EXTRACELLULAR MATRIX IN SYNAPSE FORMATION IN THE CNS

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DESCRIPTION (Verbatim from applicant's abstract): Laminins are biologically-active molecules which function as cell adhesion molecules, regulate various aspects of development, and serve to stabilize complex anatomical structures. They are large extracellular matrix molecules that are composed of three subunit chains, designated alpha, beta and gamma. Five alpha, three beta and three gamma chains have been identified. 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) map to the site of the gamma3 gene. Laminins are widely expressed in the CNS; we have shown that in the human, rat, bovine and mouse retina, four laminin chains (alpha3, alpha4, beta2 and gamma3) are found in the interphotoreceptor matrix and in the matrix of the outer plexiform layer (OPL). These chains are likely to form two heterotrimers, laminin-13 and laminin-14. The retinal laminin chains 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 chains, beta2, results in the production of dysmorphic photoreceptors with aberrant function. Specifically, photoreceptor outer segments are reduced in length; the photoreceptor terminal in the OPL are disrupted: finally, in ERGs, the amplitude of the b-wave is drastically diminished, suggesting that transmission between photoreceptors and bipolar cells is disrupted by loss of laminin beta2 chain function. We hypothesize that laminins-13 and -14 are critical mediators of synapse formation and stabilization between photoreceptors and second order cells in the OPL. Furthermore, we hypothesize that laminins-13 and -14 form unique substrates with which photoreceptor axons interact and to which they adhere in order to elaborate synapses, and, finally, that the molecular structure of the synapse is dependent on the interactions between these laminins and their receptors. We propose to test several aspects of this hypothesis. We will ask several specific questions: (1) what the spatial and temporal expression of laminin-binding molecules is in the OPL; (2) whether these molecules mediate the binding of cells to OPL laminins; and (3) what anatomical and physiological alterations in the photoreceptor synapse result from laminin gene disruptions.