Allelic Dio3 control of brain development and behavior

About This Grant

Abstract Neurodevelopmental and neurological and mood disorders manifest a high prevalence in modern society and a marked sex bias, but their etiology remain poorly understood, hampering our efforts for their prevention, diagnosis and treatment. Although genome-wide association studies in the last two decades have greatly advanced our knowledge of the genetic basis for these conditions, identified candidate genes and their genetic variations only explain a small percentage of clinical cases. This divergence is dramatically illustrated by autism and schizophrenia, whose heritability is close to 80%, but for which genetic factors account for less than 20% of clinical cases. To identify new contributors to the etiology of these and related neurodevelopmental conditions, we propose that alterations in thyroid hormone states during development, which may occur due to environmentally-driven epigenetic phenomena, maternal thyroid disease or exposure to endocrine disruptors, contribute to the generation of neurodevelopmental disease and fit two well-established but undefined components in their etiology: environmental influence via epigenetic alterations and sex bias. We hypothesize that changes in the allelic expression and gene dosage of the imprinted gene Dio3, which controls thyroid hormone action in the developing central nervous system, leads to neurological deficits, affecting gene expression programs in the developing brain, brain sexual differentiation, brain morphology and behavior of relevance to neurodevelopmental and psychiatric conditions. We will use transgenic mouse models with alteration in Dio3 and developmental thyroid hormone exposure to test these hypotheses in the following Specific Aims: (i) To determine the neurological impact of aberrant Dio3 allelic expression; (ii) To evaluate the role of full DIO3 deficiency and altered Dio3 allelic expression in brain sexual differentiation and associated disease-relevant behaviors with a sexual bias. By using a dynamic mouse model of epigenetic dysregulation of Dio3, we anticipate our project will demonstrate that modifications in brain thyroid hormone states during development exert a substantial effect on the gene expression programs of the central nervous system, ultimately leading to disease-relevant neurological deficits impacting corticogenesis, brain morphology and hydrocephalus, and behaviors related to depression, anxiety, sociability, hyperactivity, sexual activity and reward. We ultimately expect that epigenetic markers and dysregulation of the Dio3 gene, and the changes in thyroid hormone status associated with them, can be used as evidence of exposures to thyroid hormone earlier in life and be utilized as predictors of susceptibility to neurodevelopmental conditions.