Zfh-1 Controls Somatic Stem Cell Self-Renewal in the Drosophila Testis and Nonautonomously Influences Germline Stem Cell Self-Renewal

Abstract

Summary The ability of adult stem cells to maintain their undifferentiated state depends upon residence in their niche. While simple models of a single self-renewal signal are attractive, niche-stem cell interactions are likely to be more complex. Many niches have multiple cell types, and the Drosophila testis is one such complex niche with two stem cell types, germline stem cells (GSCs) and somatic cyst progenitor cells (CPCs). These stem cells require chemokine activation of Jak/STAT signaling for self-renewal. We identified the transcriptional repressor Zfh-1 as a presumptive somatic target of Jak/STAT signaling, demonstrating that it is necessary and sufficient to maintain CPCs. Surprisingly, sustained zfh-1 expression or intrinsic STAT activation in somatic cells caused neighboring germ cells to self-renew outside their niche. In contrast, germline-intrinsic STAT activation was insufficient for GSC renewal. This data reveals unexpected complexity in cell interactions in the niche, implicating CPCs in GSC self-renewal.

Dual roles of Hh signaling in the regulation of somatic stem cell self-renewal and germline stem cell maintenance in Drosophila testis

“…Similar trends were also observed when Hh signaling activity was manipulated through altering Hh or Ptc expression level (Supplementary information, Figure S3). In addition, Smo 3 and Ptc IIW null alleles were used to inactivate and activate Hh signaling, respectively, in mosaic analysis with a repressible cell marker (MARCM). The results showed that Smo 3 mutant CySCs disappeared rapidly, while Ptc IIW mutant CySCs were found in all testes (Supplementary information, Table S1, Figures S4 and S5), which is consistent with the recent findings by others [7].…”

“…These results demonstrate that Hh signaling acts in parallel with JAK-STAT signaling to promote CySCs self-renewal, and that enhanced Hh signaling activities can compensate for the loss of Stat92E activity to maintain CySCs. In Drosophila testis niche, GSCs could be regulated by CySCs through CySC-secreted BMP as a niche signal as well as cell competition between GSCs and CySCs [3,8]. To determine whether Hh signaling affects GSCs through CySCs, we quantified GSC number after altering Hh activities in cyst cells (Supplementary information, Data S1).…”

“…JAK-STAT signaling does not directly regulate the selfrenewal of GSCs, but governs GSC-niche adhesion [5]. Although Zfh-1 is a direct target of activated STAT, eliminating STAT activity only decreased but did not abolish Zfh-1 expression [3], suggesting that a paralleled pathway(s) may be involved in the regulation of Zfh-1 expression. In the course of immunostaining adult flies expressing a hh enhancer trap, hh-lacZ [6], we observed a strong hh-lacZ staining at the apex of testis (Supplementary information, Figure S1), which is consistent with a previous observation that hh-lacZ was expressed in the hub cells [6], suggesting a potential function of Hedgehog (Hh) signaling in the testis.…”

Somatic cell lineage is required for differentiation and not maintenance of germline stem cells in Drosophila testes

“…Rather, activity of Stat in the germline is essential for continued attachment of GSCs to the hub and retains GSCs in their niche (13). Several lines of evidence suggest that CySCs provide a niche for maintenance of GSCs (13)(14)(15). Consistent with this model, it has been proposed that self-renewal of GSCs is specified by instructive signal(s) from the CySCs, with a likely candidate being TGF-β signaling (13).…”

Role of regeneration in tissue repairing and therapies

“…The let-7-Imp axis regulates ageing of the Drosophila testis stem-cell niche [170]. More often, micro niche affect oocyte formation by mitotically active germ cells obtained from ovaries of reproductive-age women [174].…”