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， 皮质脊髓束和痉挛性下肢轻瘫是由 基因编码L1，神经细胞粘附分子。 L1是神经元 一种通过嗜同性L1-L1指导轴突生长的跨膜糖蛋白 在长时程增强和学习中起作用。 细胞外IG和FN III结构域介导嗜同性结合， 胞质结构域介导信号转导。 使用基因敲除小鼠， 研究者已经确定L1通过一个信号传导轴突生长， 酪氨酸激酶src家族成员（pp 60 c-src和p59 fyn）， 它绑定。 假设L1在神经生长锥中的粘附相互作用 激活非受体src调节的细胞内信号通路 在正常轴突生长或导向中达到顶点的酪氨酸激酶家族。 L1基因中自然发生的突变可能干扰src激酶 信号传导，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， 在整个L1中，尽管不知道这些突变如何破坏L1 功能 L1正常激活的信号通路的信息 将有助于理解轴突的基本机制， 生长和指导中枢神经系统的发展，并进入分子机制， X染色体连锁的精神发育迟滞 具体目标是： 1. 为了表征L1与src家族激酶的正常相互作用， 小鼠脑和神经元培养物。 2. 要确定是否选定 细胞质中的L1突变， 胞外结构域破坏L1-src/fyn相互作用。 3. 到 确定L1突变是否会导致神经突生长缺陷， cultures. 4. 为了确定是否存在主要轴突的体内缺陷， 道 （皮质脊髓束，胼胝体）在小鼠与L1基因 击倒， L1/src、L1/fyn和L1/CAM双敲除。

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.