Notch and Egfr signaling act antagonistically to regulate germ-line stem cell niche formation in Drosophila male embryonic gonads

Abstract

Germ-line stem cells (GSCs) are maintained by the somatic microenvironment, or GSC niche, which ensures that GSCs can both self-renew and produce functional gametes. However, it remains unclear how the proper niche size and location are regulated within the developing gonads. In the Drosophila testis, the hub cells that form the GSC niche are derived from a subset of somatic gonadal precursors (SGPs) in the anterior portion of the embryonic gonad. Here we show that Notch signaling induces hub differentiation. Notch is activated in almost all SGPs in the male embryonic gonad, but Epidermal growth factor receptor (Egfr) is activated in posterior SGPs to repress hub differentiation, thereby restricting the expansion of hub differentiation in the embryonic gonad. We further show that Egfr is activated in posterior SGPs by Spitz ligand secreted from primordial germ cells (PGCs), whereas the Notch ligand Serrate is expressed in SGPs. This suggests that varying the number of PGCs alters niche size. Indeed, a decrease in the number of PGCs causes ectopic hub differentiation, which consequently increases their opportunity to recruit PGCs as GSCs. When ectopic hub differentiation is repressed, the decreased number of PGCs fails to become GSCs. Thus, we propose that SGPs sense PGC number via signals from PGCs to SGPs that modulate niche size, and that this serves as a mechanism for securing GSCs.

Crucial Genes and Pathways in Chicken Germ Stem Cell Differentiation

“…TGF-␤ signaling could regulate testis formation and male germ cell development (9). Notch signaling was reported antagonistically to regulate germ line stem cell niche formation in Drosophila male embryonic gonads (19) and deletion of Jagged1, a Notch ligand, could lead to the formation of multicystic follicles in the mouse ovary (20). These reports provide support that our selected candidate key signaling pathways play an important role in the differentiation of the male germ cells.…”

NOTCH signaling in Sertoli cells regulates gonocyte fate

“…5,7,8 In mice, this pathway's role in the development of the ovaries and oocytes has begun to be clarified; 88,89 however, its role in controlling the fate of gonocytes and the development of male germ cells after birth and into adulthood is still not clear. We have now demonstrated that NOTCH signaling in Sertoli cells is a crucial modulator of germ cell development, and that when overactivated, NOTCH signaling inhibits quiescence and pushes germ cells toward differentiation and meiosis (Fig.…”

“…6 However, it has recently become apparent that in Drosophila, NOTCH signaling is crucial for niche cell specification. 7,8 Because evolutionarily conserved intracellular signaling mechanisms (such as NOTCH) are often employed to regulate germline niche formation and germ cell development, NOTCH signaling might also be employed in mammalian Sertoli cells PAPer tyPe extrA VIew to specify the fate of germ cells during embryonic development and after birth.…”

Somatic gonadal cells: The supporting cast for the germline

“…While Notch signaling is permissive for hub formation, it is receptor tyrosine kinase signaling that regulates which SGPs give rise to the hub. In particular, the receptor tyrosine kinases, Epidermal growth factor receptor (EGFR), and Sevenless (SEV), are expressed in the posterior SGPs of the male embryonic gonad to restrict formation of the hub to anterior SGPs (Kitadate and Kobayashi, 2010;Kitadate et al, 2007). The ligands for each of these receptors, Spitz (SPI) and Bride of Sevenless (BOSS), respectively, are expressed in the PGCs (Kitadate and Kobayashi, 2010;Kitadate et al, 2007).…”

“…Studies have shown that activation of Notch signaling in the SGPs is required for SGP competence to become hub cells during embryogenesis (Kitadate and Kobayashi, 2010;Okegbe and Dinardo, 2011). One study suggests that Serrate (SER) expressed from the SGPs is required for Notch activation in the SGPs, while a second study demonstrates that Delta (DL) expressed in the endoderm is also important for Notch activation in the SGPs in the embryo (Kitadate and Kobayashi, 2010;Okegbe and Dinardo, 2011). While Notch signaling is permissive for hub formation, it is receptor tyrosine kinase signaling that regulates which SGPs give rise to the hub.…”