Cell adhesion molecules of the Ig family (L1 ,NCAM) play important roles in axonal growth throughout the nervous system, and have potentially novel functions in axon targeting, dendrite development, and synapse formation. These responses are regulated by multiple attractive and repulsive guidance cues (extracellular matrix, Ephrins, Semaphorins). We will investigate the hypothesis that cell adhesion molecules are necessary for neurons to respond to multiple regulatory cues important to migration, dendritic growth and axon specificity by elucidating their molecular and cellular mechanisms. L1 and the 140 kD isoform of NCAM activate MAPK signaling pathways governed by distinct Src family kinases (Src, Fyn) and RhoGTPases (Rac, Rho).
In Aim 1, we will investigate the molecular mechanism of L1 and NCAM 140-induced growth by identifying effectors of Rac and Rho signaling that regulate axon growth and actin dynamics in growth cones.
In Aim 2 we will study the regulation of guidance in vivo by analyzing the retinocollicular projection of L1 knock-out mice and the interactions of L1 with repulsive Ephrin/Eph guidance cues.
In Aim 3 we will extend our studies of L1 function to regulation of dendrite growth and migration of cortical pyramidal cells by time lapse videomicroscopy of fluorescently labeled neurons in L1 null mutants.
In Aim 4 we will explore a potential role for the 180 kD NCAM isoform in synapse development by identifying proteins that bind uniquely to the cytoplasmic domain of NCAM180 not found in NCAM 140 using yeast two hybrid cloning. We will determine if NCAM 140 induces axon growth by Fyn-mediated endocytosis, whereas the cytoplasmic sequence of NCAM 180 prevents endocytosis and allows synapse formation. L1 is the target gene for the X-linked mental retardation and hydrocephalus syndrome termed CRASH, and variant NCAM expression is linked to schizophrenia; thus this research has implications for understanding normal and pathological aspects of nervous system development.
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