Title

Dynamics of Polydendrocyte Proliferation, Differentiation, and Their Interaction with Axons

Date of Completion

January 2012

Keywords

Biology, Cell|Biology, Neurobiology|Health Sciences, Human Development

Degree

Ph.D.

Abstract

Polydendrocytes represent the fourth major glial cell population and constitute 2–9% of all cells in the central nervous system. They are the major proliferative population and their primary function is the production of myelinating oligodendrocytes during development and in the adult. Whether or not polydendrocytes in different brain regions and at different developmental stages are functionally different is not clear. We developed a slice culture system that maintains tissue cytoarchitecture to analyze functional differences between polydendrocytes in different regions. Using transgenic mice and this slice culture system, we discovered region and age-specific differences in the proliferative capacity of polydendrocytes and their rate of oligodendrocyte differentiation in the postnatal rodent brain. ^ We tracked the fate of polydendrocytes in various regions and at different ages using inducible polydendrocyte-specific expression of fluorescent proteins and found that polydendrocytes in white matter regions and at younger postnatal ages generated oligodendrocytes at a faster rate. Furthermore, we found that oligodendrocyte differentiation after polydendrocyte division was faster in white matter regions and could be further enhanced after myelin membrane damage. ^ Consistent with the differences in polydendrocyte differentiation, we found region-dependent differences in the platelet-derived growth factor induced polydendrocyte proliferation. Using transplant and isolated explant cultures we further demonstrated that the differential proliferative response was due to cell-intrinsic mechanisms suggesting that polydendrocytes from different regions may have unique intracellular mechanisms that influence their proliferative capacity. ^ In addition to their progenitor role, polydendrocytes receive synaptic input from neurons and interact closely with growing axons. We used the somatosensory barrel cortex to analyze interactions between growing axons and polydendrocytes along with the effects of axonal activity on polydendrocyte proliferation and differentiation. We found that polydendrocytes did not influence barrel formation however neuronal activity changed the temporal dynamics of oligodendrocyte differentiation. ^ This thesis provides a substantial amount of evidence suggesting that polydendrocytes in different brain regions and at different developmental stages are functionally diverse. These data suggest that these differences might influence the ability of polydendrocytes to respond to environmental changes during normal development, after brain injury, and in demyelinating diseases. ^