Universität zu Köln

Nonninger, Tim Janis (2024). The Interplay of nutrient cues and growth signaling in diapause reveals novel mechanisms of stem cell longevity and cellular senescence. PhD thesis, Universität zu Köln.

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Abstract

Diapause is a long-lived state of resilience that allows organisms to outlast adversity. C. elegans can endure months in a fasting-induced adult reproductive diapause (ARD) and, upon refeeding, regenerate and reproduce. Here we find that mutants of ARD master regulator hlh-30/TFEB arrest in a novel senescence-like state during ARD and refeeding, in which germline stem cells are characterized by DNA damage, nucleolar expansion, cell cycle arrest, and mitochondrial fusion, alongside dysregulated immune and growth metabolic signatures, elevated senescence-associated β-galactosidase and premature aging at the organismal level. Forward genetic screens reveal a TFEB-TGFβ signaling axis that systemically controls diapause, stem cell longevity, and senescence, aligning nutrient supply to proper metabolism and growth signaling. hlh-30 mutation causes a misalignment between nutrient cues and growth signaling-induced senescence (MINGIS) that abrogates stem cell and organismal longevity, which can be restored by downregulating TGFβ signaling. Notably, TFEB’s vital role is conserved in mouse embryonic and human cancer diapause. Thus, ARD offers a powerful model to rapidly characterize diapause-related regulatory pathways, and study stem cell longevity and senescence in vivo, directly relevant to mammals.

Item Type:	Thesis (PhD thesis)
Creators:	Creators Email ORCID ORCID Put Code Nonninger, Tim Janis UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-748498
Date:	30 December 2024
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Außeruniversitäre Forschungseinrichtungen > MPI for Biology of Ageing
Subjects:	Life sciences
Uncontrolled Keywords:	Keywords Language Adult reproductive diapause, C. elegans, Stem cells, Senescence, Aging, Resilience, HLH-30/TFEB UNSPECIFIED
Date of oral exam:	18 November 2024
Referee:	Name Academic Title Antebi, Adam Prof. Dr. Thorsten, Hoppe Prof. Dr. Keith, Blackwell Prof. Dr.
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/74849