through membrane-bound receptors and related intracellular signaling molecules. Integrin-linked kinase (ILK) is an important protein that is expressed at the inner margins of the plasma membrane and can mediate some of these signals. The current studies demonstrate that ILK deletion reduces the proliferation and differentiation of OPCs in the developing CNS. There was a significant decrease in the number of OPCs and mature oligodendrocytes throughout postnatal development in Olig1Cre^+/− × ILK^fl/fl mice. These changes were accompanied by reduced numbers of myelinated axons. Key proteins involved in cell cycle regulation were dysregulated. Cyclin D1/D3 and cyclin-dependent kinase 2/4 (cdc2/cdc4) were downregulated and the cell cycle inhibitor protein p27 Kip1 was upregulated. Therefore, ILK deletion impaired the developmental profile, proliferation, and differentiation of OPCs by altering the expression of regulatory cytoplasmic and nuclear factors. <b>SIGNIFICANCE STATEMENT</b> Integrin-linked kinase (ILK) is a scaffolding protein involved in integrating signals from the extracellular environment and communicating those signals to downstream effectors within cells. It has been proposed to regulate aspects of oligodendrocyte process extension and thereby myelination. However, the current studies demonstrate that it has an earlier impact on cells in this lineage. Knocking down ILK in Olig1-Cre-expressing cells reduces the pool of oligodendrocyte progenitor cells (OPCs). This smaller pool of OPCs results from altered cell cycle and reduced cell proliferation. These cells myelinate fewer axons than in wild-type mice and, in corpus callosum, the myelin is thinner than in controls. Interestingly, the smaller pool of spinal cord oligodendrocytes generates myelin that is of normal thickness.