Coordinate Regulation of Stem Cell Competition by Slit-Robo and JAK-STAT Signaling in the Drosophila Testis

摘要

Stem cells in tissues reside in and receive signals from local microenvironments called niches. Understanding how multiple signals within niches integrate to control stem cell function is challenging. The Drosophila testis stem cell niche consists of somatic hub cells that maintain both germline stem cells and somatic cyst stem cells (CySCs). Here, we show a role for the axon guidance pathway Slit-Roundabout (Robo) in the testis niche. The ligand Slit is expressed specifically in hub cells while its receptor, Roundabout 2 (Robo2), is required in CySCs in order for them to compete for occupancy in the niche. CySCs also require the Slit-Robo effector Abelson tyrosine kinase (Abl) to prevent over-adhesion of CySCs to the niche, and CySCs mutant for Abl outcompete wild type CySCs for niche occupancy. Both Robo2 and Abl phenotypes can be rescued through modulation of adherens junction components, suggesting that the two work together to balance CySC adhesion levels. Interestingly, expression of Robo2 requires JAK-STAT signaling, an important maintenance pathway for both germline and cyst stem cells in the testis. Our work indicates that Slit-Robo signaling affects stem cell function downstream of the JAK-STAT pathway by controlling the ability of stem cells to compete for occupancy in their niche. Author Summary Stem cells adhere to niches, or local microenvironments, which provide essential maintenance cues. In the Drosophila testis niche, quiescent hub cells maintain adjacent germline and somatic stem cells (or cyst stem cells, CySCs) via local JAK-STAT signaling. Here, we show that the Slit-Robo and JAK-STAT pathways integrate to modulate stem cell-niche cell adhesion. The ligand Slit is expressed in the hub, and Slit's receptor Robo2, which is transcriptionally activated by JAK-STAT signaling, is required in adjacent CySCs to promote ECad-based adhesion to the hub. Abl tyrosine kinase acts downstream of Robo2 to attenuate CySC-hub adhesion and prevent CySCs from outcompeting neighboring cells from the niche. Interestingly, Robo receptors mediate stem cell-niche adhesion during hematopoiesis, but the mechanisms are not understood. We suggest that the Slit-Robo-Abelson and JAK-STAT pathways may coordinately regulate stem cell-niche cell adhesion more generally.