Genomes and Genes
SACRAL CREST CELLS AND ENTERIC NEURODEVELOPMENT
Principal Investigator: Raj Kapur
Abstract: DESCRIPTION (Applicant's Abstract): Hirschsprung disease, hypoganglionosis, intestinal neuronal dysplasia and other disorders of intestinal motility are characterized by defects in the enteric nervous system, particularly in the large intestine. The complex nervous network in this region contains biochemically and electrophysiologically distinct classes of neurons, which derive embryologically from vagal or sacral neural crest lineages. The investigator has developed a model system to discriminate vagal and sacral crest-derived neurons in explants of murine embryonic large intestinal segments that are allowed to develop under the adult renal capsule. The investigator hypothesizes that enteric neurons, derived from sacral crest, are biochemically and functionally distinct from other intestinal ganglion cells. The subcapsular system will be used to investigate immunohistochemically the neuronal and/or glial phenotypes of neurons produced by sacral crest cells and compare them with the phenotypes of vagal crest cells. A candidate marker for sacral crest-derived neurons that may determine their phenotype is the transcription factor, Hox11L1; because it is putatively expressed in ganglion cells of the post-umbilical gut, but not more proximal bowel. More importantly, mice lacking Hox11L1 have intestinal hyperganglionosis and die from intestinal pseudo-obstruction and may serve as a model for some forms of human intestinal dysmotility. This group has created transgenic mice that will be used to determine whether Hox11L1-expression is a specific property of sacral crest-derived neurons. The investigator will determine the influence of Hox11L1 on neuronal differentiation, including transmitter phenotypes and neuroanatomical properties. A heterologous promoter will be used to express Hox11L1 ectopically and determine the transcription factor's influence on the properties of other classes of enteric ganglion cells. In addition, a transgenic model will be created to examine the fates, in Hox11L1 -/- mice, of cells that would normally express Hox11L1. The results of this study will further our understanding of normal enteric neurodevelopment and congenital disorders of intestinal motility.
Funding Period: 2001-06-01 - 2007-03-31
more information: NIH RePORT
- Hox11L1 expression by precursors of enteric smooth muscle: an alternative explanation for megacecum in HOX11L1-/- miceRaj P Kapur
Department of Pathology, Children s Hospital and Regional Medical Center, 4800 Sand Point Way NE, Seattle, WA 98105, USA
Pediatr Dev Pathol 8:148-61. 2005....
- Multiple endocrine neoplasia type 2B and Hirschsprung's diseaseRaj P Kapur
Department of Pathology, Children s Hospital and Regional Medical Center and University of Washington, Seattle, 91805, USA
Clin Gastroenterol Hepatol 3:423-31. 2005..In this review, the molecular genetics of the 2 conditions are discussed, and the clinical implications of existing data and future studies are summarized...
- Evaluation of Hox11L1 in the fmc/fmc rat model of chronic intestinal pseudo-obstructionMelissa A Parisi
Department of Pediatrics, Children s Hospital and Regional Medical Center and University of Washington, Seattle, WA 98105, USA
J Pediatr Surg 40:1760-5. 2005..We hypothesized that fmc is a mutant allele of the rat Hox11L1 gene and tested this hypothesis by direct sequencing...
- Inhibition of protein kinase A in murine enteric neurons causes lethal intestinal pseudo-obstructionDouglas G Howe
Department of Pharmacology, University of Washington, Seattle, Washington 98195 7750, USA
J Neurobiol 66:256-72. 2006....