Date of Degree

9-2015

Document Type

Dissertation

Degree Name

Ph.D.

Program

Biology

Advisor

Carmen V. Melendez-Vasquez

Subject Categories

Biology

Keywords

ECM; Glia; Mechanotransduction; Myelination; Oligodendrocyte; Schwann Cell

Abstract

Studies from our laboratory have shown that inhibition of non-muscle myosin II (NMII) activity has opposite effects on the formation of myelin by oligodendrocytes (OL), the myelinating glia of the central nervous system (CNS) and Schwann cells (SC), which perform the same function in the peripheral nervous system (PNS). The decrease of NMII activity in SC impairs their ability to establish polarity and myelinate, while its inhibition in OL enhances process branching and increases the amount of myelin formed in vitro an in vivo. A growing number of studies have shown that NMII also plays a role in the ability of cells to sense and respond to the stiffness of the surrounding extracellular matrix (ECM). In the PNS, the ECM consists of a dense SC-secreted basal lamina, which displays significantly higher rigidity than the more loosely organized CNS matrix.

In order to evaluate whether the opposing effects of inhibiting NMII in glial cell differentiation and myelination are partly the result of NMII-mediated sensing of ECM stiffness, we have grown cultures of primary rat OL and SC on variable rigidity polyacrylamide matrices coated with covalently bound ECM proteins. We found that stiffer matrices inhibit OL branching as well as their expression of differentiation markers, and that these effects are correlated with increased NMII activity. SC also respond to changes in ECM stiffness, and those grown on rigid matrices adopt a more polygonal morphology with fewer actin-based protrusions than those grown on soft matrices. Interestingly, and unlike what we have observed in the OL, stimulation of SC differentiation after cAMP treatment is not affected by differences in matrix stiffness alone. However, SC differentiation is potentiated on rigid matrices at high laminin concentration, which are conditions that mimic a mature basal lamina. Taken together, our data indicate that myelinating glial cell differentiation is sensitive to changes in the mechanical properties of the ECM and that in the case of SC, these responses may be modulated by the maturity and composition of their basal lamina.

Included in

Biology Commons

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