Trophic interactions during visual system development

University Of California-Irvine, Irvine CA

Investigators

Linked publications & trials

Abstract

? DESCRIPTION (provided by applicant): Proper development of the nervous system requires the coordinated, timely growth and differentiation of axons and dendrites in order to generate precise neuronal connections and functional neural circuits. The goal of the proposed studies is to further explore molecular and cellular mechanisms of visual circuit formation, particularly those that influence both pre- and postsynaptic neuronal morphology and connectivity during retinotectal wiring. Here, we will test the hypothesis that Down-Syndrome Cell Adhesion Molecule (DSCAM), a gene implicated in a number of developmental disorders, differentially influences early events in the targeting and branching of retinal ganglion cell (RGC) axons as well as in the maturation of their target neurons in the brain, and that this in turn modulates the establishment of functional visual circuits. The proposed studies build on our laboratory's novel and important finding that DSCAM, a molecule implicated in Down Syndrome and in Fragile X, plays a distinct, but key role in both the early development of neuronal morphology and the connectivity of central neurons, particularly of those neurons that receive input from RGCs. Specifically, our studies show that DSCAM limits dendrite growth and influences the directionality and branching of dendritic arbors in optic tectal neurons in a manner that is independent from its regulation of RGC axon branching. These proposed studies utilize real-time imaging of neurons in developing Xenopus laevis embryos, and state-of-the art gain and loss-of-function approaches to manipulate DSCAM expression in single neurons. By inducing both localized and rapid cell-autonomous responses in both retinal and central neurons, we aim to demonstrate that regulated expression of DSCAM shapes both pre- and postsynaptic connectivity in the developing retinotectal system. These studies will also examine mechanisms by which DSCAM collaborates with netrin 1 to establish the patterning of tectal neuron dendritic arbors. Furthermore, our studies will explore the hypothesis that global dysregulation of DSCAM expression within the retina or optic tectum impacts retinotectal circuit formation and the functional maturation of the visual circuit. By imaging responses of individual neurons in the intact, developing brain, and correlating structural changes with functional assays that test vision, our studies aim to advance our understanding of the organizing principles that shape functional connectivity in the central nervous system. Elucidating early molecular mechanisms of circuit development that differentially impact pre- and postsynaptic connectivity has broad implications for understanding human neurodevelopmental disorders in which altered brain function is associated with deficits in early connectivity as seen in Down syndrome, mental retardation, and autisms.