The what, where, when and how of Wnt/β-catenin signaling in pancreas development

Abstract

The Wnt/β-catenin signaling pathway, conserved across the animal kingdom, is critical for the development of numerous tissues. Several recent studies have focused on the roles that this pathway plays at different stages of pancreatic organogenesis, including specification, proliferation, differentiation and function. Whereas, during early endoderm development, inhibition of the pathway is required for pancreatic specification, subsequent growth and differentiation of the fetal organ depends on the pathway being active. This appears especially true for exocrine acinar cells, the specification and differentiation of which also depend on β-catenin function. Whether the pathway plays an important role in development or function of endocrine islet cells, including insulin-producing β-cells, remains controversial. This question is particularly important in light of recent studies that implicate a downstream component of the pathway, TCF7L2, in human β-cell function. This review will cover recent work on Wnt/β-catenin signaling in pancreas development, emphasizing those points of controversy that most urgently require further investigation.

Specification of hepatopancreas progenitors in zebrafish by hnf1ba and wnt2bb

“…Notably, our work suggests that there is a narrow developmental window when positive Wnt signaling input is required for specification of both liver and pancreas progenitors. Because Wnt signaling outside this window may have negative effects on pancreas specification (Murtaugh, 2008), precise stimulation of HNF1B+ endoderm cells by Wnt signaling in differentiation protocols may be necessary. Future studies to determine how progenitors specified by Hnf1b and Wnt signaling are subsequently allocated into distinct liver, pancreas, gall bladder, or duct fate will be important to further enhance stem cell differentiation efforts.…”

“…Studies in frog showed that Wnt signaling before early somitogenesis plays a negative role in liver and pancreas development by inhibiting foregut identity (McLin et al, 2007). Studies in mice suggest that ectopic Wnt signaling during early pancreas development can antagonize pancreas specification (Heller et al, 2002;Heiser et al, 2006;Murtaugh, 2008). However, between these developmental stages, whether endogenous Wnt signaling regulates ventral pancreas specification has yet to be determined.…”

Mesenchymal Hox6 function is required for pancreatic endocrine cell differentiation

“…Wnt has largely been studied in the pancreas through manipulation of required canonical Wnt signaling components, such as β-catenin. Others have shown specific roles for individual Wnt ligands and, taken together, there are significant roles for both Wnt/β-catenin signaling and the non-canonical Wnt planar cell polarity pathway for the proper development of both endocrine and exocrine pancreas (Heller et al, 2002;Kim et al, 2005;Murtaugh et al, 2005;Heiser et al, 2006;Attali et al, 2007;Wells et al, 2007;Jonckheere et al, 2008;Murtaugh, 2008;Baumgartner et al, 2014;Afelik et al, 2015).…”

Wingless-type MMTV integration site family (WNT) signalling in pancreatic beta cells—more complex than expected

“…One lesson that we can learn from the animal studies in prenatal beta cell development is that accurate timing of the activation of canonical WNT signalling is crucial to allow for normal beta cell function [8]. Similarly, in adult mice, canonical WNT signalling might be switched on and off according to physiological demands at different time points of adult life.…”