Postembryonic brain development is dependent on thyroid hormone (TH). Thyroid hormone deficiency during critical periods of human development leads to a condition of severe mental and growth retardation known as cretinism. Thyroid hormone has pleiotropic actions in the developing brain, including regulating cell proliferation, cell cycle exit and differentiation (neurogenesis). The goal of this research is to investigate the mechanisms by which TH promotes cell cycle exit and neurogenesis through its regulation of the de novo DNA methyltransferase DNMT3a. Amphibian development (metamorphosis) is dependent on TH, and we propose to use Xenopus tadpoles for our studies. We found that expression of the dnmt3a gene is strongly upregulated in subventricular zones (neurogenic zones) of the tadpole brain during spontaneous metamorphosis, or following treatment with TH. The frog dnmt3a gene has a putative TH response element (TRE) located in the intron, supporting direct TH receptor (TR) regulation. Comparative genomic analysis identified a similar, putative TRE in the mouse genome, supporting evolutionarily conservation of dnmt3a regulation by TR. Furthermore, TH induced dnmt3a mRNA in the mouse neuroblastoma cell line N2a[TR21]. Thyroid hormone is essential for neurogenesis during the early postnatal period. Recent findings showed that dnmt3a is required for neurogenesis. Gene expression analysis of neural stem cells (NSCs) from dnmt3a- deficient mice showed upregulation of genes involved in cell cycle control, supporting a defect in cell cycle exit and differentiation into the neuronal lineage. Several lines of evidence support that cyclin D1 is directly regulated by DNMT3a-mediated DNA methylation. Based on our preliminary findings and data reported in the scientific literature, we hypothesize that TH influences cell cycle exit in neural stem cells and neurogenesis through induction of Dnmt3a. To test this hypothesis we will investigate: 1) the functionality of the evolutionarily conserved TREs in frog and mouse dnmt3a genes;2) a role for DNMT3a in repression of cyclin D1 through methylation of its promoter;and 3) the effects of altering DNMT3a expression in vivo on cell cycle exit and lineage specification of NSCs. Successful completion of the proposed research will lead to advances in our understanding of the mechanisms by which TH controls neurological development through its influence on DNA methylation. Such understanding can contribute to the prevention, diagnosis and treatment of human neurological conditions such as mental retardation, autism spectrum disorder and schizophrenia.

Public Health Relevance

Thyroid hormone (TH) plays a critical role in early brain development. An important action of TH on the developing brain is to promote neurogenesis, or the production of neurons. Our preliminary work showed that an enzyme that methylates DNA is regulated by TH and plays an important role in neurogenesis. The proposed research will help us to understand how TH controls early brain development through DNA methylation. Such findings can contribute to the prevention, diagnosis and treatment of human neurological conditions.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1-F03A-F (20))
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Riddle, Robert D
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University of Michigan Ann Arbor
Schools of Arts and Sciences
Ann Arbor
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Kyono, Yasuhiro; Sachs, Laurent M; Bilesimo, Patrice et al. (2016) Developmental and Thyroid Hormone Regulation of the DNA Methyltransferase 3a Gene in Xenopus Tadpoles. Endocrinology 157:4961-4972