Wnt Pathway in Pancreatic Development and Pathophysiology

Abstract

The pancreas is an abdominal gland that serves 2 vital purposes: assist food processing by secreting digestive enzymes and regulate blood glucose levels by releasing endocrine hormones. During embryonic development, this gland originates from epithelial buds located on opposite sites of the foregut endoderm. Pancreatic cell specification and maturation are coordinated by a complex interplay of extrinsic and intrinsic signaling events. In the recent years, the canonical Wnt/β-catenin pathway has emerged as an important player of pancreas organogenesis, regulating pancreatic epithelium specification, compartmentalization and expansion. Importantly, it has been suggested to regulate proliferation, survival and function of adult pancreatic cells, including insulin-secreting β-cells. This review summarizes recent work on the role of Wnt/β-catenin signaling in pancreas biology from early development to adulthood, emphasizing on its relevance for the development of new therapies for pancreatic diseases.

Keywords: Wnt pathway; diabetes; embryonic development; pancreas; β-catenin; β-cells.

Figure 1

Canonical Wnt signaling pathway. (A) In the absence of Wnt ligands, cytoplasmic β-catenin is phosphorylated by the destruction complex, which includes Axin, adenomatosis polyposis coli (APC), glycogen synthase kinase 3 (GSK3) and casein kinase 1 (CK1). Phosphorylation of β-catenin within this complex by CK1 and GSK3 targets it for ubiquitination and subsequent proteolytic destruction by the proteosomal machinery. In the absence of nuclear β-catenin, TCFs engage with Groucho, which prevents the transcription of Wnt target genes. (B) The interaction of Wnt with its receptors FZD and LRP5/6 leads to the binding of Axin with phosphorylated LRP5/6 and the stabilization and nuclear accumulation of β-catenin. β-catenin is subsequently translocated into the nucleus where it interacts with TCFs and upregulate the transcription of Wnt target genes.

Figure 2

Schematic representation of canonical Wnt pathway activity during pancreas organogenesis. The blastocyst comprises an outer layer of trophoblats and an inner collection of cells termed the inner cell mass (ICM) cells. During gastrulation, the ICM is reorganized into three germ layers: the endoderm, the ectoderm and the mesoderm. At this stage, Wnt/β-catenin signaling activity plays a critical role for the progression of gastrulation and formation of mesoderm and endoderm [16,52,53,54,55,56,57,58,59,60]. Following gastrulation, the endoderm germ layer forms a primitive gut tube from which pancreatic buds emerge. While pancreas specification relies on the repression of the Wnt/β-catenin pathway [61,62,63], subsequent expansion and compartmentalization of multipotent progenitor cells strongly depends on the pathway being active [64,65,66,67]. Finally, Wnt/β-catenin signaling regulates homeostasis and expansion of terminally differentiated adult acinar and endocrine cells [68,69].

Figure 3

The “β-cell Wntmill”: Wnt/β-catenin pathway has been shown to play a role in β-cell proliferation and function in several experimental settings. The activation of this pathway has been demonstrated to induce β-cell proliferation and insulin secretion in immortalized cells in vitro [69,87], in isolated mouse islets ex vivo [69,92] and in vivo [69]. Also, activation of Wnt signaling is involved in β-cell regeneration and expansion in in diabetic neonatal rats [89] and in high-fat-induced diabetic mice [90,91]. Finally, Wnt ligands appear also to increase proliferation of human β-cells ex vivo [94].