TY - JOUR T1 - Celsr1a is essential for tissue homeostasis and onset of aging phenotypes in the zebrafish JF - bioRxiv DO - 10.1101/714063 SP - 714063 AU - Chunmei Li AU - Carrie Barton AU - Katrin Henke AU - Jake Daane AU - Joana Caetano-Lopes AU - Robert Tanguay AU - Matthew P. Harris Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/07/24/714063.abstract N2 - The 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. ER -