Cell Cycle Regulation as Determinant of Brain Size and Histogenesis

以往的研究表明，G1期活性细胞周期蛋白D2（cD 2）在哺乳动物细胞的模式和功能中的作用， 个脑袋出乎意料的细胞周期蛋白，cD 2的丢失导致小的大脑和选择性的丧失。 小脑的中间神经元本项目将研究cD 2在祖细胞调节中的作用， 端脑中间神经元的分裂和发生。试点数据表明，就像美国 小脑颗粒和星状神经元在该模型中，cD 2-/-新皮质和海马含有 含小白蛋白（Pv）的中间神经元明显减少，而钙网膜蛋白（Calretinin）似乎减少， 生长抑素（SSN）亚型。这些小鼠表现出罕见的自发性癫痫发作， 表明cD 2无效对影响GABA能系统药物具有较低的发作阈值。四个假言 将在四个具体目标下进行： 1. cD 2调节大脑皮层中选定神经前体的数量和分化。 实验将确定： a.端脑组织发生过程中的cD 2表达。 B.哪些祖细胞库在无cD 2的脑中受影响最大。 C.这些神经元类型在组织发生期间依赖于cD 2表达。 2.细胞分裂减少会不成比例地影响皮质中间神经元的亚群。的 将鉴定在cD 2-/-中丢失中间神经元亚型，并与投射神经元进行比较 人口。 3. cD 2促进对称的祖细胞分裂，有利于次级增殖群体， 以保持否则会退出的前体循环。研究将使用：用途： a.来自WT、cD 2-/-和cD 1-/-小鼠的切片培养物中的祖细胞的延时成像（在 项目3）。 B.体内和体外cD 2蛋白的急性过度表达和表达不足。 4. cD 2的条件性丢失可用于探测cD 2对皮质与皮质下的贡献， 大脑结构和行为将产生一只CDDP cD 2小鼠，并将其用于将cD 2在小鼠中表达。 MGE或新皮层/海马。 a.将在项目1中审查结构后果。 B.行为研究将在项目4中进行。

Previous studies indicate a role for G1 active cyclin D2 (cD2) in the patterning and function of mammalian brain. Unexpected of a cell cycle protein, loss of cD2 leads to small brains and to selective loss of interneurons in the cerebellum. This project will examine cD2's role in the regulation of progenitor cell divisions and genesis of telencephalic interneurons. Pilot data indicate that, like the striking deficits in cerebellar granule and stellate neurons in this model, cD2-/- neocortex and hippocampus contain significantly fewer parvalbumin (Pv) containing interneurons while seeming to spare calretinin (CLR) and somatostatin (SSN) subtypes. These mice display rare spontaneous seizures and studies with Project 4 indicate cD2 nulls have a lower seizure threshold to drugs affecting GABAergic systems. Four hypotheses will be pursued in four Specific Aims: 1. cD2 regulates the number and differentiation of selected neural precursors in cerebral cortex. Experiments will determine: a. cD2 expression mapped during histogenesis of the telencephalon. b. which progenitor pools are most affected in cD2 null brain. c. which neuronal types are dependent upon cD2 expression during histogenesis. 2. Reduced cell division can affect subpopulations of cortical interneurons disproportionately. The interneuron subtypes lost in cD2-/- will be identified and compared with projection neuron populations. 3. cD2 promotes symmetric progenitor divisions, favoring the secondary proliferative population, to keep precursors in cycle that would otherwise exit. Studies will use: a. time-lapse imaging of progenitors in slice cultures from WT, cD2-/- and cD1-/- mice (in collaboration with Project 3). b. acute over- and under-expression of cD2 protein in vivo and in vitro. 4. Conditional loss of cD2 can be used to probe cortical vs. subcortical contributions of cD2 to brain structure and behavior. A floxP cD2 mouse will be produced and used to inactivate cD2 in MGE or neocortex/hippocampus. a. structural consequences will be examined in Project 1. b. behavioral studies will be pursued in Project 4.