Integration of diet, stress, and hunger signals by the SIK kinase to coordinate gene expression, development and behavior

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McDonagh, Aja Erin

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2023

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Dissertation

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Caenorhabditis elegans , gene expression , KIN-29 , SIK , sleep , stress-induced sleep

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Abstract

Animals change their behavior and development depending on environmental and internal signals, but the underlying mechanisms are poorly understood. We postulate that the integration of diet, stress, and hunger signals by the SIK kinase acting in a subset of sensory neurons, coordinates gene expression, development and behavior. Understanding the mechanisms of SIK is therefore critical to understand the ways in which environmental signals like food or stress, and internal state signals such as hunger or fatigue, act to modulate gene expression, development, and behavior. Chapter 1 describes the role of salt-inducible kinases (SIKs) and their downstream targets as a signal integrator of external food and stress cues and internal signals such as hunger and fatigue, to coordinate development, gene expression, and behavior. With only one SIK isoform, KIN-29, the nematode Caenorhabditis elegans lends itself as an attractive model to study SIK signaling. In Chapter 2, using the nematode C. elegans, I show that the KIN-29/SIK dependent chemoreceptor gene srh-234 is regulated by dietary vitamin B12 via the myocyte enhancer transcription factor 2 (MEF-2) identifying a mechanism in which animals may fine tune their chemoreceptor gene expression to allow them to modify their behavioral responses. Chapter 3 identifies a role for KIN-29/SIK in aging and longevity and how it regulates lifespan via the class II histone-deacetylase HDA-4. Lastly, Chapter 4 explores the role of food and the downstream phosphorylation target of KIN-29/SIK, the CREB-regulated transcription cofactor 1 (CRTC-1) in the regulation of stress-induced sleep.

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