Regulation of Stem Cell Proliferation and Cell Fate Specification by Wingless/Wnt Signaling Gradients Enriched at Adult Intestinal Compartment Boundaries.

Ai Tian,Zhenghan Wang,Hassina Benchabane,Yashi Ahmed,Ken M Cadigan

doi:10.1371/journal.pgen.1005822

Abstract

Intestinal stem cell (ISC) self-renewal and proliferation are directed by Wnt/β-catenin signaling in mammals, whereas aberrant Wnt pathway activation in ISCs triggers the development of human colorectal carcinoma. Herein, we have utilized the Drosophila midgut, a powerful model for ISC regulation, to elucidate the mechanisms by which Wingless (Wg)/Wnt regulates intestinal homeostasis and development. We provide evidence that the Wg signaling pathway, activation of which peaks at each of the major compartment boundaries of the adult intestine, has essential functions. Wg pathway activation in the intestinal epithelium is required not only to specify cell fate near compartment boundaries during development, but also to control ISC proliferation within compartments during homeostasis. Further, in contrast with the previous focus on Wg pathway activation within ISCs, we demonstrate that the primary mechanism by which Wg signaling regulates ISC proliferation during homeostasis is non-autonomous. Activation of the Wg pathway in absorptive enterocytes is required to suppress JAK-STAT signaling in neighboring ISCs, and thereby their proliferation. We conclude that Wg signaling gradients have essential roles during homeostasis and development of the adult intestine, non-autonomously controlling stem cell proliferation inside compartments, and autonomously specifying cell fate near compartment boundaries.

Highlights

The evolutionarily conserved Wnt/β-catenin signal transduction pathway regulates cell proliferation and tissue patterning in metazoans, and deregulation of this pathway is associated with numerous human diseases [1,2]
Novel sources of Wg are detected in the epithelium and surrounding visceral muscle at adult intestinal compartment boundaries
We identified a zone of wg expression in the visceral muscle at the posterior terminal midgut, immediately anterior to the R5-hindgut proliferation zone (HPZ) border [23,34] (Fig 1H–1H”)

Summary

Introduction

The evolutionarily conserved Wnt/β-catenin signal transduction pathway regulates cell proliferation and tissue patterning in metazoans, and deregulation of this pathway is associated with numerous human diseases [1,2]. The fly gut undergoes rapid turnover and is replenished by ISCs. The ISCs, which are distributed along the basement membrane of the gut epithelium, divide asymmetrically to give rise to enteroblasts and pre-enteroendocrine cells that differentiate into either absorptive enterocytes or secretory enteroendocrine cells, respectively [13,14,15,16,17]. The ISCs, which are distributed along the basement membrane of the gut epithelium, divide asymmetrically to give rise to enteroblasts and pre-enteroendocrine cells that differentiate into either absorptive enterocytes or secretory enteroendocrine cells, respectively [13,14,15,16,17] The peak expression of frizzled 3 (fz3), a direct target gene of the Wg pathway [21,22], occurs at four of these compartment boundaries (cardia-R1, R2-R3, R3-R4 and R5-hindgut) [18]

Methods

Results

Discussion

Conclusion