Regulation of the Balance Between Proliferation and Differentiation in Germ Line Stem Cells

Abstract

In many animals, reproductive fitness is dependent upon the production of large numbers of gametes over an extended period of time. This level of gamete production is possible due to the continued presence of germ line stem cells. These cells can produce two types of daughter cells, self-renewing daughter cells that will maintain the stem cell population and differentiating daughter cells that will become gametes. A balance must be maintained between the proliferating self-renewing cells and those that differentiate for long-term gamete production to be maintained. Too little proliferation can result in depletion of the stem cell population, while too little differentiation can lead to a lack of gamete formation and possible tumor formation. In this chapter, we discuss our current understanding of how the balance between proliferation and differentiation is achieved in three well-studied germ line model systems: the Drosophila female, the mouse male, and the C. elegans hermaphrodite. While these three systems have significant differences in how this balance is regulated, including differences in stem cell population size, signaling pathways utilized, and the use of symmetric and/or asymmetric cell divisions, there are also similarities found between them. These similarities include the reliance on a predominant signaling pathway to promote proliferation, negative feedback loops to rapidly shutoff proliferation-promoting cues, close association of the germ line stem cells with a somatic niche, cytoplasmic connections between cells, projections emanating from the niche cell, and multiple mechanisms to limit the spatial influence of the niche. A comparison between different systems may help to identify elements that are essential for a proper balance between proliferation and differentiation to be achieved and elements that may be achieved through various mechanisms.

TOR Signaling in Caenorhabditis elegans Development, Metabolism, and Aging

“…C. elegans germline tumor formation has become a significant model for the study of tumorigenesis (Singh and Hansen 2017). The IIS signaling target DAF-16/FoxO plays both cell autonomous and nonautonomous roles in germline proliferation, and tumor formation.…”

Planarian stem cell niche, the challenge for understanding tissue regeneration

“…For example, in mouse, Drosophila melanogaster and Caenorhabditis elegans gonads, germ stem cells (GSCs) occupy a special microenvironment within the germ line in which they interact with somatic cells that express signaling molecules (especially adhesion molecules) that maintain stemness and proliferation of GSCs within the niche. If GSCs move away from the niche, they begin to lose their stem cell identity and ability to self-renew [7]. Drosophila also possesses complex niches for follicle stem cells (FSCs) in the ovary and the intestinal stem cells (ISCs) in the posterior midgut.…”

Redundant mechanisms regulating the proliferation vs. differentiation balance in the C. elegans germline

“…Genetic analyses of the proliferation vs. differentiation decision in model organisms has uncovered significant complexity, with many factors and cellular processes, contributing to the robustness of the systems [reviewed in (Lin, 1997;Singh and Hansen, 2017;Hubbard and Schedl, 2019)]. For example, analyses of the regulation of this balance in the C. elegans germline has revealed a core genetic pathway that contains many redundant factors, and many additional inputs that appear to fine-tune the balance.…”