Molecular Mechanisms of Glial Progenitor Cell Differentiation

胶质祖细胞分化的分子机制

• 批准号: 0316893
• 负责人: Akiko Nishiyama
• 金额: $ 36万
• 依托单位: University of Connecticut
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-15 至 2007-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0316893&HistoricalAwards=false
• 关键词: Molecular; Mechanisms; Glial; Progenitor; Cell

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.

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体内研究表明，少突胶质细胞祖细胞（未成熟）细胞并不都分化成成熟的少突胶质细胞，但它们中的相当数量仍然存在于成年大脑和脊髓中。 在祖细胞和分化的少突胶质细胞之间存在广泛的细胞接触，表明未成熟细胞和成熟细胞之间存在活跃的信号传导。 目前还不清楚一些祖细胞是如何被刺激分化成成熟的髓鞘形成少突胶质细胞，而在同一地区的其他人仍然未分化。 本研究的目的是探讨局部接触依赖性信号是否诱导少突胶质细胞分化，同时触发信号抑制邻近祖细胞分化。 将测试以下假设：1）增加的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Jagged 1基因的转录，这反过来激活相邻祖细胞上的Notch 1并抑制它们的分化，从而抵消了密度和接触依赖性的分化刺激。 使用少突胶质细胞系统作为模型的拟议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，该项目每年将通过PI的大型讲座影响400多名学生，包括少数民族学生。 PI还通过一项年度大学范围的促进妇女参与科学的方案，参与针对中学女生的外联活动。