Fibroblast growth factor-10 serves a regulatory role in duodenal development Robert C. Kanard, Timothy J. Fairbanks, Stijn P. De Langhe, Fred G. Sala, Pierre M. Del Moral, Chrissy A. Lopez, David Warburton, Kathryn D. Anderson, Saverio Bellusci, R. Cartland Burns * 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 Abstract Purpose: 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 (Fg f10 ) is a known regulatory molecule relevant to mesenchymal-epithelial interactions, and mice deficient in Fg f10 demonstrate congenital anomalies in several organ systems including the gastrointestinal tract. The authors hypothesized that Fg f10 could serve a regulatory role in establishing normal duodenal development. Methods: Wild-type mice with b-galactosidase under the control of the Fg f10 promoter were harvested from timed-pregnancy mothers. The expression of Fg f10 in the duodenum during development was evaluated by developing the embryos in X-Gal solution. Wild-type and mutant Fg f10 À/À 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 Fg f10 À/À 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 Fg f10 function in foregut development, the authors hope to better understand these anomalies and to explore possible therapeutic alternatives. D 2005 Elsevier Inc. All rights reserved. 0022-3468/05/4002-0004$30.00/0 D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.jpedsurg.2004.10.057 Presented at the 51st Annual Congress of the British Association of Paediatric Surgeons, Oxford, England, July 27-30, 2004. * Corresponding author. University of Virginia Health System, 4th Floor Private Clinics, Hospital Drive, Rm 4531A, Box 800709, Charlottesville, VA 22908, USA. Tel.: +1 434 924 2476; fax: +1 434 924 2656. E-mail address: rcb5y@virginia.edu (R.C. Burns). Index words: Duodenal atresia; Intestinal atresia; Fibroblast growth factor-10; Fgf10; Gastrointestinal tract development Journal of Pediatric Surgery (2005) 40, 313–316 www.elsevier.com/locate/jpedsurg