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FOREWORD
PREFACE
ACKNOWLEDGEMENTS
DEDICATION
An Introduction to Thyroid Physiology
Abstract
INTRODUCTION
THE UNIQUENESS OF THE THYROID GLAND
Embryology
The Thyroid Follicles
Thyroid Hormone Synthesis
CIRCULATING THYROID HORMONES
THYROID HORMONE METABOLISM
Deiodinases
Type 1 Deiodinase (DIO1)
Type 2 Deiodinase (DIO2)
Type 3 Deiodinase (DIO3)
Thyronamines
THYROID HORMONE ACTION
Type 1: Nuclear Receptor-Dependent Signaling with Direct Binding to DNA
Type 2: Nuclear Receptor-Dependent Signaling with Indirect Binding to DNA
Type 3: Nuclear Receptor-Dependent Signaling without DNA Binding
Type 4: Nuclear Receptor-Independent Signaling
The Endocrine Disruptor Bisphenol A (BPA) and its Interaction with Thyroid Hormone Receptors
EVOLUTIONARY ASPECTS OF THYROID HORMONES
CONCLUDING REMARKS
REFERENCES
Congenital Hypothyroidism
Abstract
INTRODUCTION
PRIMARY CONGENITAL HYPOTHYROIDISM
Thyroid Dysgenesis
Thyroid Dyshormonogenesis
Iodide Transporters
Iodide Oxidation and Organification
Thyroglobulin
Dehalogenase
TSH Resistance
CENTRAL CONGENITAL HYPOTHYROIDISM
DEVELOPMENTAL ARREST IN CONGENITAL HYPOTHYROIDISM
Untreated Congenital Hypothyroidism
Persistence of Brain Damage Despite Early Treatment
CONCLUDING REMARKS
REFERENCES
Deiodinases in the Brain
Abstract
INTRODUCTION
THYROXINE, A TRIIODOTHYRONINE PRECURSOR
DEIODINASES IN THE RODENT BRAIN
Type 1 Deiodinase
Type 2 Deiodinase
Developmental Changes in Type-2 Deiodinase Activity
Dio2 Regional and Cellular Expression in the Brain
The Paracrine Model of Deiodination and Action
The Significance of Dio2 Expression in Astrocytes
How the Lack of DIO2 Impacts the Brain
Type 3 Deiodinase
Developmental Changes in Type-3 Deiodinase Activity
How the Lack of DIO3 Impacts the Brain
REGULATION OF DEIODINASE BRAIN EXPRESSION AND ACTIVITY
DEIODINASES IN THE HUMAN BRAIN
Thyroid Hormone Concentrations and Deiodinase Activity in the Human Fetal Brain
DIO2 in Stem Cells of the Developing Human Fetal Cerebral Cortex
Genetic Deficiencies in Deiodinase Function
The Thr92Ala-DIO2 Polymorphism
CONCLUDING REMARKS
REFERENCES
Unraveling the Role of Maternal Thyroid Hormones on Fetal Development
Abstract
INTRODUCTION
PLACENTAL PERMEABILITY TO THYROID HORMONES IN RODENTS
The Relevance of T4 as the Source of T3 in the Fetal Brain
THE PERMEABILITY OF THE HUMAN PLACENTA TO THYROID HORMONES
Maternal Thyroid Hormones in the Fetus During Early Pregnancy
MATERNAL HYPOTHYROIDISM AND HYPOTHYROXINEMIA
Maternal Hypothyroidism and Infant Brain Development: Experimental Studies
Maternal Clinical Hypothyroidism
Maternal Hypothyroxinemia
CONCLUDING REMARKS
REFERENCES
Endemic Goiter and Cretinism: Pathophysiology of Iodine Deficiency
Abstract
INTRODUCTION
THE IODINE CYCLE
Iodine Requirements
ENDEMIC GOITER AND CRETINISM
Neurological Manifestations of Endemic Cretinism
Pathogenesis
Myxedematous Cretinism
PHYSIOLOGICAL MECHANISMS SET IN MOTION BY IODINE DEFICIENCY IN EXPERIMENTAL ANIMALS
Thyroid Autoregulation
Thyroidal Iodotyrosine Dehalogenase
Mechanisms Leading to Preferential Secretion of T3
Changes in Thyroid Hormone Deiodination in Extrathyroidal Organs
Iodine Deficiency in Developing Rats
The Sheep Model
CONCLUDING REMARKS
REFERENCES
Cellular Transporters for Thyroid Hormones
Abstract
INTRODUCTION
PROTEIN FAMILIES WITH THYROID HORMONE TRANSPORTING ACTIVITY
Bile Acid Transporters
Amino Acid Transporters
Organic Anion Transporter Polypeptides (OATPs)
A Syndrome of Cerebral Hypometabolism and Juvenile Neurodegeneration Caused by Mutated SLCO1C1
Monocarboxylate Transporters
Monocarboxylate Transporter 8 (MCT8)
Monocarboxylate Transporter 10 (MCT10)
TRANSPORT OF THYROID HORMONES THROUGH THE BRAIN BARRIERS
The Blood-Brain Barrier (BBB)
The Blood-Cerebrospinal Fluid Barrier (BCSFB)
The Meningeal Barrier
Circumventricular Organs
Transient Embryonic CSF-Brain Barrier
TRANSPORT OF THYROID HORMONES IN OTHER ORGANISMS
Thyroid Hormone Transporters in Zebrafish
Thyroid Hormone Transport in Chicken
CONCLUDING REMARKS
REFERENCES
The Allan-Herndon-Dudley Syndrome: Pathophysiology and Mouse Models of MCT8 Deficiency
Abstract
INTRODUCTION
THE ALLAN-HERNDON-DUDLEY SYNDROME (ORPHANET #300523)
Clinical Aspects
Histopathological Changes in the MCT8-Deficient Brain
Histopathology of MCT8-Deficient Fetus Brain
Histopathology of an MCT8-Deficient Child Brain
MCT8 DEFICIENCY IN MICE
Altered Thyroid Gland Secretion and Tissue Deiodinase Activity
Changes in Thyroid Gland Secretion
Changes in Deiodinase Activities
Proposed Sequence of Events in MCT8 Deficiency
The Phenotype of MCT8-Deficient Mice
Peripheral Metabolism
Brain Metabolism
Brain Architecture and Function
Perinatal Brain Hyperthyroidism
MOUSE MODELS OF ALLAN-HERNDON-DUDLEY SYNDROME
Mice Deficient in MCT8 and OATP1C1
Mice Deficient in MCT8 and DIO2
The MCT8P253L Variant
THERAPEUTIC APPROACHES
Thyroxine
Intraamniotic Thyroxine Treatment
Diiodothyropropionic Acid (DITPA)
3,5,3’-Triiodothyroacetic Acid
Sobetirome
Sodium Phenylbutyrate (NaPB)
Gene Therapy
CONCLUDING REMARKS
REFERENCES
Thyroid Hormone Receptors in the Brain: Distribution and Deletion Effects on Brain Structure and Behavior
Abstract
INTRODUCTION
T3 RECEPTOR EXPRESSION IN THE RODENT BRAIN
Early Expression and Distribution of Receptor mRNAs
Receptor Protein Distribution
Receptor Expression in Different Cell Types
UNDERSTANDING RECEPTOR FUNCTION THROUGH MOUSE GENETIC MODIFICATIONS
The Phenotypes of Thyroid Hormone Receptor Knockout Mice
TRα1 in the Control of Emotions, Learning, and Memory
What the Receptor Gene Deletions Tell About Their in vivo Functions
Why Receptor Deletion is Not Equivalent to Hormone Deprivation: Aporeceptor Function
Aporeceptor Function in Developmental Timing Control
T3 RECEPTOR EXPRESSION IN THE HUMAN FETAL BRAIN
CONCLUDING REMARKS
REFERENCES
Pathophysiology and Mouse Models of Thyroid Hormone Resistance Syndromes: A Focus on the Brain
Abstract
INTRODUCTION
GENERAL ASPECTS OF RTH
THE BRAIN PHENOTYPE OF RTH
Resistance to Thyroid Hormone Due to THRB Mutations (RTHβ)
Resistance to Thyroid Hormone Due to THRA Mutations (RTHα)
Compound TRα1 and TRα2 Mutations
MOUSE MODELS OF RTH
The PV Mutation
The Family S Mutation
The R384C Mutation
The ThraAMI Allele and TRα1L400R Mutation
CONCLUDING REMARKS
REFERENCES
Thyroid Hormone-Regulated Genes in the Brain
Abstract
INTRODUCTION
PATTERNS OF BRAIN GENE REGULATION BY THYROID HORMONE in vivo
Controlling Gene Expression Timing
Reelin Expression
Myelin Gene Expression
Regional Control of Gene Expression
Regional Control of Neurogranin (Nrgn) Expression
THOUSANDS OF GENES ARE SENSITIVE TO THYROID HORMONE in vivo
The Diversity of Genes Regulated by Thyroid Hormone
Are There Universal T3 Transcriptionally-Responsive Genes?
THE CAMK4 SIGNALING NETWORK
PRIMARY AND SECONDARY T3 RESPONSES IN PRIMARY CEREBRO-CORTICAL CELLS
Developmental and Growth Factor Genes
Genes Involved in the Control of Cell Migration
Ephrins and Ephrin Receptors
Chemorepulsive Molecules: Slit and Robo
Semaphorins
Genes Encoding Extracellular Matrix Proteins
Transcription Factors
Retinoic Acid Metabolism
Potassium Channels
Neurotransmitter Receptors
Genes Enriched in Cortex Layers Neurons
THYROID HORMONE SIGNALING IN GABAERGIC CELLS
THYROID HORMONE SIGNALING IN ASTROCYTES
CONCLUDING REMARKS
REFERENCES
Actions of Thyroid Hormones on Myelination
Abstract:
INTRODUCTION
THE GENERATION OF OLIGODENDROCYTES
Oligodendrogenesis in Humans
THYROID HORMONES AND MYELINATION
Actions of Thyroid Hormone on Oligodendrocyte Differentiation
Regulated Genes
Role of the Thyroid Hormone Receptor Isoforms
NUCLEAR MAGNETIC RESONANCE TECHNIQUES FOR STUDYING MYELINATION in vivo
T1- and T2-Weighted Images
Diffusion Tensor Imaging
Magnetization Transfer Imaging
Magnetic Resonance Spectroscopy
Brain Magnetic Resonance Studies on Hypothyroid States
Congenital Hypothyroidism
Maternal Hypothyroidism
Allan-Herndon-Dudley Syndrome
CONCLUDING REMARKS
REFERENCES
How Thyroid Hormones Shape the Brain
Abstract
INTRODUCTION
THYROID HORMONES PROMOTE AXODENDRITIC DEVELOPMENT
ROLE OF THYROID HORMONES IN THE DEVELOPMENT OF SPECIFIC BRAIN REGIONS
The Cerebral Cortex
The First Trimester
Thyroid Hormones During the First Trimester
The Second Trimester and Beyond
Thyroid Hormones During the Second Trimester
The Impact of Thyroid Hormone Deficiency on the Cerebral Cortex
Thyroid Hormone Action during Cortical Development: Unraveling the Complexity
Cajal-Retzius Cells
Subplate Neurons
T3 Target Genes in Cortical Layering
The Adult Cerebral Cortex
The Hippocampus
Cell Types of the Hippocampus
The Role of Thyroid Hormones
The Cerebellum
Cerebellar Cell Types
Cerebellar Cortical Development
The Purkinje Cells
The Granular Cells
Interneurons
Glial Cells
The Hypothyroid Cerebellum
Gene Expression
Role of Thyroid Hormone Receptors
The Striatum
Effects of Experimental Hypothyroidism
Genes Regulated by Thyroid Hormones in the Striatum
Genes Regulated by Thyroid Hormones in the Adult Striatum
SENSE ORGANS
The Retina
Retinal Cell Types
Role of Thyroid Hormones
The Cochlea
Role of Deiodinases
Role of Transporters
Role of Receptors
CONCLUDING REMARKS
REFERENCES
Mechanisms of Thyroid Hormone Action on Adult Neurogenesis
Abstract
INTRODUCTION
NEUROGENESIS IN THE ADULT RODENT SUBVENTRICULAR ZONE
ADULT HIPPOCAMPAL NEUROGENESIS
Effects of Hypothyroidism
Role of Thyroid Hormone Receptors
Role of MCT8 and OATP1C1 Transporters
Behavioral Impact of Impaired Neurogenesis
CONCLUDING REMARKS
REFERENCES
Thyroid Hormones and Mood Disorders
Abstract
INTRODUCTION
THYROID FUNCTION AND MOOD DISORDERS
Hypothyroidism
Hyperthyroidism
Subclinical Thyroid Disease
USING THYROID HORMONES IN THE TREATMENT OF MOOD DISORDERS WITHOUT THYROID DYSFUNCTION
Association of Mood Disorders with Thyroid Hormone Levels in Euthyroid Individuals
CONCLUDING REMARKS
REFERENCES
Thyroid and Brain: Understanding the Actions of Thyroid Hormones in Brain Development and Function
Authored by
Juan Bernal
Sols-Morreale Institute for Biomedical Research
Consejo Superior de Investigaciones Científicas
Madrid, Spain
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FOREWORD
Thyroid hormones, small iodine-containing molecules, play a key role in the growth, development, and metabolism of mammals and the metamorphosis of amphibians. The demand for iodine in hormone synthesis imposed additional stress on creatures transitioning from sea to land. Despite efforts to implement iodine supplementation, 35% of the world population remains iodine deficient today, with 35 million severely affected individuals. A significant proportion exhibits enlarged thyroid glands (goiter) and experiences growth and mental retardation. Furthermore, thyroid hormone deficiency affects one in every 2,500 newborns in iodine-sufficient areas. Timely correction of thyroid hormone deficiency induces catch-up growth, while delays in treatment result in irreversible defects in brain development. This has led to the global implementation of routine newborn screening for early detection of congenital hypothyroidism.
The book titled “Thyroid and Brain: Understanding the Actions of Thyroid Hormones in Brain Development and Function”, is authored by a preeminent expert who has devoted his entire career to the study of thyroid hormone action in the brain, thus gaining the respect of his peers for his extensive knowledge of the field. The book covers in-depth brain development, structure, and function as related to the thyroid. It provides timely, up-to-date information that will serve as a valuable resource to both specialists and non-experts. The intricate actions of these hormones are lucidly described, creating a narrative that reads almost like a novel, with each fact leading to new information, expanding the horizons of current knowledge.
The fourteen chapters delve into thyroid hormone transport, metabolism, and action as they pertain to the brain, encompassing the spectrum of thyroid hormone effects in health and disease. The book provides detailed descriptions of molecules regulating thyroid hormone action on the brain, including gene expression, properties, biochemistry, localization, and physiology. Recent advances in genetics and molecular biology are presented. While central regulation of thyroid hormone secretion involving the hypothalamus and pituitary is important, in situ thyroid hormone metabolism provides appropriate local hormone bioactivity. It ensures optimal concentrations of the biologically active thyroid hormone, T3, to brain cells as required for the particular period of development. These mechanisms regulate thyroid hormone action with a timeline specific to different brain regions. Although the book focuses on the human brain, it presents animal studies, particularly in rodents, as vital for expanding knowledge on the subject. This research reveals that gene dependence of T3 is age and brain region-dependent, with diverse time window sensitivity. T3 regulates genes involved in nearly all aspects of brain function, from developmental genes to genes involved in metabolic and cell signaling pathways. Finally, the author includes a historical overview of each topic, giving due credit for important key discoveries.
Samuel Refetoff
The University of Chicago
Chicago, United States
PREFACE
Thyroid hormones play a pivotal role in orchestrating a myriad of biological and physiological functions. These encompass the regulation of vertebrate growth and development, amphibian metamorphosis, circadian rhythms, photoperiod, metabolism, body temperature, heart rate, and crucially, brain development and function. The mechanism through which these effects are predominantly mediated involves T3 binding to nuclear receptors, serving as ligand-regulated transcription factors.
Among the myriad actions of thyroid hormones, one of paramount importance is their profound influence on brain development and function. Thyroid hormones intricately regulate processes such as neurogenesis and gliogenesis and the migration, differentiation, and synaptogenesis of neuronal and glial cells. Notably, a deficiency in thyroid hormones during development, or disruption of the mechanisms of thyroid hormone action, results in severe neurological impairment and intellectual retardation. In the adult human brain, thyroid disorders may manifest as psychiatric disturbances. The intricate interplay of thyroid hormones in these processes underscores their indispensable role in maintaining optimal neurological function throughout the lifespan.
This book represents a comprehensive endeavor to distill the wealth of information accumulated over the past five decades into a single volume. The field has witnessed a remarkable acceleration, propelled by groundbreaking advances in cellular and molecular neurobiology, facilitated by breakthroughs in molecular genetics and transcriptomics methodologies. Though many questions remain unanswered, the convergence of these advancements has ushered in a new era of understanding, providing a solid foundation for the exploration and elucidation of intricate neurological processes and, in particular, the action of thyroid hormones in the brain.
Juan Bernal
Sols-Morreale Institute for Biomedical Research
Consejo Superior de Investigaciones Científicas
Madrid, Spain
ACKNOWLEDGEMENTS
The author extends profound gratitude to Prof. Samuel Refetoff of the University of Chicago, USA, for his enduring friendship, scientific guidance, and invaluable contributions while writing this book. Special acknowledgment is also reserved for the insightful comments provided by distinguished researchers in the field: Drs. Frederic Flamant, Ecole Superieur de Lyon, France; Douglas Forrest, National Institutes of Health, Bethesda, Maryland, USA; Arturo Hernandez, MaineHealth Institute for Research, Scarborough, Maine, USA; Jose Carlos Moreno, Hospital La Paz, Madrid, Spain; Beatriz Morte, Center for Biomedical Research in Rare Diseases, Madrid, Spain; Federico Salas-Lucia, University of Chicago, USA; and Pilar Santisteban, High Council for Scientific Research, Madrid, Spain. Their expertise and feedback have significantly enriched the content and quality of this work.
DEDICATION
To my beloved grandchildren,
Adrian, Emma, and Marcos
May this book inspire you to explore, learn, and chase your dreams. Your curiosity and joy for life are a constant source of wonder and pride. This work is a testament to the power of knowledge, and I hope it encourages you to seek out the mysteries of the world with the same passion and dedication.
With all my love,
Juan Bernal
An Introduction to Thyroid Physiology
Juan Bernal1,*
1 Consejo Superior de Investigaciones Científicas, Madrid, Spain
Abstract
This chapter is a general introduction to this book and contains basic concepts of thyroid hormone signaling for a better understanding of the book’s subject. It begins with an introduction that offers a simplified view of thyroid hormones as iodine-containing compounds and the regulatory function of the hypothalamus-pituitary-thyroid axis, followed by a description of the thyroid gland and thyroid hormone synthesis. Iodide transporters concentrate iodide in the gland and after oxidation, it is incorporated into thyroglobulin tyrosyl residues. The coupling of iodotyrosyl residues forms T4 and T3, which are released after thyroglobulin hydrolysis. Thyroid hormones act via nuclear receptors, which are ligand-regulated transcription factors, and T3 is the primary active thyroid hormone that binds to the receptors. T3 is produced primarily in extrathyroidal tissues by the action of deiodinase enzymes catalyzing the removal of an iodine atom from T4. Thyroid hormones are ancient signaling molecules with critical actions on growth and metabolism that regulate many developmental transitions, with evolutionary roots at the base of the chordate species.
Keywords: Amphioxus, Colloid, DUOX2, Dehalogenase, Deiodinases, DIO, Evolution, Endostyle, Follicles, Genomic actions, Iodine, lamprey, Metamorphosis, Nuclear receptors, Non-genomic, NIS, Peroxidase, Selenium, Thyroglobulin.
*Corresponding author Kapil Dev: Consejo Superior de Investigaciones Científicas, Madrid, Spain; E-mail:
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