L1 SIGNALING IN X-LINKED MENTAL RETARDATION

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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.