Fibroblast growth factor-10 serves a regulatory role in duodenal development
Robert C Kanard1, Timothy J Fairbanks, Stijn P De Langhe
1Department 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.
Insights
Fibroblast growth factor-10 (Fgf10) regulates duodenal development. Its absence causes duodenal atresia in mice, challenging previous theories and offering a new model for studying this congenital anomaly.
Area of Science:
- Developmental Biology
- Genetics
- Gastroenterology
Background:
- Duodenal atresia, a congenital obstruction, affects 1 in 6000 births and requires immediate surgery.
- The exact cause of duodenal atresia is not fully understood, though developmental failure of recanalization is a common hypothesis.
- While familial cases and syndromic associations exist, a specific genetic cause for duodenal atresia remains unidentified.
Purpose of the Study:
- To investigate the role of Fibroblast growth factor-10 (Fgf10) in normal duodenal development.
- To test the hypothesis that Fgf10 acts as a regulatory molecule in mesenchymal-epithelial interactions during duodenal formation.
- To explore Fgf10 as a potential genetic factor in the pathogenesis of duodenal atresia.
Main Methods:
- Examined Fgf10 expression in developing mouse duodenum using beta-galactosidase reporter mice and X-Gal staining.
- Analyzed duodenal morphology in wild-type and Fgf10-deficient (Fgf10(-/-)) mouse embryos at 18.5 days postconception.
- Utilized photomicrography for detailed morphological assessment of embryonic duodenal development.
Main Results:
- Fibroblast growth factor-10 (Fgf10) is expressed in the developing duodenum during a critical late developmental stage.
- Fgf10(-/-) mutant mice exhibited duodenal atresia, characterized by a lack of luminal continuity and proximal dilation, mirroring human conditions.
- The observed duodenal atresia in mutants followed an autosomal recessive inheritance pattern with incomplete penetrance (38%).
Conclusions:
- Fibroblast growth factor-10 (Fgf10) is essential for normal duodenal growth and development.
- Fgf10 deficiency causes duodenal atresia, presenting a novel genetic mechanism that contrasts with established theories of pathogenesis.
- This genetically induced animal model of duodenal malformation provides a platform for further research into the underlying mechanisms and potential therapeutic strategies for this surgically correctable condition.
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 (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.
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