Dr. Gregg Duester
Focus: Development, Aging and Regeneration Mostly mouse models, and sometimes collaborator with Xenopus researchers. Some milestones made by our laboratory: Genetic Identification of Enzymes Controlling Retinoic Acid Synthesis Raldh1, Raldh2, and Raldh3 encode retinaldehyde dehydrogenases essential for oxidation of retinaldehyde to RA. Knockout mice for Raldh1, Raldh2, and Raldh3 lose RA synthesis in specific tissues during embryogenesis resulting in abnormal development. Raldh1-/-, Raldh2-/-, and Raldh3-/- mice as well as compound knockout mice are being used to learn more about the mechanism of RA signaling during development of specific tissues. Retinoic Acid Signaling Does Not Require 9-cis-Retinoic Acid Two isomers of RA were originally thought to function as receptor ligands: all-trans-RA for retinoic acid receptors (RAR) and 9-cis-RA for retinoid X receptors (RXR). However, our Raldh2-/- rescue studies show that 9-cis-RA is not required to correct a lethal defect in RA synthesis as an RAR-specific synthetic ligand can rescue Raldh2-/- embryos. Also, HPLC analyses demonstrate that 9-cis-RA is not detectable in mouse embryos unless treated with high doses of retinoids. Retinoic Acid Acts as an Instructive Signal for Neural Development During gastrulation, RA synthesized in the somitic mesoderm travels to the adjacent neuroectoderm where it acts as an instructive signal to induce Hoxb1, Hnf1b, and Olig2 needed for development of the hindbrain and spinal cord. This pathway leads to development of hindbrain rhombomeres and facial motor neurons as well as motor neuron differentiation along the spinal cord. Retinoic Acid Represses FGF8 Expression During Early Organogenesis to Allow Proper Differentiation of Trunk Mesoderm: Limb Buds, Somites and Heart During gastrulation, RA acts as a permissive signal for differentiation of mesoderm by limiting the size of the primitive streak and cardiac Fgf8 expression domains, thus creating an FGF-free zone in between where the trunk develops. RA thus sets the anterior boundary of the primitive streak to allow proper somitogenesis and the posterior boundary of the heart to allow proper heart and forelimb bud development. We hypothesize that failure of this mechanism generates excessive FGF8 signaling to adjacent mesoderm resulting in smaller somites (vertebra precursors) displaying left-right asymmetry, a larger heart domain, and a failure to initiate forelimb budding. Retinoic Acid Initiates Limb Budding But is Not Required for Limb Patterning Our findings show that RA signaling is not required for limb proximodistal or anteroposterior patterning as originally postulated, but that RA inhibition of FGF8 signaling during the early stages of body axis extension provides an environment permissive for induction of forelimb buds.