TAp63 Prevents Premature Aging by Promoting Adult Stem Cell Maintenance

The regulation of stem cell survival, self-renewal, and differentiation is critical for the maintenance of tissue homeostasis. Although the involvement of signaling pathways and transcriptional control mechanisms in stem cell regulation have been extensively investigated, the role of post-transcriptional control is still poorly understood. Here we show that the nuclear activity of the RNA-binding protein Second Mitotic Wave Missing (Swm) is critical for Drosophila intestinal stem cells (ISCs) and their daughter cells, enteroblasts (EBs), to maintain their identity and function. Loss of swm in these intestinal progenitor cells leads ISCs and EBs to lose defined cell identities, fail to proliferate, and detach from the basement membrane, resulting in severe progenitor cell loss. swm loss further causes nuclear accumulation of poly(A)+ RNA in progenitor cells. Swm associates with transcripts involved in epithelial cell maintenance and adhesion, and the loss of swm, while not generally affecting the levels of these Swm-bound mRNAs, leads to elevated expression of proteins encoded by some of them, including the fly orthologs of Filamin and Talin. Taken together, this study indicates a role for Swm in adult stem cell maintenance, and raises the possibility that nuclear post-transcriptional gene regulation plays vital roles in controlling adult stem cell maintenance and function.

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Adult stem cell maintenance and tissue regeneration in the ageing context: the role for A-type lamins as intrinsic modulators of ageing in adult stem cells and their niches

Journal of Anatomy ◽

10.1111/j.1469-7580.2008.00928.x ◽

2008 ◽

Vol 213 (1) ◽

pp. 5-25 ◽

Cited By ~ 46

Author(s):

Vanja Pekovic ◽

Christopher J. Hutchison

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Tissue Regeneration ◽

Adult Stem Cells ◽

Adult Stem Cell ◽

Stem Cell Maintenance ◽

Cell Maintenance

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Coupling of Hedgehog and Hippo pathways promotes stem cell maintenance by stimulating proliferation

The Journal of Cell Biology ◽

10.1083/jcb.201309141 ◽

2014 ◽

Vol 205 (3) ◽

pp. 325-338 ◽

Cited By ~ 38

Author(s):

Jianhua Huang ◽

Daniel Kalderon

Keyword(s):

Stem Cells ◽

Cell Proliferation ◽

Stem Cell ◽

Ovarian Follicle ◽

Adult Stem Cell ◽

Cell Therapies ◽

Stem Cell Proliferation ◽

Stem Cell Maintenance ◽

Hh Signaling ◽

Cell Maintenance

It is essential to define the mechanisms by which external signals regulate adult stem cell numbers, stem cell maintenance, and stem cell proliferation to guide regenerative stem cell therapies and to understand better how cancers originate in stem cells. In this paper, we show that Hedgehog (Hh) signaling in Drosophila melanogaster ovarian follicle stem cells (FSCs) induces the activity of Yorkie (Yki), the transcriptional coactivator of the Hippo pathway, by inducing yki transcription. Moreover, both Hh signaling and Yki positively regulate the rate of FSC proliferation, both are essential for FSC maintenance, and both promote increased FSC longevity and FSC duplication when in excess. We also found that responses to activated Yki depend on Cyclin E induction while responses to excess Hh signaling depend on Yki induction, and excess Yki can compensate for defective Hh signaling. These causal connections provide the most rigorous evidence to date that a niche signal can promote stem cell maintenance principally by stimulating stem cell proliferation.

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Control of the dynamics and homeostasis of the Drosophila Hedgehog receptor Patched by two C2-WW-HECT-E3 Ubiquitin ligases

Open Biology ◽

10.1098/rsob.150112 ◽

2015 ◽

Vol 5 (10) ◽

pp. 150112 ◽

Cited By ~ 4

Author(s):

Amira Brigui ◽

Line Hofmann ◽

Camilla Argüelles ◽

Matthieu Sanial ◽

Robert A. Holmgren ◽

...

Keyword(s):

Stem Cell ◽

Control Animal ◽

Adult Stem Cell ◽

Ubiquitin Ligases ◽

Animal Development ◽

Stem Cell Maintenance ◽

Gradient Formation ◽

Lysosomal Targeting ◽

Py Motif ◽

Cell Maintenance

The conserved Hedgehog (HH) signals control animal development, adult stem cell maintenance and oncogenesis. In Drosophila , the HH co-receptor Patched (PTC) controls both HH gradient formation and signalling. PTC is post-translationally downregulated by HH, which promotes its endocytosis and destabilization, but the mechanisms of PTC trafficking and its importance in the control of PTC remain to be understood. PTC interacts with E3 Ubiquitin (UB)-ligases of the C2-WW-HECT family; two of them—SMURF and NEDD4—are known to regulate its levels. We demonstrate that mutation of the PTC PY motif, which mediates binding of C2-WW-HECT family members, inhibits its internalization but not its autonomous and non-autonomous signalling activities. In addition, we show that the two related UB-C2-WW-HECT ligases NEDD4 and SU(DX) regulate PTC trafficking and finely tune its accumulation through partially redundant but distinct functions. While both NEDD4 and SU(DX) promote PTC endocytosis, only SU(DX) is able to induce its lysosomal targeting and degradation. In conclusion, PTC trafficking and homeostasis are tightly regulated by a family of UB-ligases.

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celsr1a is essential for tissue homeostasis and onset of aging phenotypes in the zebrafish

eLife ◽

10.7554/elife.50523 ◽

2020 ◽

Vol 9 ◽

Cited By ~ 1

Author(s):

Chunmei Li ◽

Carrie Barton ◽

Katrin Henke ◽

Jake Daane ◽

Stephen Treaster ◽

...

Keyword(s):

Stem Cell ◽

Progenitor Cell ◽

Tissue Homeostasis ◽

Premature Aging ◽

Vertebrate Development ◽

Loss Of Function ◽

Mutagenesis Screen ◽

Stem Cell Maintenance ◽

Late Stages ◽

Cell Maintenance

The use of genetics has been invaluable in defining the complex mechanisms of aging and longevity. Zebrafish, while a prominent model for vertebrate development, have not been used systematically to address questions of how and why we age. In a mutagenesis screen focusing on late developmental phenotypes, we identified a new mutant that displays aging phenotypes at young adult stages. We find that the phenotypes are due to loss-of-function in the non-classical cadherin celsr1a. The premature aging is not associated with increased cellular senescence or telomere length but is a result of a failure to maintain progenitor cell populations. We show that celsr1a is essential for maintenance of stem cell progenitors in late stages. Caloric restriction can ameliorate celsr1a aging phenotypes. These data suggest that celsr1a function helps to mediate stem cell maintenance during maturation and homeostasis of tissues and thus regulates the onset or expressivity of aging phenotypes.

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