The trachea and esophagus are respectively respiratory and digestive organs that originate from a common foregut endoderm during development. Perturbed patterning in this endodermal tissue can result in a variety of foregut anomalies, such as tracheal agenesis (TA), esophageal atresia (EA) and tracheoesophageal fistula (TEF); however, their etiologies remain unknown.
We found that mice lacking Noggin displayed Type C EA/TEF, the most common form in humans, and notochordal defects strikingly similar to the adriamycin-induced rat EA/TEF model. In accord with esophageal atresia, Noggin-/- embryos displayed reduction in the dorsal foregut endoderm which was associated with reduced adhesion and disrupted basement membrane. However, no significant apoptosis in the Noggin-/- dorsal foregut was observed. Instead, non-notochordal, likely endodermal, cells were found in Noggin-/- notochord suggesting that Noggin function is required in the notochordal plate for its proper delamination from the dorsal foregut. Notably, ablating Bmp7 function in Noggin-/- embryos rescued EA/TEF and notochord branching defects, establishing a critical role of Noggin-mediated Bmp7 antagonism in EA/TEF pathogenesis.
In addition to the critical role of Bmp signaling in EA/TEF pathogenesis, it also plays a vital role in tracheal development. We found that conditional ablation of Bmp4 in the primitive foregut by Foxg1Cre resulted in complete loss of trachea. While tracheal specification was not affected in Bmp4-deficient foreguts, tracheal outgrowth was severely impaired. The anterior foregut domain also displayed significantly reduced epithelial and mesenchymal proliferation without apparent alteration in apoptotic cell death. While we did not observe alteration in Wnt/รข-catenin signaling in the Bmp4-deficient foregut, we detected consistent reduction in the expression level of Shh, a signaling molecule known to promote cell proliferation. In line with this observation, expression of Cyclin D1, a known downstream target of Shh signaling, was also found to be reduced in Bmp4- deficient foreguts. Taken together, these findings elucidate a critical role of Bmp signaling and cell proliferation in tracheal morphogenesis and implicate potential Bmp-Shh crosstalk in anterior foregut morphogenesis.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-02272007-151325 |
| Date | 28 February 2007 |
| Creators | Li, Yina |
| Contributors | David B. Polk, Robert Coffey, David Miller, Chin Chiang, Roy Zent |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-02272007-151325/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
Page generated in 0.0026 seconds