Regulation of Drosophila germline stem cells

Abstract

The asymmetric division of adult stem cells into one self-renewing stem cell and one differentiating cell is critical for maintaining homeostasis in many tissues. One paradigmatic model of this division is the Drosophila male and female germline stem cell, which provides two model systems not only sharing common features but also having distinct characteristics for studying asymmetric stem cell division in vivo. This asymmetric division is controlled by a combination of extrinsic signaling molecules and intrinsic factors that are either asymmetrically segregated or regulated differentially following division. In this review, we will discuss recent advances in understanding the molecular and cellular mechanisms guiding this asymmetric outcome, including extrinsic cues, intrinsic factors governing cell fate specification, and cell cycle control.

Figure 1:. Anatomy of the male and female Drosophila germline stem cell (GSC) niche.

Both female (A) and male (B) GSCs (green) serve as excellent models to study asymmetric cell division at single cell resolution in vivo. GSCs are attached to somatic niche cells (light blue) via Cadherin molecules. GSCs divide asymmetrically away from the niche to produce differentiating daughter cells called cystoblasts (CBs) in females (A) and gonialblasts (GBs) in males (B). CBs and GBs undergo four rounds of mitosis and become increasing differentiated (red) and are supported by somatic gonadal cells called escort cells in females and cyst cells in males. The germline is further supported by a specialized organelle called the spectrosome (purple dot) that branches into a fusome as the GB or CB differentiates (purple lines).

Figure 2:. Summary of recent studies on extrinsic cues in GSC niche.

(A) In the female, extrinsic regulation can come from the GSCs themselves to regulate their own niche, can arise from other tissues, or from known regulators in new roles. (B) In male GSC niche, several extrinsic cues regulate GSC maintenance and differentiation. Beyond the well-established signaling role of the niche, cyst stem cells (CySC) and cyst cells play crucial signaling roles regulating cell fate specification, dedifferentiation, and cell death.

Figure 3:. Summary of cell cycle changes in the female GSC lineage.

While the cell cycle is dramatically remodeled during female germline differentiation (right), well known cell cycle regulatory proteins fulfill a surprising number of non-canonical roles in GSC maintenance and differentiation. Furthermore, the levels of these proteins, typically tightly coupled to the cell cycle stages, are far more stable and differentially accumulated throughout the germline.

Figure 4:. Mitotic asymmetries in the male GSCs.

In late G2 and early mitosis (A), proper positioning of the centrosome is upstream of proper orientation of the centrosome. Signaling from the hub, adherence, and GSC intrinsic factors establish this polarity and are ultimately necessary for proper polarity in division. Along with the regulated positioning, microtubule polymerization is also asymmetric from the two centrosomes, which is important for the proper recognition and eventual segregation (B) of sister chromatids with different epigenomes.