Investigating the Role of Nephronectin in Establishing Retinotectal Circuit Specificity

University Of California, San Francisco, San Francisco CA

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Abstract

PROJECT ABSTRACT An impressive feature of the nervous system is the specificity of its synaptic connections. Within the brain, a single neuron is able to correctly identify and synapse onto its proper signaling partner over billions of other neurons. How this degree of specificity is achieved is the subject of intense research. While great progress has been made in identifying molecules that participate in long-range axon guidance and topographic positioning, little is known in what molecules guide axons into their proper lamina once they reach their destined target region. Through screening for extracellular matrix proteins differentially expressed by wide-field neurons in the retinorecipient stratum griseum superficiale (SGS) of the superior colliculus (SC), I identified nephronectin (Npnt) as a candidate for mediating synaptic specificity in retinotectal circuits. Npnt belongs to the EGF-like superfamily of extracellular matrix glycoproteins and has been biochemically well-characterized to bind strongly and specifically to integrin ?8?1 (Itg?8?1). My preliminary data show that 1) Npnt is exclusively expressed by wide-field neurons of the SC, whose cell bodies define a lamina within the lower SGS; 2) Npnt deposits on the somata and proximal dendrites of wide- field neurons, 3) loss of Npnt in the SGS results in ectopic ?RGC axons within the upper SGS, and 4) alpha retinal ganglion cells (?RGCs) express Itg?8?1 during development, consistent with Itg?8?1 acting as the receptor for Npnt on ?RGCs. Taken altogether, I hypothesize that Npnt instructs ?RGC axons to laminate within the lower SGS through binding Itg?8?1 on ?RGCs, thereby conferring synaptic specificity of ?RGCs onto wide- field neurons. This proposal will address how RGCs form precise connections to their neuronal partners within the SC by studying how Npnt regulates axon laminar targeting and synapse formation. In Aim 1, I will determine how Npnt mediates axon laminar targeting of ?RGCs by focusing on its interactions with Itg?8?1. In Aim 2, I will determine how Npnt affects ?RGC synaptic partner choice within the SC. Completion of the proposed experiments will reveal unique molecular and cellular mechanisms regarding the role of Npnt in specifying neuronal pairing from ?RGCs to wide-field neurons and will shed light on the function of Npnt in the mammalian nervous system.