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

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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Celsr1a is essential for tissue homeostasis and onset of aging phenotypes in the zebrafish

10.1101/714063 ◽

2019 ◽

Author(s):

Chunmei Li ◽

Carrie Barton ◽

Katrin Henke ◽

Jake Daane ◽

Joana Caetano-Lopes ◽

...

Keyword(s):

Stem Cell ◽

Cell Fate ◽

Progenitor Cell ◽

Genetic Basis ◽

Premature Aging ◽

Vertebrate Development ◽

Loss Of Function ◽

Mutagenesis Screen ◽

Stem Cell Maintenance ◽

Type Receptor

SUMMARYThe use of experimental genetics has been invaluable in defining the complex mechanisms by which aging and longevity are regulated. Zebrafish, while a prominent model for understanding the genetic basis of 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, fruehrentner, that displays typical signs of aging already at young adult stages. We find that the phenotype is due to loss-of-function in the non-classical cadherin EGF LAG seven-pass G-type receptor 1a (celsr1a). The premature aging phenotype is not associated with increased cellular senescence or decreased telomere length but is a result of a broad failure to maintain progenitor cell populations in tissues. Through the analysis of a knockin reporter line, we find that celsr1aGFP is expressed broadly in early development but becomes restricted during maturation. We show that celsr1a is essential for maintenance of stem cell progenitors and leads to shifts in cell fate determination. Although celsr1a has many signaling functions including establishment of polarity within tissues, we show that caloric restriction can ameliorate the effect of celsr1a on lifespan in part through compensatory upregulation of celsr1 paralogues. 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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TAp63 Prevents Premature Aging by Promoting Adult Stem Cell Maintenance

Cell Stem Cell ◽

10.1016/j.stem.2009.04.003 ◽

2009 ◽

Vol 5 (1) ◽

pp. 64-75 ◽

Cited By ~ 162

Author(s):

Xiaohua Su ◽

Maryline Paris ◽

Young Jin Gi ◽

Kenneth Y. Tsai ◽

Min Soon Cho ◽

...

Keyword(s):

Stem Cell ◽

Adult Stem Cell ◽

Premature Aging ◽

Stem Cell Maintenance ◽

Cell Maintenance

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The RNA binding protein Swm is critical for Drosophila melanogaster intestinal progenitor cell maintenance

10.1101/2022.01.03.474858 ◽

2022 ◽

Author(s):

Ishara S Ariyapala ◽

Kasun Buddika ◽

Heather A Hundley ◽

Brian Calvi ◽

Nicholas Sokol

Keyword(s):

Stem Cell ◽

Progenitor Cells ◽

Progenitor Cell ◽

Transcriptional Control ◽

Rna Binding ◽

Rna Binding Protein ◽

Adult Stem Cell ◽

Stem Cell Maintenance ◽

And Function ◽

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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