Opposing JAK-STAT and Wnt signaling gradients define a stem cell domain by regulating differentiation at two borders.

David Melamed,Daniel Kalderon

doi:10.7554/elife.61204

Abstract

Many adult stem cell communities are maintained by population asymmetry, where stochastic behaviors of multiple individual cells collectively result in a balance between stem cell division and differentiation. We investigated how this is achieved for Drosophila Follicle Stem Cells (FSCs) by spatially-restricted niche signals. FSCs produce transit-amplifying Follicle Cells (FCs) from their posterior face and quiescent Escort Cells (ECs) to their anterior. We show that JAK-STAT pathway activity, which declines from posterior to anterior, dictates the pattern of divisions over the FSC domain, promotes more posterior FSC locations and conversion to FCs, while opposing EC production. Wnt pathway activity declines from the anterior, promotes anterior FSC locations and EC production, and opposes FC production. The pathways combine to define a stem cell domain through concerted effects on FSC differentiation to ECs and FCs at either end of opposing signaling gradients, and impose a pattern of proliferation that matches derivative production.

Highlights

The physiological role of each type of adult stem cell is to maintain appropriate production of a restricted set of cell types throughout life (Clevers and Watt, 2018; Post and Clevers, 2019)
Cell lineage approach to measure five separable parameters of Follicle Stem Cells (FSCs) behavior Prior to 2017, when each ovariole was thought to harbor just two or three FSCs, the cell autonomous effects of altered genotypes on FSC biology were ascertained by measuring the frequency of surviving marked FSC clones, defined by the presence of labeled Follicle Cells (FCs) and a putative FSC, at various times after clone induction relative to control genotypes tested in parallel (Castanieto et al, 2014; Kirilly et al, 2005; O’Reilly et al, 2008; Song and Xie, 2003; Vied et al, 2012; Wang et al, 2012)
Our investigations have generated a detailed picture of how a variety of fundamental stem cell behaviors, including precise location, division, differentiation, survival and amplification, respond to positional cues relayed by the activity levels of two major signaling pathways that are graded with complementary polarities across the stem cell domain

Summary

Introduction

The physiological role of each type of adult stem cell is to maintain appropriate production of a restricted set of cell types throughout life (Clevers and Watt, 2018; Post and Clevers, 2019). A group of stem cells in a given location is maintained by ‘population asymmetry’, where individual stem cells exhibit non-uniform, stochastic behaviors and differentiation is commonly not temporally or mechanistically linked to division of the same stem cell (Reilein et al, 2018; Ritsma et al, 2014; Rompolas et al, 2016; Simons and Clevers, 2011) The behavior of such stem cells is likely guided substantially by extracellular signals and it is commonly presumed that regulation is achieved substantially by defining a compartment with fixed dimensions that can maintain stem cells. Drosophila ovarian Follicle Stem Cells (FSCs) provide an outstanding paradigm to pursue these questions

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