Retinoic Acid: A Link Between Body Plan and Neural Sexual Dimorphism

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Many vertebrate animals develop differences in body structure between males and females, known as sexual dimorphism, which traditionally is considered to be regulated by the hormones estrogen and testosterone. Some recent evidence shows that molecular analogs of vitamin A called retinoids, including the metabolite retinoic acid, also play a role in many endocrine pathways. Retinoic acid exerts its effects by binding to molecular receptor molecules in the cell nucleus. This binding activates complex programs including development, cell differentiation and cell death, and is thought to control sequential expression of the homeobox genes which are crucial in the timing of patterns of development. A central question is how amounts of retinoic acid are spatially and temporally controlled during development. This project uses as a model a teleost fish species with prominent post-embryonic development of a sexual dimorphism in skeletal structure and spinal cord. The hypotheses are first, that retinoic acid is differentially synthesized and catabolized in the spinal cord of the nervous system, and second, that the consequent gradients of retinoic acid establish coordinates for developmental control of genes producing the sex-specific pattern of particular vertebrae, spinal ganglia and motor neurons within the spinal cord. Biochemical and molecular approaches are used to determine when, where and how two specific enzymes control the synthesis (retinaldehyde dehydrogenase, RALDH) and degradation (retinoic acid hydroxylase, CYP26) of retinoic acid, thus allowing retinoic acid to be manipulated to study its effects. Results are expected to establish for the first time a link between retinoic acid and sexually dimorphic post-embryonic development and differentiation of the body plan and nervous system. The findings will have an impact beyond neuroendocrinology to developmental biology and physiology. Additional impacts come from promoting the career of a young scientist from an underrepresented group, and training students also largely from underrepresented groups, in a state institution eligible for the Experimental Program to Stimulate Competitive Research (EPSCoR)