JAK/STAT autocontrol of ligand-producing cell number through apoptosis

Abstract

SUMMARYDuring development, specific cells are eliminated by apoptosis to ensure that the correct number of cells is integrated in a given tissue or structure. How the apoptosis machinery is activated selectively in vivo in the context of a developing tissue is still poorly understood. In the Drosophila ovary, specialised follicle cells [polar cells (PCs)] are produced in excess during early oogenesis and reduced by apoptosis to exactly two cells per follicle extremity. PCs act as an organising centre during follicle maturation as they are the only source of the JAK/STAT pathway ligand Unpaired (Upd), the morphogen activity of which instructs distinct follicle cell fates. Here we show that reduction of Upd levels leads to prolonged survival of supernumerary PCs, downregulation of the pro-apoptotic factor Hid, upregulation of the anti-apoptotic factor Diap1 and inhibition of caspase activity. Upd-mediated activation of the JAK/STAT pathway occurs in PCs themselves, as well as in adjacent terminal follicle and interfollicular stalk cells, and inhibition of JAK/STAT signalling in any one of these cell populations protects PCs from apoptosis. Thus, a Stat-dependent unidentified relay signal is necessary for inducing supernumerary PC death. Finally, blocking apoptosis of PCs leads to specification of excess adjacent border cells via excessive Upd signalling. Our results therefore show that Upd and JAK/STAT signalling induce apoptosis of supernumerary PCs to control the size of the PC organising centre and thereby produce appropriate levels of Upd. This is the first example linking this highly conserved signalling pathway with developmental apoptosis in Drosophila.

Organ sculpting by patterned extracellular matrix stiffness

“…The GAL4 drivers used were tjGAL4, mirrGAL4 and fruGAL4 (Borensztejn et al, 2013); tubGAL80ts was used to control expression temporally by shifting flies to 29°. The Drosophila genome contains two Collagen IV subunit-encoding genes: ColIV α 1 (Flybase: Cg25c ) and ColIV α 2 (Flybase: vkg ).…”

Diversity of cell death pathways: insight from the fly ovary

“…By stage 5, the number of polar cells in each cluster is reduced to two, as supernumerary polar cells are eliminated by the canonical apoptotic pathway: Hid ⊣ DIAP1 ⊣ Dronc → Drice [32, 33]. Recently, it has been shown that the JAK/STAT pathway promotes this cascade [34]. Supernumerary polar cell death is developmentally important, as it is required for proper migration of border cells which produce the micropyle [32].…”

JAK-STAT signaling in stem cells and their niches inDrosophila

“…2C). Wingless (Wg) signaling emanating from the GSC niche also contributes to the optimal FSC positioning within the germarium, although it only supplements Hh and JAK-STAT signals, and is insufficient to rescue loss of either of these 58 . However, considering Wg forms a gradient along the anterior-posterior axis, and gradient levels detected even slightly more anterior than the FSCs have been found to be detrimental for FSC establishment, it is possible that Wg signaling is needed to prevent FSC formation too close to the CC/TF niche.…”

“…Surprisingly, hyperactivation of either Hh or JAK-STAT signaling can compensate for DE-cadherin-mediated FSC loss, suggesting that these pathways can strongly influence adhesive properties to support FSC maintenance 58 . Evidence suggests that JAK-STAT signaling promotes Integrin-mediated FSC:basement membrane interactions, indicating a potential mechanism.…”

“…It will be interesting to investigate the mechanisms triggering and controlling EC apoptosis, and to identify the spatial and/or temporal cues. Given the recent finding that JAK-STAT signaling is responsible for the apoptosis of super-numerous polar cells during cell fate specification, 58 it would be exciting to investigate whether JAK-STAT’s regulation of ECs also extends to their programmed cell death.…”