L1 SIGNALING IN X-LINKED MENTAL RETARDATION

描述：几种X-连锁精神发育迟滞综合征，包括 脑积水、Masa综合征、胼胝体发育不全和 皮质束和痉挛瘫痪是由基因突变引起的 编码神经细胞黏附分子L1的基因。L1是一种神经元 通过亲和性L1-L1引导轴突生长的跨膜糖蛋白 结合和在长时程增强和学习中的功能。 胞外Ig和Fn III结构域介导亲同性结合，并且 胞质结构域介导信号转导。使用基因敲除小鼠， 研究人员已经证实，L1通过一种信号转导信号传递轴突生长 酪氨酸激酶src家族成员(pp60 c-src和p59 fyn)，至 它把它捆绑在一起。 假设L1在神经元生长锥体中的黏附相互作用 激活非受体src调控的细胞内信号通路 家族酪氨酸激酶，最终导致正常的轴突生长或引导。 自然发生的L1基因突变可能会干扰src激酶 信号，导致L1患者的轴突生长缺陷 疾病情结。 人类L1基因突变图谱显示病变分布 在整个L1中，尽管尚不清楚这些突变是如何破坏L1的 功能。L1正常激活的信号通路信息 将有助于理解轴突的基本机制 中枢神经系统发育中的生长和引导以及探讨 X连锁精神发育迟滞。具体目标是： 1.研究L1与src家族激酶的正常相互作用。 小鼠脑和神经元培养。2.确定是否选中 细胞质和细胞质中的L1突变 胞外结构域破坏L1-src/fyn相互作用。3.至 确定L1突变是否导致神经突起生长缺陷 文化。4.确定主轴突体内是否存在缺陷 大片地区 携带L1基因的小鼠(皮质脊髓束、胼胝体) 淘汰赛， 在L1/src、L1/Fyn和L1/CAM双基因敲除中。

DESCRIPTION: Several X-linked mental retardation syndromes including hydrocephalus, MASA syndrome, agenesis of the corpus callosum and corticopinal tract and spastic paraparesis are caused by mutations in the gene encoding L1, a neural cell adhesion molecule. L1 is a neuronal transmembrane glycoprotein that directs axon growth through homophilic L1-L1 binding and functions in long term potentiation and learning. Extra-cellular Ig and FN III domains mediate homophilic binding, and the cytoplasmic domain mediates signal transduction. Using gene knockout mice, the investigator has established that L1 signals axon growth through a member of the src family of tyrosine kinases (pp60 c-src and p59 fyn), to which it binds. The hypothesis is that adhesive interactions of L1 in neuronal growth cones activate intracellular signaling pathways modulated by non-receptor src family tyrosine kinases that culminate in normal axon growth or guidance. Naturally occuring mutations in the L1 gene may interfere with src kinase signaling, resulting in axonal growth defects in individuals with the L1 disease complex. Mapping of human mutations in the L1 gene has revealed lesions distributed throughout L1, although it is not known how such mutations disrupt L1 function. Information of the signaling pathways activated normally by L1 will help in the understanding of the basic mechanism underlying axonal growth and guidance in CNS development and into the molecular mechanism of X-linked mental retardation. Specific aims are : 1. To characterize the normal interaction of L1 with src family kinases in mouse brain and neuronal cultures. 2. To determine whether selected L1 mutations in the cytoplasmic and extracellular domains disrupt L1-src/fyn interactions. 3. To determine if L1 mutations cause defects in neurite outgrowth in cultures. 4. To determine if there are in vivo defects in major axon tracts (corticospinal tract, corpus callosum) in mice with an L1 gene knockout, and in L1/src, L1/fyn and L1/CAM double knockouts.