Regulation of germline stem cell proliferation downstream of nutrient sensing

Stem cells have recently attracted significant attention largely due to their potential therapeutic properties, but also because of their role in tumorigenesis and their resemblance, in many aspects, to cancerous cells. Understanding how stem cells are regulated, namely with respect to the control of their proliferation and differentiation within a functional organism, is thus primordial to safely profit from their therapeutic benefits. Here, we review recent advances in the understanding of germline stem cell proliferation control by factors that respond to the nutritional status and/or insulin signaling, through studies performed in C. elegans and Drosophila. Together, these data uncover some shared fundamental features that underlie the central control of cellular proliferation within a target stem cell population in an organism. These features may indeed be conserved in higher organisms and may apply to various other stem cell populations

DAF-18/PTEN signals through AAK-1/AMPK to inhibit MPK-1/MAPK in feedback control of germline stem cell proliferation

Under replete growth conditions, abundant nutrient uptake leads to the systemic activation of insulin/IGF-1 signalling (IIS) and the promotion of stem cell growth/proliferation. Activated IIS can stimulate the ERK/MAPK pathway, the activation of which also supports optimal stem cell proliferation in various systems. Stem cell proliferation rates can further be locally refined to meet the resident tissue’s need for differentiated progeny. We have recently shown that the accumulation of mature oocytes in the C. elegans germ line, through DAF-18/PTEN, inhibits adult germline stem cell (GSC) proliferation, despite high systemic IIS activation. We show here that this feedback occurs through a novel cryptic signalling pathway that requires PAR-4/LKB1, AAK-1/AMPK and PAR-5/14-3-3 to inhibit the activity of MPK-1/MAPK, antagonize IIS, and inhibit both GSC proliferation and the production of additional oocytes. Interestingly, our results imply that DAF-18/PTEN, through PAR-4/LKB1, can activate AAK-1/AMPK in the absence of apparent energy stress. As all components are conserved, similar signalling cascades may regulate stem cell activities in other organisms and be widely implicated in cancer

DAF-18/PTEN locally antagonizes insulin signalling to couple germline stem cell proliferation to oocyte needs in C. elegans

During development, stem cell populations rapidly proliferate to populate the expanding tissues and organs. During this phase, nutrient status, by systemically affecting insulin/IGF-1 signalling, largely dictates stem cell proliferation rates. In adults, however, differentiated stem cell progeny requirements are generally reduced and vary according to the spatiotemporal needs of each tissue. We demonstrate here that differential regulation of germline stem cell proliferation rates i

Deficient Induction Response in a Xenopus Nucleocytoplasmic Hybrid

Defects in induction signaling and response underlie the nucleocytoplasmic incompatibility between two evolutionarily distant frog species, while specific treatments partially restore this response in explants and whole embryos

Roles of LKB1/AMPK signalling in the «C.elegans» dauer larva

Many organisms can execute a dormant state or diapause to survive harsh environmental conditions for extended durations. When Caenorhabditis elegans larvae enter the dauer diapause, they completely arrest development and feeding, but remain active and motile, yet become stress-resistant and extremely long-lived. Entry into dauer is associated with a reduction in insulin-like signalling, the establishment of a generalized cell cycle arrest, the accumulation of nutritive resources and a concomitant global change in metabolism. The precise molecular and physiological processes that induce cell cycle quiescence and enable long-term survival in the absence of caloric intake however remain largely unknown. I show here that the C. elegans orthologs of PTEN, STRAD, LKB1 and AMPK (α1, α2, β1, β2 subunits) cooperate to establish quiescence in the germline stem cell population during dauer development. Interestingly, germline mutations in LKB1 cause predisposition to cancer in humans, while mutations in STRAD or AMPK subunits do not seem to cause cancer. In C. elegans, LKB1 also regulates embryonic polarity, while STRAD and AMPK are dispensable for this process. Thus, my data suggest that LKB1/STRAD regulate cell growth/proliferation through AMPK, while LKB1 also acts independently to regulate polarity, and that this function may be critical for tumor suppression in human. In addition, I show that C. elegans larvae that lack LKB1/AMPK signalling rapidly consume their stored energy and prematurely expire following vital organ failure. This signalling pathway acts in adipose-like tissues to downregulate triglyceride hydrolysis so that these fat reserves are rationed to last thePlusieurs organismes peuvent entrer en dormance, ou diapause, pour survivre à des conditions environnementales précaires pour une durée prolongée. Lorsque des larves de Caenorhabditis elegans entrent en diapause dauer, elles cessent complètement de se développer ainsi que de se nourrir, cependant elles demeurent actives et mobiles, tout en acquérant une résistance au stress et une longévité extrême. L'entrée en stade dauer est accompagnée d'une réduction de signalisation par l'insuline, de l'établissement d'un arrêt généralisé du cycle cellulaire, de l'accumulation de ressources nutritives et d'un changement global au niveau du métabolisme. Les processus physiologiques et moléculaires précis qui induisent la quiescence cellulaire et permettent la survie prolongée en l'absence de tout apport calorique, demeurent toutefois essentiellement inconnus. Je montre ici que les orthologues de PTEN, STRAD, LKB1 et de AMPK (sous-unités α1, α2, β1, β2) chez C. elegans coopèrent dans l'optique d'établir la quiescence cellulaire dans la population de cellules germinales souches durant le développement de la larve dauer. Il est intéressant de préciser que chez l'humain, une mutation de LKB1 dans la lignée germinale provoque une prédisposition au cancer, tandis qu'une mutation dans une sous-unité de STRAD ou d'AMPK ne semble pas causer de cancer. Chez C. elegans, LKB1 régule aussi la polarité embryonnaire, tandis que STRAD et AMPK sont dispensables pour ce processus. Donc, mes données suggèrent que LKB1/STRAD régulent la croissance et la prolifération des cellules à travers AMPK, tandis que LKB1 fonctionne aussi indépendamment pour contrôle

DAF-18/PTEN signals through AAK-1/AMPK to inhibit MPK-1/MAPK in feedback control of germline stem cell proliferation

<div><p>Under replete growth conditions, abundant nutrient uptake leads to the systemic activation of insulin/IGF-1 signalling (IIS) and the promotion of stem cell growth/proliferation. Activated IIS can stimulate the ERK/MAPK pathway, the activation of which also supports optimal stem cell proliferation in various systems. Stem cell proliferation rates can further be locally refined to meet the resident tissue’s need for differentiated progeny. We have recently shown that the accumulation of mature oocytes in the <i>C</i>. <i>elegans</i> germ line, through DAF-18/PTEN, inhibits adult germline stem cell (GSC) proliferation, despite high systemic IIS activation. We show here that this feedback occurs through a novel cryptic signalling pathway that requires PAR-4/LKB1, AAK-1/AMPK and PAR-5/14-3-3 to inhibit the activity of MPK-1/MAPK, antagonize IIS, and inhibit both GSC proliferation and the production of additional oocytes. Interestingly, our results imply that DAF-18/PTEN, through PAR-4/LKB1, can activate AAK-1/AMPK in the absence of apparent energy stress. As all components are conserved, similar signalling cascades may regulate stem cell activities in other organisms and be widely implicated in cancer.</p></div