WD40 Wuho regulates intestinal stem cell homeostasis for Gut integrity and Longevity
Authors: Kreeti Kajal 1,2,3; Hwei-Jan Hsu 1,2,3
Affiliations: 1) Molecular and Biological Agricultural Sciences Program, Taiwan International Graduate Program, National Chung Hsing University and Academia Sinica, Taipei; 2) Graduate Institute of Biotechnology, National Chung Hsing University, Taichung; 3) Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan
Keywords: d. intestinal stem cells; q. homeostasis
Animal health and longevity require proper maintenance of gut homeostasis, which is largely supported by intestinal stem cells. However, the genetic regulators of stem cell activation and differentiation remain poorly understood. Here, we report that Wuho (Wh, a conserved WD40 protein) maintains the balance between intestinal stem cell (ISC) proliferation and differentiation, which affects the intestinal epithelial barrier and longevity in Drosophila females. Wh is enriched in ISCs; mutation of wh or knockdown in ISCs leads to ISC over-proliferation and aberrant differentiation of ISCs toward absorptive enterocytes. Furthermore, wh mutants exhibit leaky gut and upregulation of antimicrobial peptide transcripts, partially accounting for the shortened lifespan of wh mutants. In addition, ROS levels and JNK signaling are increased in the ISC lineage of the wh mutant gut, possibly due to bacterial infection. Elevated ROS and JNK signaling are known to enhance ISC proliferation and cause gut dysplasia. Thus, Wh appears to intrinsically and extrinsically regulate ISCs in order to promote gut homeostasis. Surprisingly, wh mutant ISCs, generated by FLP/FRT-induced mitotic recombination, show limited proliferation and differentiation capacities, suggesting a role of Wh in keeping ISCs in a quiescent state within the young gut. We speculate that when Wh is dysfunctional in all ISCs, a compensatory mechanism may be triggered to promote ISC proliferation, resulting in gut dysplasia. Furthermore, Wh expression is decreased in aged ISCs, and wh mutant guts mimic the aged gut phenotype, suggesting that Wh maintains gut physiological aging. We are currently working to identify Wh-interacting partners in the ISC lineage. Nevertheless, our results thus far suggest that Wh may prevent age-associated intestinal dysplasia and inflammation.