Faulty bone morphogenetic protein signaling in esophageal atresia with tracheoesophageal fistula.
BACKGROUND
The organogenesis of esophageal atresia with tracheoesophageal fistula remains unclear. We have previously demonstrated that the fistula tract develops from a trifurcation of the embryonic lung bud and displays pulmonary lineage traits. Unlike the lung, the fistula grows without branching. Bone morphogenetic proteins (BMPs) are known to be important in lung branching. We studied possible BMP signaling defects as a potential cause for the absence of branching in the fistula tract.


METHODS
Adriamycin was administered to pregnant rats on days 6-9 of gestation to induce tracheoesophageal fistula. Microdissection was performed at E13 and E17 isolating the foregut. Tissues were analyzed using immunohistochemistry for BMP ligand (BMP2, BMP4, BMP7) and receptor (BMPRIA, BMPRIB, BMPRII) expression.


RESULTS
Immunohistochemistry revealed the presence of all 3 BMP ligands at E13, localized specifically to the esophageal mucosa but absent in the fistula and lung. At E17, the ligands were again present in the esophageal mucosa, and additionally in the fistula tract mucosa, but remained absent in the lung. At E17, all of the BMP receptors were also localized to the luminal surface of esophagus and fistula. However, in the lung epithelium, only BMPRII was found, whereas BMPRIA and BMPRIB remained absent.


CONCLUSIONS
The normal expression pattern of BMP4 was increased at the branch tips and low between branches. Among other results, we show here a constant expression level of BMP ligands throughout the entire epithelium of the fistula tract. This diffuse expression suggests defective BMP signaling in the fistula tract and explains its nonbranching phenotype.
Crowley
Amanda R
AR
Laboratory for Surgical Organogenesis, Department of Surgery, Children's Mercy Hospital, Kansas City, MO 64108, USA.
Mehta
Sheilendra S
SS
Hembree
Mark J
MJ
Preuett
Barry L
BL
Prasadan
Krishna L
KL
Sharp
Susan W
SW
Yew
Hooi
H
McFall
Christopher R
CR
Benjes
Christina L
CL
Tulachan
Sidhartha S
SS
Gittes
George K
GK
Snyder
Charles L
CL
D000014:Abnormalities, Drug-Induced / Q000503:physiopathology; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000502:physiology*; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000009:adverse effects; D004933:Esophageal Atresia / Q000150:complications / Q000503:physiopathology*; D005260:Female; D007150:Immunohistochemistry; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology*; D013723:Teratogens / Q000494:pharmacology; D014138:Tracheoesophageal Fistula / Q000139:chemically induced / Q000150:complications / Q000503:physiopathology*
D019485:Bone Morphogenetic Proteins; D013723:Teratogens; D004317:Doxorubicin