Regulation of Stem Cells by Intersecting Gradients of Long-Range Niche Signals

Abstract

SUMMARY We have used Drosophila ovarian Follicle Stem Cells (FSCs) to study how stem cells are regulated by external signals and draw three main conclusions. First, the spatial definition of supportive niche positions for FSCs depends on gradients of Hh and JAK-STAT pathway ligands, which emanate from opposite, distant sites. FSC position may be further refined by a preference for low-level Wnt signaling. Second, hyperactivity of supportive signaling pathways can compensate for the absence of the otherwise essential adhesion molecule, DE-cadherin, suggesting a close regulatory connection between niche adhesion and niche signals. Third, FSC behavior is determined largely by summing the inputs of multiple signaling pathways of unequal potencies. Altogether our findings indicate that a stem cell niche need not be defined by short-range signals and invariant cell contacts; rather, for FSCs, the intersection of gradients of long-range niche signals regulates the longevity, position, number and competitive behavior of stem cells.

Novel Tools for Genetic Manipulation of Follicle Stem Cells in the Drosophila Ovary Reveal an Integrin-Dependent Transition from Quiescence to Proliferation

“…This makes it challenging to pinpoint whether defects observed in integrin mutants are due to loss of function within the FSC itself (O'Reilly et al 2008) or whether defective signals from clonally identical integrin-mutant daughter cells influence FSC function (Vied et al 2012). A third possibility is that the marked cells observed are not FSCs but instead are differentiated daughter cells that cannot effectively incorporate into the developing epithelium and are gradually pushed toward the anterior.…”

“…Recently, it was shown that differentiated daughter cells influence FSCs via a signaling feedback mechanism (Vied et al 2012). This makes it challenging to pinpoint whether defects observed in integrin mutants are due to loss of function within the FSC itself (O'Reilly et al 2008) or whether defective signals from clonally identical integrin-mutant daughter cells influence FSC function (Vied et al 2012).…”

“…However, FSCs are separated from apical cells by six to eight somatic inner germarial sheath cells (IGS cells, also called escort cells) that provide additional growth factors for FSC control and adhesive signals that maintain FSC positioning SahaiHernandez and Nystul 2013). Finally, FSC daughter cells, called follicle cells, influence FSC behavior from the posterior by creating gradients of signals that intersect with anterior signals produced by apical cells and escort cells (Vied et al 2012).…”

A genome-scale in vivo RNAi analysis of epithelial development in Drosophila identifies new proliferation domains outside of the stem cell niche

“…Follicle cells continue to divide to generate ,30 epithelial cells, which are sufficient for the formation of an epithelial monolayer covering the cyst when it exits the germarium (Nystul and Spradling, 2010). Although it has been shown that Hedgehog, Wnt, BMP and JAK/STAT signalling pathways control division in the follicle stem cell niche (Forbes et al, 1996;Zhang and Kalderon, 2000;Zhang and Kalderon, 2001;Song and Xie, 2003;Kirilly et al, 2005;Vied et al, 2012), it is unclear how follicle cell proliferation is controlled outside of the niche.…”

Sorting Out Identities: An Educational Primer for Use with “Novel Tools for Genetic Manipulation of Follicle Stem Cells in the Drosophila Ovary Reveal an Integrin-Dependent Transition from Quiescence to Proliferation”

“…Two FSCs are located halfway down the germarium at the junction of regions 2A and 2B (Figure 1; Margolis and Spradling 1995;Nystul and Spradling 2007). Their proliferation depends on signals received from regions located both anterior and posterior to the FSCs (Sahai-Hernandez et al 2012;Vied et al 2012;Sahai-Hernandez and Nystul 2013). Similar to GSCs, FSCs divide asymmetrically, giving rise to one daughter cell that remains in the niche as a FSC, and a second daughter cell that exits the niche and begins to differentiate (Morrison and Spradling 2008).…”