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Heterozygous deletion in Foxd3, in mice, alters morphology of interstitial cells of the cajal in the gastrointestinal tract and causes megaesophaus

Thursday, October 11, 2012 — Poster Session III

10:00 a.m. – Noon

Natcher Conference Center, Building 45




  • E Szarek
  • MF Starost
  • M Abu Asab
  • L Dye
  • ER Ball
  • A Horvath
  • M Nesterova
  • CA Stratakis


The aim was to investigate the effects of heterozygous deletion of Foxd3(Foxd3+/-) on interstitial cell of Cajal(ICC) in the ileum. Foxd3 is critical during neural crest cell lineage specification and represses melanocyte development. We identified genetic defects in FOXD3 in patients with non-KIT/PDGFRA gastrointestinal stromal tumors(GISTs), or wild-type(WT)-GISTs; rare gastrointestinal tract(GIT) tumors thought to arise from ICCs - pacemaker cells of the GIT. WT-GISTs identified by absence of c-KIT/PDGFRA mutations. For normal development, ICCs and melanocytes require c-KIT. It is interesting to note that siRNA knockdown of FOXD3 in embryonic cell lines resulted in an increase in c-KIT expression, conversely, FOXD3 ectopic expression down-regulated c-KIT. We utilized a mouse model with altered Foxd3 expression. Mice (6-, 12- and 15-months(mo)) were presented for necropsy. A section of the ileum was saved for electron microscopy(EM) studies of ICC morphology. Fewer ICCs were observed in Foxd3+/- mice. At 15-mo Foxd3+/- mice presented megaesophagus. No abnormalities at 6- and 12-mo. Our results indicate that if Foxd3 plays role in ICC function, loss of that function could potentially contribute to weakening, or poor contractility. We are currently further elucidating the role and significance of a heterozygous loss of Foxd3 in ICC development and GIST development/progression.

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