Sex, stem cells and tumors in the Drosophila ovary

Abstract

The Drosophila Sex-lethal (Sxl) gene encodes a female-specific RNA binding protein that in somatic cells globally regulates all aspects of female-specific development and behavior. Sxl also has a critical, but less well understood, role in female germ cells. Germ cells without Sxl protein can adopt a stem cell fate when housed in a normal ovary, but fail to successfully execute the self-renewal differentiation fate switch. The failure to differentiate is accompanied by the inappropriate expression of a set of male specific markers, continued proliferation, and formation of a tumor. The findings in Chau et al., (2012) identify the germline stem cell maintenance factor nanos as one of its target genes, and suggest that Sxl enables the switch from germline stem cell to committed daughter cell by posttranscriptional downregulation of nanos expression. These studies provide the basis for a new model in which Sxl directly couples sexual identity with the self-renewal differentiation decision and raises several interesting questions about the genesis of the tumor phenotype.

Keywords: Sxl; bam; germline tumors; nanos; sex determination; stem cell differentiation.

Figure 1. Drawing of the ovarian niche with one GSC cell. The daughter CB lies just outside of the niche. The ovary is composed of about 20 ovarioles each of which contains an linear array of germ cells at progressive stages of development. The somatic niche, the microenvironment that maintains GSC fate by a BMP signaling cascade is located at the tip of each ovariole. (A) In wild type the GSC to CB cell fate switch occurs as one of the daughter cells moves out of this microenvironment permitting the initiation of the differentiation program that includes significant accumulation of the Bam protein and rapid downregulation of a set of GSC specific markers including Nanos protein. Note that Nanos and Bam proteins are expressed in non-overlapping domains. In contrast, Sxl protein (not shown) is expressed in both Nanos- and Bam-expressing cells. (B) Germ cells that lack Sxl protein fail to exit the stem cell stage, continue to proliferate, and form a tumor. GSC markers, including Nanos protein, are co-expressed with Bam in the majority of the tumor cells, except for the presumptive GSCs located at the tip of the ovariole.

Figure 2. Model for integration of female sexual identity with the self-renewal/differentiation decision by a Sxl/Bam partnership. Recent studies suggest that Nanos maintains GSC cell fate by repressing RNAs, such as brat, required for differentiation. In CBs, Bam/Sxl inhibits nanos translation, thereby promoting differentiation. In addition, Sxl/Bam maintains female sexual identity by repressing a male-specific network of genes that includes chinmo, most likely through attenuation of Jak/Stat signaling.