The fibroblast growth factor pathway serves a regulatory role in proliferation and apoptosis in the pathogenesis of intestinal atresia.
OBJECTIVE
Intestinal atresia occurs in 1:5000 live births and is a neonatal challenge. Fibroblast growth factor receptor 2b (Fgfr2b) is a critical developmental regulator of proliferation and apoptosis in multiple organ systems including the gastrointestinal tract (GIT). Fgfr2b invalidation results in an autosomal recessive intestinal atresia phenotype. This study evaluates the role of Fgfr2b signaling in regulating proliferation and apoptosis in the pathogenesis of intestinal atresia.


METHODS
Wild-type and Fgfr2b-/- embryos were harvested from timed pregnant mice. The GIT was harvested using standard techniques. Terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling) was used to evaluate apoptosis and bromodeoxyuridine to assess proliferation by standard protocols. Photomicrographs were compared (Institutional Animal Care and Use Committee-approved protocol 32-02).


RESULTS
Wild-type and mutant GIT demonstrate that deletion of the Fgfr2b gene results in inhibition of epithelial proliferation and increased apoptosis. Inhibited proliferation and increased apoptosis are specific to those tissues of normal Fgfr2b expression, corresponding to the site of intestinal atresia.


CONCLUSIONS
The absence of embryonic GIT Fgfr2b expression results in decreased proliferation and increased apoptosis resulting in GIT atresia. The regulation of proliferation and apoptosis in intestinal cells as a genetically based cause of intestinal atresia represents a novel consideration in the pathogenesis of intestinal atresia.
Fairbanks
Timothy J
TJ
Developmental Biology Program, Division of Pediatric Surgery, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.
Sala
Frederic G
FG
Kanard
Robert
R
Curtis
Jennifer L
JL
Del Moral
Pierre M
PM
De Langhe
Stijn
S
Warburton
David
D
Anderson
Kathryn D
KD
Bellusci
Saverio
S
Burns
R Cartland
RC
D000818:Animals; D017209:Apoptosis / Q000235:genetics* / Q000502:physiology; D049109:Cell Proliferation; D003106:Colon / Q000166:cytology; D015536:Down-Regulation; D047108:Embryonic Development / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D007409:Intestinal Atresia / Q000235:genetics / Q000503:physiopathology*; D007413:Intestinal Mucosa / Q000166:cytology; D051379:Mice; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000235:genetics* / Q000502:physiology*
D051497:Receptor, Fibroblast Growth Factor, Type 2