Investigating the Role of Nephronectin in Establishing Retinotectal Circuit Specificity

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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 α8β1 (Itgα8β1). 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 αRGC axons within the upper SGS, and 4) alpha retinal ganglion cells (αRGCs) express Itgα8β1 during development, consistent with Itgα8β1 acting as the receptor for Npnt on αRGCs. Taken altogether, I hypothesize that Npnt instructs αRGC axons to laminate within the lower SGS through binding Itgα8β1 on αRGCs, thereby conferring synaptic specificity of αRGCs 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 αRGCs by focusing on its interactions with Itgα8β1. In Aim 2, I will determine how Npnt affects αRGC 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 αRGCs to wide-field neurons and will shed light on the function of Npnt in the mammalian nervous system.