Our long term goal is to understand how the vertebrate enteric nervous system (ENS) is specified and patterned during embryogenesis. Understanding the cellular and molecular processes involved in ENS formation will provide insights into how a complex structure, such as a nervous system arises, during development. Furthermore, our studies are of potential clinical importance in understanding the mechanisms and molecules that underlie pediatric conditions where the ENS fails to form correctly, such as Hirschsprung disease (HSCR). The ENS is derived from the neural crest, a multipotent population of cells that migrates from the neural tube along specific pathways to generate a wide variety of neural and non-neural tissues. Different axial populations of neural crest cells contribute to specific structures and tissues. In this proposal we will address where, when, and how ENS precursors are specified during embryogenesis. Our studies use the zebrafish due to the model system's cell biological, molecular and genetic strengths that are uniquely appropriate for our proposed experiments. Specifically, we aim to answer the following questions: 1) Do zebrafish enteric neural crest precursors arise from a distinct subset of vagal neural crest cells? We will determine the origin of the zebrafish ENS by lineage analysis. We will then investigate by cell transplantation the role of regulative interactions in specifying ENS precursor cell fate within the premigratory neural crest; 2) What gene is affected in the zebrafish ENS mutant, enema? We have identified several zebrafish mutants that have significant reductions in the number of enteric neurons. One of these mutants is enema another is lessen. We recently determined that lessen has a mutation in TRAP100. We will now identify the gene that is lesioned in enema that results in the mutant phenotype; 3) Which steps in ENS precursor development are affected in lessen and enema? We will characterize these mutants to determine cell biologically where, when, and how these mutations cause their phenotypes.Together the proposed aims will help increase our understanding of the mechanisms and molecules involved in generating the ENS and may provide valuable insights into the underlying causes of HSCR.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Neurogenesis and Cell Fate Study Section (NCF)
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Karp, Robert W
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Emory University
Schools of Arts and Sciences
United States
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Shepherd, Iain; Eisen, Judith (2011) Development of the zebrafish enteric nervous system. Methods Cell Biol 101:143-60
Uyttebroek, Leen; Shepherd, Iain T; Harrisson, Fernand et al. (2010) Neurochemical coding of enteric neurons in adult and embryonic zebrafish (Danio rerio). J Comp Neurol 518:4419-38
de Jong-Curtain, Tanya A; Parslow, Adam C; Trotter, Andrew J et al. (2009) Abnormal nuclear pore formation triggers apoptosis in the intestinal epithelium of elys-deficient zebrafish. Gastroenterology 136:902-11
Burzynski, G; Shepherd, I T; Enomoto, H (2009) Genetic model system studies of the development of the enteric nervous system, gut motility and Hirschsprung's disease. Neurogastroenterol Motil 21:113-27
Burzynski, Grzegorz M; Delalande, Jean-Marie; Shepherd, Iain (2009) Characterization of spatial and temporal expression pattern of SCG10 during zebrafish development. Gene Expr Patterns 9:231-7
D'Costa, Allison; Shepherd, Iain T (2009) Zebrafish development and genetics: introducing undergraduates to developmental biology and genetics in a large introductory laboratory class. Zebrafish 6:169-77
Delalande, Jean-Marie; Guyote, Meaghann E; Smith, Chelsey M et al. (2008) Zebrafish sip1a and sip1b are essential for normal axial and neural patterning. Dev Dyn 237:1060-9
Reichenbach, Bettina; Delalande, Jean-Marie; Kolmogorova, Ekaterina et al. (2008) Endoderm-derived Sonic hedgehog and mesoderm Hand2 expression are required for enteric nervous system development in zebrafish. Dev Biol 318:52-64
Pietsch, Jacy; Delalande, Jean-Marie; Jakaitis, Brett et al. (2006) lessen encodes a zebrafish trap100 required for enteric nervous system development. Development 133:395-406
Durr, Katrin; Holzschuh, Jochen; Filippi, Alida et al. (2006) Differential roles of transcriptional mediator complex subunits Crsp34/Med27, Crsp150/Med14 and Trap100/Med24 during zebrafish retinal development. Genetics 174:693-705