Molecular Mechanisms of Glial Progenitor Cell Differentiation

成熟的少突胶质细胞形成髓鞘，使轴突绝缘，并允许电信号的快速传导。PI和其他研究人员最近的活体研究表明，少突胶质前体(未成熟)细胞不会全部分化为成熟的少突胶质细胞，但其中相当数量的细胞持续存在于成人的大脑和脊髓中。祖细胞和分化的少突胶质细胞之间有广泛的细胞接触，表明未成熟细胞和成熟细胞之间存在活跃的信号转导。目前尚不清楚一些祖细胞如何被刺激分化为成熟的髓鞘形成的少突胶质细胞，而同一区域的其他祖细胞仍未分化。这项研究的目的是研究局部接触依赖的信号是否诱导少突胶质细胞分化，同时触发抑制相邻祖细胞分化的信号。将检验以下假设：1)增加祖细胞密度和接触抑制细胞间Notch信号；2)Notch活性抑制Nkx2.2的转录激活，从而抑制OL分化；3)Nkx2.2促进OL分化并激活Jagged1基因的转录，进而激活邻近祖细胞上的Notch1并抑制其分化，从而抵消密度和接触依赖性的分化刺激。所提出的以少突胶质细胞系统为模型的研究将解决发育生物学中的基本问题，即如何调节未成熟细胞类型的分化和维持。同时，还将为一名研究生和两名本科生提供培训机会。此外，这个项目每年将通过国际宣讲会的大型讲座影响400多名学生，其中包括少数族裔学生。该协会还通过一年一度的全大学范围的促进妇女参与科学的计划，参加针对中学女孩的外展活动。

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.