Wells Lab

Wells Lab

Molecular Mechanisms that Establish Organ Domains Along the Anterior-Posterior Axis

What are molecular mechanisms that specify A-P endoderm pattern at this stage in development?

The mechanisms by which organ domains are established are highly conserved across vertebrate species, and as such our lab uses several model organisms to investigate endoderm patterning including frogs, chick, mouse and human pluripotent stem cells. We have used these systems to investigate and identify a complex and interactive network of signaling pathways acting in different combinations and at different stages of development to establish presumptive organ domains and help drive morphogenesis and assembly of organ primordia. 

endoderm formation through differentiation
Figure From McGrath and Wells, Cell. 2015.

Establishing Organ Domains

During development in mice (left panel), the blastula gives rise to the three germ layers (ectoderm, mesoderm, and definitive endoderm) through the process of gastrulation (middle panel), which occurs between embryonic day 5 and 7.5 (e5-e7.5).

After gastrulation, the two-dimensional sheet of definitive endoderm is patterned along the anterior-posterior (A-P) axis and undergoes morphogenesis to form a three-dimensional gut tube that is surrounded by a primitive mesenchyme (e8.5).

The Wells and Zorn labs have extensively studied the anterior-posterior (A-P) and dorsal-ventral (D-V) patterning mechanisms that subdivide the developing gut tube into presumptive organ domains (for review see Zorn and Wells Ann. Rev. Cell and Dev. Bio. 2009; McGrath and Wells, Cell. 2015).

For example, the A-P patterning of the definitive endoderm occurs through reciprocal signaling with the mesenchyme involving growth factors such as WNTs, FGFs, and BMPs. At this stage in development these factors largely act to promote posterior fate and repress anterior fate. The anterior endoderm gives rise to the foregut (thyroid, lungs, esophagus, liver, stomach, pancreas) while the midgut and hindgut give rise to the small and large intestines, respectively. The first evidence of organ specification occurs in the early gut tube by the expression transcription factors that begin to demarcate specific organ domains including the respiratory tract (Nkx2.1), liver (Hhex), stomach (Sox2 and Pdx1), extrahepatic biliary system (Sox17), pancreas (Pdx1 and Ptf1a), duodenum (Pdx1 and Cdx2), and intestine (Cdx2). The spatially restricted expression of these transcription factors predicts where organs will begin to form starting around e9.5-10. By e13.5, the organs of the respiratory and GI tracts are formed and undergoing growth and differentiation into specialized lineages.