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Nuclear Receptors in Development and Disease

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Contents

Contributors

Preface

Chapter One: Evolution of Nuclear Receptors and Ligand Signaling: Toward a Soft Key-Lock Model?

1. Introduction

2. The Ligand-Receptor Couple for NRs

3. NR Diversification During Animal Evolution

4. Evolution of Ligand Binding

5. Alternative Ligands

6. Generalization

References

Chapter Two: The Function and Evolution of Nuclear Receptors in Insect Embryonic Development

1. Introduction: Nuclear Receptor Structure and Function

2. Roles of NRs in Drosophila Embryonic Development

2.1. Nuclear Receptors and Early Patterning Mechanisms

2.2. Functions of NRs During Neurogenesis

2.3. A Cascade of NR Activity in Response to Ecdysone Mediates Mid-Embryogenesis Morphogenetic Movements and Recalibrates ...

2.4. Functions of NRs in Morphogenesis and Maturation of Metabolic Organs

2.5. Other NR Functions During Organogenesis

2.6. Future Directions

3. Functional Analysis of NRs in Nonmodel Insects

3.1. Insects Are the Most Diverse Group on the Planet

3.2. Genomic Inventory of NRs Across Insect Species

3.3. Functional Studies of NRs in Emerging Insect Model Systems

Acknowledgments

References

Chapter Three: Nuclear Receptors in Skeletal Homeostasis

1. Introduction

1.1. Bone and Bone Cells

1.2. Nuclear Receptors

2. NRs and Bone Homeostasis

2.1. Estrogen Receptor

2.1.1. Estrogens and Bone Health

2.1.2. ER Knockout Models

2.1.3. Mechanisms

2.2. Androgen Receptor

2.3. Glucocorticoid Receptor

2.4. Peroxisome Proliferator-Activated Receptor

2.4.1. Peroxisome Proliferator-Activated Receptor α

2.4.2. Peroxisome Proliferator-Activated Receptor δ/β

2.4.3. Peroxisome Proliferator-Activated Receptor γ

2.5. Vitamin D Receptor

2.6. Retinoid Acid Receptor and RXR

2.7. Estrogen Receptor-Related Receptor

2.8. NR4A Orphan NRs

3. Conclusions

Acknowledgments

References

Chapter Four: Estrogen Hormone Biology

1. Introduction

2. Cell Mechanisms

3. Uterine Estrogen Response

3.1. Genetic Control of Estrogen Responses

3.2. ERα Mutations Demonstrate Uterine Mechanisms

3.3. Tethered Pathway Analysis Using DNA-Binding Deficient ERα Mutants

3.4. Analysis of AF-1- and AF-2-Mediated Responses

3.5. Analysis of Biological Impact of Membrane-Initiated Signaling

3.6. ERβ Does Not Impact Uterine Responses

3.7. Importance of ERα to Uterine Function Informs Mechanisms of Disease

4. ER in the Ovary

4.1. Ovarian Phenotypes of ERα Mutant Mice

4.2. Ovary-Specific ERα Knockouts

4.3. Ovarian Phenotypes of ERβ Mutant Mice

4.4. Role of ERβ Signaling in Granulosa Cells

4.5. Ovarian Phenotypes of ERα and ERβ Compound Mutant Mice

4.6. Ovarian Phenotypes in Mice Lacking Estradiol Synthesis

5. ER in Metabolism

5.1. Metabolic Phenotype of ERα Knockout Mice

5.2. Physiological Role of ERα Transactivation Domains in Metabolism

5.3. Phenotype of ERα DNA-Binding Domain Mutant Mice in Metabolism

References

Chapter Five: Mechanisms of Glucocorticoid Action During Development

1. Introduction

2. Adrenal Gland Morphology and Embryology

3. Production and Metabolism of Glucocorticoids in the Adult and the Fetus

4. Signaling and Function of the Glucocorticoid Receptor

5. The Impact of Glucocorticoid Signaling on Fetal Development

6. Concluding Remarks

Acknowledgment

References

Chapter Six: Progesterone Receptor Signaling in Uterine Myometrial Physiology and Preterm Birth

1. Introduction

2. Ligand Availability

3. Composition of PGR Isoforms

4. The PGR–NF-κB Axis

5. The PGR-ZEB-MicroRNA Regulatory Circuit

6. Endoplasmic Reticulum Stress and Unfolded Protein Response

7. Concluding Remarks and Future Perspectives

Acknowledgment

References

Chapter Seven: Roles of Retinoic Acid in Germ Cell Differentiation

1. Introduction

2. ATRA Signaling in the Fetal Gonads

2.1. CYP26B1 Acts as an MPS for Male Gonocytes

2.2. CYP26B1 Prevents Proliferation As Well As Death of Male Gonocytes

2.3. ATRA Is Required for the Production of "Differentiating" Spermatogonia From Male Gonocytes

2.4. ATRA Possibly Acts as a MIS for Female Gonocytes

2.5. Stra8 as the Meiotic Gatekeeper

2.6. An Alternative Viewpoint of Meiosis Induction in Female Gonocytes

3. ATRA Signaling Is Instrumental to Spermatogonia Differentiation in the Prepubertal and Adult Testis

3.1. The Transition From Undifferentiated to Differentiating Spermatogonia Critically Relies on ATRA

3.2. The Sources of ATRA Destined for Spermatogenesis Are Intrinsic to the SE

4. ATRA Signaling Is Instrumental to Meiosis in Spermatocytes

5. ATRA Metabolism Within the SE Controls the Timing and Spatial Patterning of Spermatogonia Differentiation

5.1. The SE Cycle and Wave Both Rely on Retinoid Signaling

5.2. Endogenous ATRA Levels in the SE Are Tightly Regulated

5.3. RALDH Activity Regulates the Spermatogenic Wave

6. Male GC Are Both Direct and Remote Targets of ATRA Action: Lessons From Mouse Mutants Lacking Retinoid Receptors

6.1. RAR in Fetal GC Differentiation

6.2. RARG Controls the Capacity of Spermatogonia to Respond to ATRA

6.3. The Response of Spermatogonia to ATRA Relies on RXR/RAR Heterodimers

6.4. RARA in Sertoli Cells Also Contribute to ATRA Functions in the SE

7. Concluding Remarks

Acknowledgments

References

Chapter Eight: Retinoid-Related Orphan Receptor β and Transcriptional Control of Neuronal Differentiation

1. Introduction

2. The Rorb Gene and RORβ Protein Isoforms

3. Response Elements for RORβ Proteins

4. Mouse Strains With Rorb Mutations

5. Expression Patterns of the Rorb Gene in the Nervous System

5.1. Sensory Systems

5.2. Circadian System

6. The Rorb Gene and Neuronal Differentiation

7. Rorb and Differentiation in the Cerebral Cortex

8. Rorb and Differentiation in the Retina

8.1. Horizontal and Amacrine Interneurons

8.2. Rod and Cone Photoreceptors

9. Partners in Plasticity: A Combinatorial Model for Differentiation

10. The RORB Gene and Human Disease

11. Circadian Rhythms, Locomotion, and Other Functions

11.1. Circadian Rhythms

11.2. Abnormal Gait and Other Functions

12. Potential Ligands for RORβ Proteins

13. Concluding Remarks

Acknowledgment

References

Chapter Nine: Nuclear Receptor TLX in Development and Diseases

1. Introduction

2. TLX in Development and Diseases

2.1. Molecular Regulation of TLX and Its Target Genes

2.2. TLX in Brain Development and Adult Neurogenesis

2.3. TLX in Senescence and Aging of the Brain

2.4. TLX in Neurological Diseases

2.5. TLX in Glioblastoma Tumorigenesis

3. Perspectives

Acknowledgments

References

Chapter Ten: COUP-TF Genes, Human Diseases, and the Development of the Central Nervous System in Murine Models

1. Introduction

2. COUP-TF Genes and Human Diseases

3. Brief Overview of the Early CNS Development

4. COUP-TF Genes and the Development of Dorsal Forebrain

4.1. COUP-TFI Gene and the Regionalization of Cerebral Cortex

4.2. COUP-TFI Gene and Neurogenesis in Cerebral Cortex

4.3. COUP-TFI and the Development of Dorsal Hippocampus

5. COUP-TF Genes and the Development of Ventral Forebrain

5.1. COUP-TF genes and the Differentiation of Cortical Interneurons

5.2. COUP-TFII Gene and the Development of Amygdala Complex

5.3. The Function of COUP-TFII Gene in Hypothalamus

6. COUP-TFII Gene and the Development of Cerebellum

7. COUP-TF Genes and Gliogenesis

7.1. COUP-TF Genes Control Temporal Gliogenesis In Vitro and In Vivo

7.2. COUP-TFI Gene and the Differentiation of Oligodendrocyte

8. COUP-TF Genes and Neural Crest Cells

9. COUP-TF Genes and Adult Neuronal Stem Cells

10. Conclusion and Perspectives

Acknowledgments

References

Chapter Eleven: Genetic Investigation of Thyroid Hormone Receptor Function in the Developing and Adult Brain

1. Introduction

2. TRs in the Brain

3. Animal Models With TR Mutations

4. Interpretation of Phenotypes Resulting From Knock-In and Knock-Out Mutations

5. Respective Functions of TRs in Neural Cell Differentiation

6. Nongenomic Signaling in the Brain

7. The Origin of Phenotype Variability

8. Distinction Between Developmental and Adult Functions of TRs in the Brain

9. TR Target Genes Definition

10. T3 Target Gene Functions

Acknowledgment

References

Chapter Twelve: Resistance to Thyroid Hormone due to Heterozygous Mutations in Thyroid Hormone Receptor Alpha

1. Introduction

2. Molecular Mechanisms Underlying RTHα

3. Clinical Phenotype

3.1. Appearance

3.2. Neurological and Cognitive

3.3. Skeletal

3.4. Cardiac and Gastrointestinal

3.5. Biochemical and Metabolic

4. Pathogenesis

5. Treatment

6. Conclusions

Acknowledgments

References

Chapter Thirteen: TR2 and TR4 Orphan Nuclear Receptors: An Overview

1. Introduction

2. Ligands/Activators That Transactivate TR4

2.1. TR4 Natural and Synthetic Ligands/Activators

2.2. Phosphorylation and Acetylation Signals That Transactivate/Induce TR4

2.3. Other Upstream Signals That Can Induce TR4 Expression

3. TR4 Downstream Target Genes

3.1. Heterodimerization With Other NRs

3.2. Competition for DNA-Binding Sites With Other NRs

3.3. Interaction With Other Coregulators

4. TR4 Roles in PPARγ-Related Diseases and Their Impacts on Drug Development

4.1. TR4 and PPARγ in Cancer

4.2. TR4 and PPARγ in Metabolic Syndromes

4.3. TR4 and PPARγ in Cardiovascular Diseases

4.4. TR4 and PPARγ in Bone Physiology

5. Summary and Future Perspectives

Acknowledgment

References

Chapter Fourteen: The Role of COUP-TFII in Striated Muscle Development and Disease

1. Introduction

2. COUP-TFII Functions in Skeletal Muscle Development

2.1. COUP-TFII Regulates Limb Myogenesis

2.2. COUP-TFII Specifies Myogenic Fate of Mesenchymal Precursors

3. COUP-TFII Functions in Skeletal Muscle Regeneration

3.1. COUP-TFII Affects SC Activation and Proliferation

3.2. COP-TFII Disrupts Myoblast Fusion In Vivo

3.3. COUP-TFII Controls SC Commitment and Self-Renewal

3.4. Distinct Acute and Chronic Regenerative Responses in COUP-TFII Mutant SCs

4. COUP-TFII Hyperactivity, SC Dysfunction, and Muscular Dystrophy

5. COUP-TFII Functions in Cardiac Muscle Development

5.1. COUP-TFII Regulates Tubular Heart Development

5.2. Fate Determination of Atrial Cardiomyocytes by COUP-TFII

5.3. COUP-TFII-Dependent Myocardial Growth

6. COUP-TFII Overexpression, Mitochondria Dysfunction, and Heart Failure

7. Concluding Remarks and Future Perspectives

Acknowledgments

References

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