Control of Germline Stem Cell Lineages by Diet and Physiology

Abstract

Tight coupling of reproduction to environmental factors and physiological status is key to long-term species survival. In particular, highly conserved pathways modulate germline stem cell lineages according to nutrient availability. This chapter focuses on recent in vivo studies in genetic model organisms that shed light on how diet-dependent signals control the proliferation, maintenance, and survival of adult germline stem cells and their progeny. These signaling pathways can operate intrinsically in the germ line, modulate the niche, or act through intermediate organs to influence stem cells and their differentiating progeny. In addition to illustrating the extent of dietary regulation of reproduction, findings from these studies have implications for fertility during aging or disease states.

Figure 1

GSC lineages. (A) Diagram of a Drosophila ovariole (top), which contains growing follicles. Each follicle is composed of a germline cyst surrounded by follicle cells and is produced from stem cell populations in the germarium (bottom). Germline stem cells (GSCs; dark purple) are juxtaposed to a somatic niche consisting primarily of cap cells (pink) and terminal filament cells (teal). GSCs divide asymmetrically, and their progeny generate 16-cell germline cysts (light purple) containing one oocyte and 15 nurse cells. The fusome (orange) becomes progressively more branched as cysts divide. Germline cysts initiately associate with escort cells (gray), and are subsequently enveloped by follicle cells (light blue) generated by follicle stem cells (dark blue) to form folicles. (B) The Drosophila testis (left) is a blind-end tube. GSCs (dark purple) reside at its apical end in close association with hub cells (pink) and cyst stem cells (CySCs, dark blue) (right). GSCs and CySCs divide asymmetrically, and their progeny (germline cysts and cyst cells, respectively) remain associated with each other during spermatogenesis. (C) Diagram showing one of the two gonad arms of adult C. elegans hermaphrodites. A niche comprising the distal tip cell (DTC; pink) maintains progenitor cells in the mitotic, proliferative zone. As progenitor cells move away from the niche, they enter meiosis. Sperm produced during larval stages are stored in the spermatheca; oocytes (purple) generate later are fertilized by stored sperm (or sperm introduced by mating) before progressing to the uterus. (D) In the mouse testis (left), spermatogenesis takes place in seminiferous tubules. Cross-section of a seminiferous tubule (right) showing different stages of the lineage supported by basally located spermatogonial stem cells (SSCs, dark purple). SSCs divide to produce mitotically active differentiating progeny (spermatogonia), which undergo meiosis (spermatocytes) and spermiogenesis (spermatids), and are released into the lumen of the tubule. Sperm undergo further maturation in the epidydimus, where they are eventually stored. Leydig cells (teal), blood vessels (red), and Sertoli cells (blue) plays important roles in support the SSC lineage.

Figure 2

Conserved nutrient sensing pathways. Cells respond to intrinsic energy and nutrient levels and external stimulation by hormones to activate an interdependent, conserved cellular response to diet. Species-specific protein names are indicated in orange (C. elegans), green (Drosophila), and purple (mammalian); common names are shown in black.

Figure 3

Cell type-specific requirements for diet-dependent pathways involved in the control of GSCs and their progeny. (A) In the Drosophila ovary, intrinsic, local, and tissue non-autonomous signals coordinately regulate the GSC lineage. In addition to the niche, the brain, follicle cells, and adipocytes all communicate with the GSC lineage as part of the response to diet. (B) GSCs in the Drosophila testis require InR intrinsically for maintenance and proliferation. EcR in cyst stem cells (CySCs) promotes GSC maintenance and the survival of their progeny. (C) In the developing C. elegans gonad, but not in the adult, proliferation is regulated intrinsically by insulin, TOR, and AMPK (AAK-1/2). TGFβ ligand (DAF-7) promotes progenitor pool maintenance via the distal tip cell (DTC). (D) The mouse SSC pool is regulated by Leydig, Sertoli, and peritubular myeloid (PTM) cells, as well as macrophages. An additional layer of control is provided by the hypothalamic-pituitary-gonad axis, which controls the activity of these somatic support cells to influence spermatogenesis. Biological processes are indicated in green and cell types in gray. For details, see text and Table 1.