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Title:An emerging role for tcf7l2 at the nexus between metabolic regulation and social behavior
Author(s):Seward, Christopher H
Director of Research:Stubbs, Lisa J
Doctoral Committee Chair(s):Stubbs, Lisa J
Doctoral Committee Member(s):Gillette, Martha; Rhodes, Justin S; Li, Xin
Department / Program:Cell & Developmental Biology
Discipline:Cell and Developmental Biology
Degree Granting Institution:University of Illinois at Urbana-Champaign
Degree:Ph.D.
Genre:Dissertation
Subject(s):social behavior
genomics
sociogenomics
neurogenomics
animal behavior
social threat
neuroscience
gene regulation
genetics
metabolism
tcf7l2
wnt
wnt signaling
behavior
mice
mouse
brain
hypothalamus
tanycyte
tanycytes
cell culture
transcriptional regulatory networks
Abstract:Most animals utilize social behaviors that are preprogrammed at birth, for example, to avoid predators or defend territory. But these programs are also certainly modified by emotional learning and subsequent events. Indeed, failure to modify and master these instinctive responses underlie many behavioral disorders, including schizophrenia, autism, post-traumatic stress disorder, and depression. Interestingly, many of these disorders also have a major metabolic component and several lines of data suggest an integral link between stress, brain metabolism, and plasticity of the adult brain. Our goal is to investigate the molecular basis of that link, focused on the gene regulatory factors with common metabolic and neurodevelopmental function. To investigate this connection, we have turned to gene expression and chromatin analysis, investigating shared genomic actions that guide social behavior across species. In a large collaborative study, we have performed comparable behavioral challenges in three model social species: mice, honeybees, and stickleback fish. We then collected brain RNA and chromatin over a time course to quantify molecular events occurring in these animals’ brains as they adapt to the social challenge. Using this information, we identified shared and unique genes and pathways that respond to social stress across socially responsive regions of the brain. Several of these pathways connected metabolic signaling to plasticity across the brain in all three model species, indicating the evolutionary importance of these links. One particular pathway called out for deeply conserved mechanistic importance was the WNT pathway, which is known to control neurogenesis and plasticity in a wide variety of species. We hypothesize that the link between metabolism and plasticity is channeled through WNT signaling in the animal brain. These experiments also revealed that the conserved pathways are orchestrated by specific transcription factors in each species. In mice, the nuclear receptor ESRRA activates early metabolic signals in the hypothalamus, and these signals, in turn, lead to up-regulation of developmental transcription factors (TFs), most notably the WNT regulator, TCF7L2. Tcf7l2 has been linked to neurodevelopmental disorders, but importantly, is also the single gene that is most highly associated with human metabolic disorders as well. These data focused my attention on understanding the role of TCF7L2 in social challenge response and behavior, with experiments conducted at the whole animal, cellular and molecular levels. Because hypothalamus is central to the regulation of both metabolism and social behavior, I used immunohistochemistry (IHC) to identify TCF7L2-expressing cells in the hypothalamus, and examined the targets of Tcf7l2 molecular actions inside one specific hypothalamic cell type with key roles in both metabolic signaling and hypothalamic plasticity: the tanycytes. Examining TCF7L2 chromatin binding and gene expression in cultured tanycytes derived from wild type and Tcf7l2 mutant mice, I present data suggesting a direct role modulating canonical WNT, BMP and glutamate signaling, and genes involved in differentiation and development of those radial glia-like cells. The data suggest a critical role for Tcf7l2 in maintaining tanycyte pluripotency and the ability of those cells to differentiate into POMC-expressing neurons, a mechanism that permits plasticity of metabolism and behavior in adults. Further Investigations of the role of Tcf7l2 in adult brain may lead to a greater understanding of social disorders and the evolution of sociality itself.
Issue Date:2020-05-07
Type:Thesis
URI:http://hdl.handle.net/2142/108316
Rights Information:Copyright 2020 Christopher H Seward
Date Available in IDEALS:2020-08-27
Date Deposited:2020-05


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