The role of Bcl-2 proteins in cell fate determination during neurogenesis.

神经发生是神经系统发育的关键。它是神经祖细胞如何产生形成大脑的神经元的过程。为了形成神经元，神经祖细胞必须从分裂产生更多祖细胞（增殖细胞）转变为分裂产生非增殖细胞，成为神经元（分化细胞）。神经发生涉及不同细胞信号通路之间的复杂相互作用，包括细胞周期机制、代谢和分化。这些通路如何相互作用以及细胞内的什么结构调节它们的及时协调正在积极研究中。研究的重点是线粒体的作用，细胞内的细胞器，产生能量的细胞功能。在神经发生过程中，观察到线粒体形状和大小的变化。线粒体大小和形状的变化是由相反的过程调节的：分裂和融合。线粒体分裂导致线粒体收缩并分裂成2个较小的线粒体，而融合则连接两个或更多个线粒体。最近，神经祖细胞中分裂和融合水平的差异被证明可以决定祖细胞是成为神经元还是保持祖细胞。线粒体分裂和融合的机制已经被理解;然而，调节分裂和融合并决定细胞是否成为神经元或祖细胞（细胞命运）的上游信号尚不清楚。 我的研究项目集中在确定一个家族的蛋白质，调节神经发生过程中的神经祖细胞的生存的作用。该蛋白质家族已被证明在细胞中除了调节细胞存活外还具有多种功能。我们正在研究家族成员Mcl-1，它在线粒体上表达。为了理解Mcl-1对线粒体的作用，我们产生了Mcl-1基因不表达（敲除）的小鼠（Mcl-1敲除= MKO）。我们的研究表明，在神经发生过程中，MKO神经祖细胞的线粒体是同窝对照小鼠神经祖细胞的两倍。MKO神经祖细胞中线粒体数量的增加表明线粒体分裂的速率更高。我们接下来检查了MKO神经祖细胞中线粒体分裂水平的增加是否对神经发生期间的细胞命运决定（增殖分裂vs分化分裂）产生影响。我们的研究结果显示，与对照组相比，MKO脑中形成了更多的神经元（分化分裂）。这些发现表明，Mcl-1抑制线粒体分裂，以调节神经发生过程中的细胞命运。这个研究项目是为了确定这是如何工作的机制。

Neurogenesis is key to development of the nervous system. It is the process of how neural progenitor cells produce neurons that form the brain. For neurons to be formed, neural progenitor cells must switch from dividing to produce more progenitor cells (proliferating cells) to dividing to produce non-proliferating cells that become neurons (differentiating cells). Neurogenesis involves a complex interaction between different cell signaling pathways including the cell cycle machinery, metabolism and differentiation. How these pathways interact and what structures within cells regulate their timely coordination is under active investigation. Research is focusing on the role of mitochondria, organelles within cells that generate energy for the cell to function. During neurogenesis, changes in mitochondrial shape and size are observed. Changes in mitochondrial size and shape are regulated by opposing processes: fission and fusion. Mitochondrial fission results in mitochondria constricting and dividing into 2 smaller mitochondria while fusion joins two or more mitochondria. Recently differences in fission and fusion levels in neural progenitor cells were shown to determine whether a progenitor cell becomes a neuron or remains a progenitor cell. Mechanisms of mitochondrial fission and fusion are understood; however, the upstream signals that regulate fission and fusion and determine whether a cell becomes a neuron or progenitor cell (cell fate) is not known.       My research program focusses on identifying the roles of a family of proteins that regulate survival of neural progenitor cells during neurogenesis. This protein family has been shown to have diverse functions in the cell besides regulating cell survival. We are examining family member Mcl-1, which is expressed on mitochondria. To understand Mcl-1's role on mitochondria, we generated mice in which the Mcl-1 gene is not expressed (knocked out) (Mcl-1 knockout = MKO). Our research shows that during neurogenesis, MKO neural progenitor cells have two-fold more mitochondria than neural progenitors from littermate control mice. Increased numbers of mitochondria in MKO neural progenitor cells suggests higher rates of mitochondrial fission. We next examined whether increased levels of mitochondrial fission in MKO neural progenitors had an impact on cell fate determination (proliferative divisions vs differentiative divisions) during neurogenesis. Our results showed more neurons formed (differentiative divisions) in MKO brains compared to control brains. These findings suggest that Mcl-1 inhibits mitochondrial fission to regulate cell fate during neurogenesis. This research project is to identify the mechanism how this works.