Wnt4 is essential to normal mammalian lung development

AbstractWnt signaling is essential to many events during organogenesis, including the development of the mammalian lung. The Wnt family member Wnt4 has been shown to be required for the development of kidney, gonads, thymus, mammary and pituitary glands. Here, we show that Wnt4 is critical for proper morphogenesis and growth of the respiratory system. Using in situ hybridization in mouse embryos, we identify a previously uncharacterized site of Wnt4 expression in the anterior trunk mesoderm. This expression domain initiates as early as E8.25 in the mesoderm abutting the tracheoesophageal endoderm, between the fusing dorsal aortae and the heart. Analysis of Wnt4−/− embryos reveals severe lung hypoplasia and tracheal abnormalities; however, aortic fusion and esophageal development are unaffected. We find decreased cell proliferation in Wnt4−/− lung buds, particularly in tip domains. In addition, we observe reduction of the important lung growth factors Fgf9, Fgf10, Sox9 and Wnt2 in the lung bud during early stages of organogenesis, as well as decreased tracheal expression of the progenitor factor Sox9. Together, these data reveal a previously unknown role for the secreted protein Wnt4 in respiratory system development

Elucidating the Role of Cellular Architecture in the Developing Pancreas

Many studies have focused on examining the intrinsic factors such as transcriptional regulators that instruct the step-wise acquisition of β-cell fate in the developing pancreas, with the intention of recapitulating the events necessary in order to generate these cells in vitro for replacement therapies. Directed differentiation protocols have improved upon transitioning from 2D to 3D cultures, indicating that the 3D microenvironment in which β cells are born is critical for the acquisition of their cell fate. However, little is known about the mechanisms through which the 3D architecture of the developing pancreas mediates cell fate specification and epithelial organization. In order to address some of the remaining gaps in the field, we proceeded to characterize the Pdx1-/- embryo, a mutant in which pancreatic cell fate and architecture had been reported to fail early in its development, to determine whether the developmental failure was related to defects in the epithelial architecture. After elucidating that Pdx1 is a transcriptional regulator of the cellular adhesion molecule E-cadherin, we then examined the effect that tissue-specific deletion of this molecule has on the developing pancreas. We determined that E-cadherin regulates both endocrine cell fate and isletogenesis, as we observe that there is a reduction in endocrine progenitors and total endocrine volume, in addition to a failure of the endocrine cells to coalesce into islets. Our findings also demonstrate that acinar cells are lost in the post-natal E-cadherinf/f;Pdx1Cre pancreas, due to an increase in cell death, suggesting that E-cadherin is capable of regulating cell survival. This body of work indicates that architectural molecules play a critical role in the regulation of cell fate specification and epithelial morphogenesis in the developing pancreas