Hexhomeobox gene-dependent tissue positioning is required for organogenesis of the ventral pancreas

Abstract

In animal development, digestive tissues emerge from different positions of the endoderm as a result of patterning signals from overlying mesoderm. Although embryonic tissue movement during gastrulation generates an initial positional relationship between the endoderm and mesoderm, the role of subsequent endoderm movement against the mesoderm in patterning is unknown. At embryonic day 8.5 in the mouse, proliferation of cells at the leading edge of ventral-lateral endoderm, where the liver and ventral pancreas emerge, helps close off the foregut. During this time, the endoderm grows adjacent to and beyond the cardiogenic mesoderm, an inducer of the liver program and an inhibitor of the pancreas program. The homeobox gene Hex is expressed in this endoderm cell domain and in the liver and ventral pancreas buds, after organogenesis. We have found that in Hex-/- embryos, there is a complete failure in ventral pancreatic specification, while the liver program is still induced. However, when Hex-null ventral endoderm is isolated prior to its interaction with cardiogenic mesoderm and is cultured in vitro, it activates early pancreas genes. We found that Hex controls the proliferation rate, and thus the positioning, of the leading edge of endoderm cells that grow beyond the cardiogenic mesoderm, during gut tube closure. Thus, Hex-controlled positioning of endoderm cells beyond cardiogenic mesoderm dictates ventral pancreas specification. Other endodermal transcription factors may also function morphogenetically rather than by directly regulating tissue-specific programs.

Type 2 diabetes-associated genetic variants discovered in the recent genome-wide association studies are related to gestational diabetes mellitus in the Korean population

“…This finding suggests that rs1111875 may be more likely to be one of the genetic factors involved in beta cell compensatory insulin secretion in the face of insulin resistance induced by pregnancy. It is known that HHEX is expressed at high levels in the fetal and adult pancreas [23] and is crucial for the development of the ventral pancreas [46]. In Europids [20][21][22][23], rs1111875 is found within an extended region of linkage disequilibrium that contains not only HHEX but also KIF11 and IDE.…”

Pancreas organogenesis: From bud to plexus to gland

“…Blocking the relative movement of the ventral lateral foregut endoderm (the prospective ventral pancreas) prevents ventral pancreas specification from occurring. It was the genetic dissection of Hhex function in the mouse that led to this connection being made, with the tissue's ''escape/repositioning'' process being promoted by an Hhex-dependent proliferation of the leading edge of endoderm to allow it to rapidly extend away from the influence zone of the cardiac mesoderm (Bort et al, 2004). How extrinsic cues affect cell-fate specification needs to be considered as a highly dynamic, level-and context-dependent process.…”

Embryonic development of the liver†

“…40 Although the absence of hepatic markers in Hex-null embryos at E9.5 would be consistent with a failure in hepatic specification, recent analysis of Hex Ϫ/Ϫ ventral endoderm from E8.5 embryos containing 10 somite pairs found that Alb, Ttr, and Prox1 could in fact be detected by reverse-transcriptase polymerase chain reaction. 41 Moreover, cardiogeneic mesoderm was capable of inducing hepatic markers within the Hex Ϫ/Ϫ endoderm in cultured tissue explants. Although hepatic markers were expressed, the proliferation of the specified endodermal cells was markedly reduced in Hex Ϫ/Ϫ embryos.…”

“…Although hepatic markers were expressed, the proliferation of the specified endodermal cells was markedly reduced in Hex Ϫ/Ϫ embryos. 41 These studies imply that although Hex is dispensable for induction of hepatic development, it is essential for expansion of the nascent hepatoblast population. In addition to being essential for development of the early liver bud, studies in chick embryos have shown that expression of Hex in the ventral endoderm requires both FGF and BMP signaling.…”