JAK/STAT signaling coordinates stem cell proliferation and multilineage differentiation in the Drosophila intestinal stem cell lineage

Abstract

Adult stem cells are the most primitive cells of a lineage and are distinguished by the properties of self-renewal and multipotency. Coordinated control of stem cell proliferation and multilineage differentiation is essential to ensure a steady output of differentiated daughter cells necessary to maintain tissue homeostasis. However, little is known about the signals that coordinate stem cell proliferation and daughter cell differentiation. Here we investigate the role of the conserved JAK/STAT signaling pathway in the Drosophila intestinal stem cell (ISC) lineage. We show first, that JAK/STAT signaling is normally active in both ISCs and their newly formed daughters, but not in terminally differentiated enteroendocrine (ee) cells or enterocyte (EC) cells. Second, analysis of ISC lineages shows that JAK/STAT signaling is necessary but not sufficient for daughter cell differentiation, indicating that competence to undergo multilineage differentiation depends upon JAK/STAT. Finally, our analysis reveals JAK/STAT signaling to be a potent regulator of ISC proliferation, but not ISC self-renewal. On the basis of these findings, we suggest a model in which JAK/STAT signaling coordinates the processes of stem cell proliferation with the competence of daughter cells to undergo multilineage differentiation, ensuring a robust cellular output in the lineage.

Calcineurin/Nfatc1 signaling links skin stem cell quiescence to hormonal signaling during pregnancy and lactation

“…In germline SCs of the Drosophila testis, local niche cells activate Jak-Stat signaling to maintain SC self-renewal (Kiger et al 2001;Tulina and Matunis 2001). Drosophila intestinal SCs also require Jak-Stat signaling to activate proliferation (Jiang et al 2009;Beebe et al 2010). Our finding that Stat5 signaling contributes to SC quiescence in the HF during pregnancy (Fig.…”

Intestinal stem cell proliferation and epithelial homeostasis in the adult Drosophila midgut

“…Low levels of Notch activity in progenitor cells (EBs) is believed to be required for their differentiation into EEs while high levels of the pathway are necessary for ECs specification (Ohlstein and Spradling, 2006) (Micchelli and Perrimon, 2006) (Bardin et al, 2010) (Perdigoto et al, 2011) (Perdigoto and Bardin, 2013). Preventing JAK/Stat signalling through knock down of Drosophila Hop/JAK, the cytokine receptor Domeless or the transcription factor Stat leads to an overrepresentation of stem/progenitor cells in the adult midgut (Beebe et al, 2010). Autocrine activation of PVF2/PVR signalling also regulates homeostatic ISC proliferation and differentiation (Bond and Foley, 2012).…”

L’intestin moyen de drosophile

“…Toutefois, d'autres voies de signalisation sont requises à cette étape de différenciation. Ainsi, la voie JAK (Janus kinase)/ STAT (signal transducer and activator of transcription) participe à la formation des cellules différenciées, comme l'indique l'accumulation de cellules ayant les caractéristiques des entéroblastes en contexte mutant [24][25][26]. La voie EGF-R (epidermal growth factor receptor) est, quant à elle, requise dans les entérocytes pour la morphogenèse de l'intestin [27].…”

“…En plus d'être impliquées dans la réparation tissulaire, les voies JAK/STAT [24,26,36,39,[45][46][47] et de l'EGF-R [27,37,38,42] exercent un rôle stimulateur sur la prolifération des CSI au cours du renouvellement naturel de l'épithélium, tout en assurant le maintien des CSI ( Figure 3A). Autrement dit, l'absence de ces voies induirait une perte des CSI au sein du tissu [42].…”