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Associate Professor of Pediatrics

• Gastroenterology and Nutrition
• Developmental Biology and Genetics
• Robert O. Heuckeroth Research Lab

Dr. Heuckeroth completed M.D. and Ph.D. studies at Washington University School of Medicine. He trained in pediatrics and gastroenterology at St. Louis Children's Hospital. Dr. Heuckeroth is board certified in Pediatrics and board-eligible in Pediatric Gastroenterology. He is a member of the North American Society for Pediatric Gastroenterology and Nutrition and the American Gastroenterological Association. Dr. Heuckeroth was a Markey Trust Scholar and a recipient of the Young Investigator Award from the North American Society for Pediatric Gastroenterology and Nutrition. He receive the Miles and Shipley Fileman Foundation Basic Research Award from the American Gastroenterological Association and the Glaxo Wellcome Institute of Digestive Health Research Award. He is also a member of the Society for Pediatric Research.

Dr. Heuckeroth's laboratory work focuses on neural crest development with a special interest in development and function of the enteric nervous system (ENS). This includes studies of the role of Ret tyrosine kinase, Ret ligands and co-receptors in ENS development. Ret is expressed in the migrating neural crest cells which form the ENS and acts as a receptor for four distinct ligands (glial cell line-derived neurotrophic factor (GDNF), neurturin, persephin, and artemin). For these ligands to activate Ret, one of the Ret co-receptors (GFR alpha-1 or GFR alpha-2 or GRF-3 alpha or GFR alpha-4) must be present. Using primary culture, we have demonstrated that GDNF and neurturin promote proliferation of gut derived neural crest cells, which form the ENS. Our recent analysis of neurturin and deficient mice suggests that different Ret ligands and co-receptors play distinct roles in formation and maintenance of a functioning enteric nervous system.

We are currently examining several other murine model systems that modulate trophic factor expression within the ENS and have demonstrated that alterations in trophic factor expression lead to dramatic changes within the ENS which modulate intestinal motility. Future studies will be directed toward uncovering the molecular mechanisms that regulate ENS development and function and have important implications for motility disorder in children, including Hirshprung's disease, constipation and irritable bowel syndrome.

Selected Publications

1. 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) 106-117.

2. Fu M, Vohra BPS, Wind D, Heuckeroth RO: BMP signaling regulates murine enteric nervous system precursor migration, neurite fasciculation, and patterning via altered Ncam1 polysialic acid addition. Developmental Biology 2006; 299(1):137-150.

3. Vohra BPS, Tsuji K, Nagashimada M, Uesaka T, Wind D, Fu M, Armon J, Enomoto H, Heuckeroth RO: Differential gene expression and functional analysis implicates novel mechanisms in enteric nervous system precursor migration and neuritogenesis. Developmental Biology 2006; 298 (1): 259-271.

4. Wang H, Vohra BPS, Zhang Y, Heuckeroth RO: Transcriptional profiling after bile duct ligation identifies PAI-1 as a contributor to cholestatic injury in mice. Hepatology 2005; 42(5): 1099-1108.

5. Srinivasan S, Anitha M, Mwangi S, Heuckeroth RO: Enteric Neuroblasts Require the Phosphatidylinositol 3-kinase/Akt/Forkhead Pathway for GDNF Stimulated Survival. Proc Natl Acad Sci 2005; 29: 107-119.

6. Gianino, S, Grider, JR, Cresswell, J, Enomoto, H, Heuckeroth RO: GDNF availability determines enteric neuron number by controlling precursor proliferation. Development 2003; 130:2187-2198.

7. Heuckeroth RO, Enomoto H, Grider JR, Golden JP, Hanke JA, Jackman A, Molliver DC, Bardgett ME, Snider WD, Johnson, EM Jr., Milbrandt J. : Gene targeting reveals a critical role for Neurturin in the development and maintenance of enteric, sensory and parasympathetic neurons. Neuron 1999; 22:253-263

8. Heuckeroth RO, Lampe PA, Johnson EM Jr, Milbrandt J. Neurturin and GDNF promote proliferation and survival of enteric neuron and glial progenitors in vitro. Developmental Biology 1998; 200:116-129.