Papers by Irene Siegl-Cachedenier
Telomerase reverses epidermal hair follicle stem cell defects and loss of long-term survival asso... more Telomerase reverses epidermal hair follicle stem cell defects and loss of long-term survival associated with critically short telomeres
Journal of Molecular Cell Biology, 2016
Physics of Life Reviews, 2013
Physics of Life Reviews, 2013
A central question in biology is how secreted morphogens act to induce different cellular respons... more A central question in biology is how secreted morphogens act to induce different cellular responses within a group of cells in a concentration-dependent manner. Modeling morphogenetic output in multicellular systems has so far employed linear diffusion, which is the normal type of diffusion associated with Brownian processes. However, there is evidence that at least some morphogens, such as Hedgehog (Hh) molecules, may not freely diffuse. Moreover, the mathematical analysis of such models necessarily implies unrealistic instantaneous spreading of morphogen molecules, which are derived from the assumptions of Brownian motion in its continuous formulation. A strict mathematical model considering Fick's diffusion law predicts morphogen exposure of the whole tissue at the same time. Such a strict model thus does not describe true biological patterns, even if similar and attractive patterns appear as results of applying such simple model. To eliminate non-biological behaviors from diffusion models we introduce flux-limited spreading (FLS), which implies a restricted velocity for morphogen propagation and a nonlinear mechanism of transport. Using FLS and focusing on intercellular Hh-Gli signaling, we model a morphogen gradient and highlight the propagation velocity of morphogen particles as a new key biological parameter. This model is then applied to the formation and action of the Sonic Hh (Shh) gradient in the vertebrate embryonic neural tube using our experimental data on Hh spreading in heterologous systems together with published data. Unlike linear diffusion models, FLS modeling predicts concentration fronts and the evolution of gradient dynamics and responses over time. In addition to spreading restrictions by extracellular binding partners, we suggest that the constraints imposed by direct bridges of information transfer such as nanotubes or cytonemes underlie FLS. Indeed, we detect and measure morphogen particle velocity in such cell extensions in different systems.
Genes & Development, 2007
Mismatch repair (MMR) has important roles in meiotic and mitotic recombination, DNA damage signal... more Mismatch repair (MMR) has important roles in meiotic and mitotic recombination, DNA damage signaling, and various aspects of DNA metabolism including class-switch recombination, somatic hypermutation, and triplet-repeat expansion. Defects in MMR are responsible for human cancers characterized by microsatellite instability. Intriguingly, MMR deficiency has been shown to rescue survival and proliferation of telomerase-deficient yeast strains. A putative role for MMR at mammalian telomeres that could have an impact on cancer and aging is, however, unknown. Here, we studied the role of MMR in response to dysfunctional telomeres by generating mice doubly deficient for telomerase and the PMS2 MMR gene (Terc−/−/PMS2−/− mice). PMS2 deficiency prolonged the mean lifespan and median survival of telomerase-deficient mice concomitant with rescue of degenerative pathologies. This rescue of survival was independent of changes in telomere length, in sister telomere recombination, and in microsatel...
Aging Cell, 2009
Mutations in the mismatch repair (MMR) pathway occur in human colorectal cancers with microsatell... more Mutations in the mismatch repair (MMR) pathway occur in human colorectal cancers with microsatellite instability. Mounting evidence suggests that cell-cycle arrest in response to a number of cellular stresses, including telomere shortening, is a potent anticancer barrier. The telomerase-deficient mouse model illustrates the anticancer effect of cell-cycle arrest provoked by short telomeres. Here, we describe a role for the MMR protein, MSH2, in signaling cell-cycle arrest in a p21/p53-dependent manner in response to short telomeres in the context of telomerasedeficient mice. In particular, progressively shorter telomeres at successive generations of MSH2-/-Terc-/-mice did not suppress cancer in these mice, indicating that MSH2 deficiency abolishes the tumor suppressor activity of short telomeres. Interestingly, MSH2 deficiency prevented degenerative pathologies in the gastrointestinal tract of MSH2-/-Terc-/mice concomitant with a rescue of proliferative defects. The abolishment of the anticancer and pro-aging effects of short telomeres provoked by MSH2 abrogation was independent of changes in telomere length. These results highlight a role for MSH2 in the organismal response to dysfunctional telomeres, which in turn may be important in the pathobiology of human cancers bearing mutations in the MMR pathway.
The Journal of Cell Biology, 2007
EMBO Molecular Medicine, 2010
Previous studies demonstrate the initiation of colon cancers through deregulation of WNT-TCF sign... more Previous studies demonstrate the initiation of colon cancers through deregulation of WNT-TCF signalling. An accepted but untested extension of this finding is that incurable metastatic colon carcinomas (CCs) universally remain WNT-TCFdependent, prompting the search for WNT-TCF inhibitors. CCs and their stem cells also require Hedgehog (HH)-GLI1 activity, but how these pathways interact is unclear. Here we define coincident high-to-low WNT-TCF and low-to-high HH-GLI transitions in patient CCs, most strikingly in their CD133 þ stem cells, that mark the development of metastases. We find that enhanced HH-GLI mimics this transition, driving also an embryonic stem (ES)-like stemness signature and that GLI1 can be regulated by multiple CC oncogenes. The data support a model in which the metastatic transition involves the acquisition or enhancement of a more primitive ES-like phenotype, and the downregulation of the early WNT-TCF programme, driven by oncogene-regulated high GLI1 activity. Consistently, TCF blockade does not generally inhibit tumour growth; instead, it, like enhanced HH-GLI, promotes metastatic growth in vivo. Treatments for metastatic disease should therefore block HH-GLI1 but not WNT-TCF activities.
Cell, 2012
Satellite cells are adult skeletal muscle stem cells that are quiescent and constitute a poorly d... more Satellite cells are adult skeletal muscle stem cells that are quiescent and constitute a poorly defined heterogeneous population. Using transgenic Tg:Pax7-nGFP mice, we show that Pax7-nGFP Hi cells are less primed for commitment and have a lower metabolic status and delayed first mitosis compared to Pax7-nGFP Lo cells. Pax7-nGFP Hi can give rise to Pax7-nGFP Lo cells after serial transplantations. Proliferating Pax7-nGFP Hi cells exhibit lower metabolic activity, and the majority performs asymmetric DNA segregation during cell division, wherein daughter cells retaining template DNA strands express stem cell markers. Using chromosome orientation-fluorescence in situ hybridization, we demonstrate that all chromatids segregate asymmetrically, whereas Pax7-nGFP Lo cells perform random DNA segregation. Therefore, quiescent Pax7-nGFP Hi cells represent a reversible dormant stem cell state, and during muscle regeneration, Pax7-nGFP Hi cells generate distinct daughter cell fates by asymmetrically segregating template DNA strands to the stem cell. These findings provide major insights into the biology of stem cells that segregate DNA asymmetrically.
Aging Cell, 2009
Mounting evidence suggests that cell-cycle arrest in response to a number of cellular stresses, i... more Mounting evidence suggests that cell-cycle arrest in response to a number of cellular stresses, including telomere shortening, is a potent anticancer barrier. The telomerase-deficient mouse model illustrates the anticancer effect of cell-cycle arrest provoked by short telomeres. Here, we describe a role for the MMR protein, MSH2, in signaling cell-cycle arrest in a p21/p53-dependent manner in response to short telomeres in the context of telomerasedeficient mice. In particular, progressively shorter telomeres at successive generations of MSH2 -/-Terc -/-mice did not suppress cancer in these mice, indicating that MSH2 deficiency abolishes the tumor suppressor activity of short telomeres. Interestingly, MSH2 deficiency prevented degenerative pathologies in the gastrointestinal tract of MSH2 -/-Terc -/mice concomitant with a rescue of proliferative defects. The abolishment of the anticancer and pro-aging effects of short telomeres provoked by MSH2 abrogation was independent of changes in telomere length. These results highlight a role for MSH2 in the organismal response to dysfunctional telomeres, which in turn may be important in the pathobiology of human cancers bearing mutations in the MMR pathway.
Genes & Development, 2007
Mismatch repair (MMR) has important roles in meiotic and mitotic recombination, DNA damage signal... more Mismatch repair (MMR) has important roles in meiotic and mitotic recombination, DNA damage signaling, and various aspects of DNA metabolism including class-switch recombination, somatic hypermutation, and triplet-repeat expansion. Defects in MMR are responsible for human cancers characterized by microsatellite instability. Intriguingly, MMR deficiency has been shown to rescue survival and proliferation of telomerase-deficient yeast strains. A putative role for MMR at mammalian telomeres that could have an impact on cancer and aging is, however, unknown. Here, we studied the role of MMR in response to dysfunctional telomeres by generating mice doubly deficient for telomerase and the PMS2 MMR gene (Terc −/− /PMS2 −/− mice). PMS2 deficiency prolonged the mean lifespan and median survival of telomerase-deficient mice concomitant with rescue of degenerative pathologies. This rescue of survival was independent of changes in telomere length, in sister telomere recombination, and in microsatellite instability. Importantly, PMS2 deficiency rescued cell proliferation defects but not apoptotic defects in vivo, concomitant with a decreased p21 induction in response to short telomeres. The proliferative advantage conferred to telomerase-deficient cells by the ablation of PMS2 did not produce increased tumors. Indeed, Terc −/− /PMS2 −/− mice showed reduced tumors compared with PMS2 −/− mice, in agreement with a tumor suppressor role for short telomeres in the context of MMR deficiencies. These results highlight an unprecedented role for MMR in mediating the cellular response to dysfunctional telomeres in vivo by attenuating p21 induction.
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Papers by Irene Siegl-Cachedenier