Molecular mechanism of action of the vitamin A metabolite, all-trans retinoic acid, in nervous system development; the therapeutic use of vitamin A and D analogs
The vitamin A metabolite, all-trans retinoic acid (atRA) is essential for reproduction, embryonic, and postnatal development, including nervous system development. Vitamin A deficiency during embryogenesis leads to defects in the patterning of the hindbrain, heart and skeleton; whereas a deficiency imposed at later times leads to a host of anomalies in the eye, kidney, diaphragm, heart, lung, urogenital system and gonad. Many of these same developing systems are subject to malformation in retinoid excess. Before the therapeutic potential of retinoids can be fully realized, it will be necessary to understand how vitamin A and its metabolites function normally at the cellular and molecular level, and how normal function is disrupted in toxicity.
A major focus of the lab has been to identify and study atRA-responsive genes that are required for normal nervous system development. Using loss- and gain- of-function studies in cells as well as mouse mutants we have shown that the atRA-responsive gene, Nav2, is essential for retinoid-induced neurite outgrowth in human neuroblastoma cells, and when expressed ectopically, can rescue the defect in mechanosensory axonal elongation in the C. elegans mutant, unc53. Nav2 is also required in vivo for normal development of the cranial nerves and their downstream control of blood pressure. Ongoing studies are directed at exploring the roles of Nav2 and other atRA-responsive genes such as Clmn and HEF1/Nedd9 in the developing cortex, hippocampus and cerebellum, and at discovering protein interacting partners using a yeast-two-hybrid screen.
We are also devoting considerable effort to the development and study of retinoids and vitamin D analogs that may be useful in medical applications. Recent studies suggest that a stable carbon linked analog of 4-hydroxyphenylretinamide, as well as several glucuronide retinoid conjugates are useful in chemoprevention and chemotherapy, and have reduced toxicity relative to the parent compounds. Recently, we have identified a unique subset of vitamin D analogs that have positive activity in a mouse model of acne. We are currently exploring the molecular basis of these positive therapeutic effects. Embryonic (day 6.5) chick sympathetic neurons cultured for 7 days with nerve growth factor in the absence of the vitamin A metabolite, all-trans retinoic acid.Embryonic (day 6.5) chick sympathetic neurons cultured for 7 days with nerve growth factor in the presence of the vitamin A metabolite, all-trans retinoic acid.
Photos of Embryonic (day 6.5) chick sympathetic neurons cultured for 7 days with nerve growth factor in the absence (left) or presence (right) of the vitamin A metabolite, all-trans retinoic acid. Only neurons receiving the vitamin A metabolite survive and extend neurites.