title: A role for sonic hedgehog signaling in the pathogenesis of human tracheoesophageal fistula.
abstract: OBJECTIVE
  Many theories of the pathogenesis of esophageal atresia with tracheoesophageal fistula (EA/TEF) have been proposed, but no specific mechanism has been demonstrated. The authors previously reported data suggesting a respiratory origin of the fistula tract in the rat model and in humans. Sonic hedgehog (Shh) "knockout" mice have the VACTERL association, and thus it was hypothesized that defects in Shh signaling may exist in the human neonatal EA/TEF fistula tract.
  
  
  METHODS
  With IRB approval, human proximal esophageal pouch and distal fistula samples were removed at the time of standard repair of EA/TEF in accordance with what the surgeons deemed appropriate in preparation for anastomosis. Tissues were processed for HE, reverse-transcriptase polymerase chain reaction (RT-PCR), and immunohistochemistry. Normal embryonic lung cDNA was used as a positive control for the RT-PCR reactions.
  
  
  RESULTS
  As expected, Shh was present by immunohistochemistry in the proximal esophageal pouch, but was specifically absent in the distal fistula tract. Gli-1, -2, and -3 (all intracellular mediators of Shh signaling) were present in the proximal pouch and distal esophagus by RT-PCR.
  
  
  CONCLUSIONS
  The absence of Shh signaling in the developing fistula tract of the human neonate was surprising given that Shh normally is present in esophagus and other gut components. These results support the conclusion that the fistula tract is not an esophaguslike structure, despite both its histologic appearance and its use as an esophageal replacement. Also, like in Shh-null mutant mice, aberrant Shh signaling may play a critical role in the pathogenesis of EA/TEF in humans.
authors.affiliation: Department of Surgery, The Laboratory for Surgical Organogenesis, Children's Mercy Hospital, Kansas City, Missouri 64108, USA.
authors.forename: Troy
authors.initials: T
authors.lastname: Spilde
authors.forename: Amina
authors.initials: A
authors.lastname: Bhatia
authors.forename: Daniel
authors.initials: D
authors.lastname: Ostlie
authors.forename: Julie
authors.initials: J
authors.lastname: Marosky
authors.forename: George
authors.initials: G
authors.lastname: Holcomb
authors.forename: Charles
authors.initials: C
authors.lastname: Snyder
authors.forename: George
authors.initials: G
authors.lastname: Gittes
mesh_terms: D000015:Abnormalities, Multiple / Q000196:embryology / Q000209:etiology* / Q000235:genetics; D003238:Connective Tissue / Q000737:chemistry / Q000648:ultrastructure; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D005314:Embryonic and Fetal Development; D004848:Epithelium / Q000737:chemistry / Q000648:ultrastructure; D004933:Esophageal Atresia / Q000196:embryology / Q000209:etiology* / Q000235:genetics; D004947:Esophagus / Q000737:chemistry / Q000196:embryology; D053823:Hedgehog Proteins; D006801:Humans; D007231:Infant, Newborn; D051741:Kruppel-Like Transcription Factors; D009024:Morphogenesis; D009130:Muscle, Smooth / Q000737:chemistry / Q000648:ultrastructure; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D015513:Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013577:Syndrome; D014132:Trachea / Q000737:chemistry / Q000196:embryology; D014138:Tracheoesophageal Fistula / Q000196:embryology / Q000209:etiology* / Q000235:genetics; D015534:Trans-Activators / Q000032:analysis / Q000172:deficiency / Q000502:physiology*; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2; D000074290:Zinc Finger Protein Gli3
chemical_list: D004268:DNA-Binding Proteins; C082593:GLI2 protein, human; C065683:GLI3 protein, human; C000618551:Gli2 protein, mouse; C465571:Gli3 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D015513:Oncogene Proteins; C509239:SHH protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2; D000074290:Zinc Finger Protein Gli3