DBBS

Our laboratory is interested in the basic mechanisms that control neuronal development including trophic factors, guidance molecules, and morphogens. In particular we are analyzing the molecular mechanisms that guide cell migration, determine neuronal polarity, and regulate neuronal precursor survival and proliferation. These basic mechanisms critically control development in every region of the nervous system. As a model system, we are focused on the neural crest. Neural crest cells migrate from the neural tube during development, migrate extensively thought the vertebrate embryo and give rise to the entire peripheral nervous system including the enteric nervous system (ENS), sensory ganglion cells (dorsal root ganglia), autonomic (sympathetic and parasympathetic) neurons, and Schwann cells. They also generate many non-neuronal derivatives including the adrenal medulla, pigment cells in the skin, great vessels of the heart, and bones of the face. These pleuripotent cells therefore provide an excellent model system to study basic mechanisms controlling embryonic development at many different levels. Current work is focused on the enteric nervous system, a complex network of cells within the bowel wall that controls many aspects of intestinal function. Within the developing enteric nervous system pleuripotent stem cells and committed progenitor cells respond to a variety of extracellular signals that control development. This system is especially interesting from the standpoint of molecular genetics since recent studies demonstrate that gene interactions determine disease penetrance for Hirschsprung disease, the most severe human defect in enteric nervous system development. Our laboratory is currently employing a variety of primary cell culture, organ culture, and molecular techniques (e.g., microarray analysis, siRNA, in situ hybridization) to identify and characterize novel mediators of neural crest development. This productive approach had led to the identification of many additional molecules that influence the developing ENS and are now being analyzed in more detail. Recent studies in our laboratory demonstrate that vitamin A deficiency severely impairs enteric nervous system development because RA signaling is needed to reduce PTEN levels in actively migrating ENS progenitors. New work in our laboratory is focused on identifying additional gene-environment interactions that are critical for ENS development with the goal of devising new strategies to prevent human neural crest associated birth defects including Hirschsprung disease.

Wang H, Hughes I, Planer W, Parsadanian A, Grider JR, Vohra BPS, Keller-Peck C, Heuckeroth RO. The timing and location of GDNF expression determines enteric nervous system structure and function. Journal of Neuroscience 2010 30(4): 1523-1538.
 
Fu M, Sato Y, Lyons-Warren A, Zhang B, Kane MA, Napoli JL, Heuckeroth RO. Vitamin A facilitates enteric nervous system precursor migration by reducing Pten accumulation. Development 2010 37(4):631-40.
 
Sato Y, Heuckeroth RO. Retinoic acid regulates murine enteric nervous system precursor proliferation, enhances neuronal precursor differentiation, and reduces neurite growth in vitro. Developmental Biology 2008 320(1):185-98.
 
Vohra BPS, Planer W, Armon J, Fu M, Jain S, Heuckeroth RO. Reduced endothelin converting enzyme-1 and endothelin-3 mRNA in the developing bowel of male mice may increase expressivity and penetrance of Hirschsprung disease like distal intestinal aganglionosis. Developmental Dynamics 2007 236(1):106-17.
 
Vohra, BPS, Fu M, Heuckeroth RO. PKCz and GSK-3b control neuronal polarity in developing rodent enteric neurons while SMURF1 promotes neurite growth but does not influence polarity. Journal of Neuroscience 200727(35):9458-68.