Extracellular matrix in synapse formation in the CNS

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DESCRIPTION (provided by applicant): Laminins are biologically active molecules that function as cell adhesion molecules, regulate various aspects of development, and serve to stabilize complex anatomical structures. They are large extracellular matrix molecules which are composed of three subunit chains, designated alpha, beta and gamma. Five alpha, three beta and three gamma chains have been identified. Laminins are widely expressed in the CNS; as are their receptors. Several disorders of the nervous system are linked to laminin genes: some congenital muscular dystrophies involve the alpha2 chain (merosin); the beta2 chain is reduced in Walker-Warburg syndrome; and a complex group of CNS developmental disorders (muscle-brain-eye disease; retinitis pigmentosa with deafness (RP21 with deafness); Walker-Warburg syndrome) maps to the site of the gamma3 gene. Genetic disruptions in some laminin-related genes also result in human disease and in dysmorphogenesis in animal models. We have identified two novel CNS laminins, alpha4beta2gamma3 and alpha5beta2gamma3 (LN 14 & LN 15, respectively); these are found in the interphotoreceptor matrix and in the matrix of the outer plexiform layer (OPL). These laminins appear to play important roles in the morphogenesis of photoreceptors. First, these chains are expressed prior to the onset of rod genesis and persist into adulthood. Second, ablation of the gene encoding one of the beta2 chains results in the production of dysmorphic photoreceptors; specifically, photoreceptor outer segments are reduced in length and the photoreceptor terminals in the OPL are disrupted. Finally the amplitude of the ERG b-wave is drastically diminished suggesting that transmission from photoreceptors to second order cells is disrupted by loss of beta2-containing laminins. We hypothesize that LN 14 and 15 are critical mediators of synapse assembly and stabilization. Furthermore, we hypothesize that LN14 and 15 form unique substrates with which photoreceptor terminals interact. Specifically, we hypothesize that the molecular assembly and structure of the photoreceptor synapse is dependent on the interactions between these laminins and their receptors. We propose to test several aspects of this hypothesis. We will ask two specific questions: 1) What is the functional composition of the laminin complex in the OPL? 2) How does disruption of the laminin complex alter the functional organization of the OPL? With these studies, we will: gain insight into the molecular mechanisms of synaptic assembly in the outer retina; define the role of the ECM in this process; and shed light on the basis of a series of genetic disorders in humans.