Research

     CONTROL OF NERVE CELL
       DIFFERENTIATION

     GENETIC DETERMINANTS
       OF NEURONAL NUMBER

     PATTERNED NERVE CELL
       DISTRIBUTIONS IN THE
       BRAIN

     RPE SIGNALLING AND
       AXONAL MISROUTING AT
       THE OPTIC CHIASM

RPE Signaling and Axonal Misrouting
at the Optic Chiasm

        Genetic mutations that alter ocular pigmentation produce abnormalities within the developing retina and visual pathways that cause permanent visual impairment. While much is known about the neural phenotype associated with ocular albinism and related hypopigmentation conditions affecting the retinal pigment epithelium (RPE) as well as the skin, how these changes affect the nervous system remain an enigma. We are seeking an integrated understanding of the relationship between tyrosinase, melanin synthesis, Oa1 signaling, G protein activation and the downstream effectors that ultimately modulate gene expression in the neural retina. Novel recombinant strategies for generating transgenic mice are being used in Professor Debora Farber’s lab at UCLA to explore these issues. Gi protein knockout mice are being examined to define the Gi protein through which Oa1 normally functions, and constitutively active Gi-expressing mice are being generated and crossed to Oa1 knockout mice to see whether their albino phenotype can be rescued.

        The primary neural abnormality associated with ocular hypopigmentation is a defect in axonal navigation at the optic chiasm during development, manifested as a misrouting of optic axons from the temporal retina into the opposite side of the brain. The decussation patterns associated with the retinofugal pathways in these various transgenic and knockout mice are being defined using anterograde and retrograde tract-tracing techniques in our lab. Finally, a subtractive hybridization strategy employing microarray analysis is being conducted in the Farber lab to identify candidate genes involved in this signaling. Using this combination of approaches drawing on the fields of developmental biology, molecular genetics and neuroanatomy, we hope to identify the critical signaling events initiated within the RPE and ultimately manifested at the optic chiasm.