Molecular Mechanisms of Glial Progenitor Cell Differentiation

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Mature oligodendrocytes make myelin sheaths that insulate axons and allow for fast conduction of electrical signal. Recent in vivo studies by the PI and other investigators have shown that oligodendrocyte progenitor (immature) cells do not all differentiate into mature oligodendrocytes, but a significant number of them persist in the adult brain and spinal cord. There is extensive cellular contact between the progenitor cells and differentiated oligodendrocytes, indicative of an active signaling between the immature and mature cells. It remains unclear how some progenitor cells are stimulated to differentiate into mature myelin-forming oligodendrocytes while others in the same region remain undifferentiated. The objective of the proposed study is to investigate whether a local contact-dependent signal induces differentiation of oligodendrocytes and simultaneously triggers a signal to inhibit differentiation of neighboring progenitor cells. The following hypotheses will be tested: 1) increased progenitor cell density and contact inhibits the intercellular Notch signal; 2) Notch activity represses transcriptional activation of Nkx2.2, thereby inhibiting OL differentiation; 3) Nkx2.2 promotes OL differentiation and activates transcription of the Jagged1 gene, which in turn, activates Notch1 on neighboring progenitor cells and inhibits their differentiation, thus counteracting the density and contact-dependent stimulus for differentiation. The proposed studies using the oligodendrocyte system as a model will address the fundamental question in developmental biology of how differentiation and maintenance of the immature cell type are regulated. At the same time, there will be training opportunities for a graduate student and two undergraduate students. In addition, this project will impact a diverse group of over 400 students each year, including minority students, through the PI's large lecture class. The PI also participates in outreach activities to girls in middle school, through an annual university-wide program to promote women in science.