Fibroblast growth factor-10 serves a regulatory role in duodenal development.
OBJECTIVE
Duodenal obstruction occurs in 1 of 6000 live births and requires urgent surgical intervention. Duodenal atresia previously has been ascribed to a developmental failure of luminal recanalization; however, the cause of duodenal atresia remains incompletely understood. Although familial intestinal atresias have been described and syndromic associations are known, no specific genetic link has been established. Fibroblast growth factor-10 (Fgf10) is a known regulatory molecule relevant to mesenchymal-epithelial interactions, and mice deficient in Fgf10 demonstrate congenital anomalies in several organ systems including the gastrointestinal tract. The authors hypothesized that Fgf10 could serve a regulatory role in establishing normal duodenal development.


METHODS
Wild-type mice with beta-galactosidase under the control of the Fgf10 promoter were harvested from timed-pregnancy mothers. The expression of Fgf10 in the duodenum during development was evaluated by developing the embryos in X-Gal solution. Wild-type and mutant Fgf10(-/-) embryos were harvested from timed-pregnancy mothers at 18.5 days postconception (near term) and were analyzed for duodenal morphology (Institutional Animal Care and Use Committee-approved protocol 32-02). Photomicrographs were reviewed.


RESULTS
Fibroblast growth factor-10 is active in the duodenum at a late stage of development. The Fgf10(-/-) mutants demonstrate duodenal atresia with a variable phenotype similar to clinical findings. The duodenum fails to develop luminal continuity and has proximal dilation. The phenotype occurs in an autosomal recessive pattern with incomplete penetrance (38%).


CONCLUSIONS
Fibroblast growth factor-10 serves as a regulator in normal duodenal growth and development. Its deletion leads to duodenal atresia and challenges traditionally accepted theories of pathogenesis. This novel, genetically mediated duodenal malformation reflects an animal model that will allow further evaluation of the pathogenesis of this surgically correctable disease. By studying the mechanism of Fgf10 function in foregut development, the authors hope to better understand these anomalies and to explore possible therapeutic alternatives.
Kanard
Robert C
RC
Department of Pediatric Surgery, Developmental Biology Program, Childrens Hospital Los Angeles, 4650 Sunset Boulevard, Saban Research Building 524, Mail stop#100, Los Angeles, CA 90027, USA.
Fairbanks
Timothy J
TJ
De Langhe
Stijn P
SP
Sala
Fred G
FG
Del Moral
Pierre M
PM
Lopez
Chrissy A
CA
Warburton
David
D
Anderson
Kathryn D
KD
Bellusci
Saverio
S
Burns
R Cartland
RC
D000818:Animals; D004380:Duodenal Obstruction / Q000151:congenital* / Q000196:embryology* / Q000235:genetics; D004386:Duodenum / Q000196:embryology*; D047109:Fetal Development / Q000235:genetics; D051526:Fibroblast Growth Factor 10 / Q000235:genetics / Q000502:physiology*; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D007409:Intestinal Atresia / Q000196:embryology* / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal
D051526:Fibroblast Growth Factor 10