Roles of Noggin, a BMP antagonist, in proper development of the mammalian notochord and foregut
Presentation
Overview
Overview
Description
The mammalian trachea and esophagus, parallel tubes with distinct identities and functions, arise during development from a single anterior foregut tube. Although malformations of the trachea and esophagus are common human birth defects (~1:3,000 live births), the morphogenetic and cellular processes that govern anterior foregut development are understudied. A growing number of rodent models now exist with which to study both the normal compartmentalization of the trachea and esophagus, and the abnormal development that leads to foregut malformations. One model, the Noggin (Nog) null mouse, very closely recapitulates the common foregut malformation esophageal atresia with tracheo-esophageal fistula (EA/TEF) with 75% penetrance. This particular malformation consists of an esophagus that ends rostrally in a blind pouch, and a communication between the trachea (or lungs) and the stomach. NOG is a secreted Bone Morphogenetic Protein (BMP) antagonist, but the mechanism by which loss ofNog causes EA/TEF is unknown. One possibility is that Nog expressed near the time of foregut compartmentalization is essential for this process. Another, arising from the fact that Nogmutants have large and disorganized notochords, is that resolution of the notochord from the dorsal foregut endoderm (future esophagus) early in embryogenesis can impact the potential of the foregut to compartmentalize later. Therefore, there are two Nog expression domains that conceivably play a role in the proper compartmentalization of the anterior foregut into the trachea and esophagus: 1) the dorsal foregut endoderm, and/or 2) the notochord. We have used tissue- and time-specific manipulation of Nog and the BMP pathway in mouse embryos to determine the spatio-temporal requirements for BMP antagonism in the process of foregut compartmentalization. Our results indicate a key role for NOG secreted from early axial structures in attenuating BMP signaling within these axial structures, rather than only in the developing foregut. In conjunction with other published results and careful histological and immunological observations of the Nog mutant notochord, these data suggest that an early embryological event, the improper resolution of the notochord from the dorsal foregut endoderm, can cause EA/TEF. Ongoing and future work aims to determine the cell biological consequences of abnormally high BMP signaling on notochord cells as they resolve from the dorsal foregut endoderm.
