Front Cover

bHLH Transcription Factors in Development and Disease

Copyright

Contents

Contributors

Preface

Chapter One: Molecular and Cellular Regulation of Skeletal Myogenesis

1. Introduction

2. Molecular Features of the Mrfs

2.1. Mrfs at the nodal point of cell identity-similarities and differences

2.2. Negative regulation of Mrf potency: establishing the onset of differentiation

3. Skeletal Muscle Development

3.1. Giving birth to muscle-some unusual twists

3.2. Diversity in origin and modular design

3.3. Lessons from gene deletions

3.4. Upstream regulators

3.5. Temporal specification of myogenesis

3.6. Enhancer interplays in regulation of the Mrfs

3.7. Lessons from lineage tracing and cell ablation studies-a cautionary tale

4. Mrfs as Transdifferentiation Factors

4.1. In vitro studies provide a new view on transdifferentiation

4.2. Transdifferentiation in vivo

4.3. From transdifferentiation studies to in-dish models of disease

5. Induction of Muscle-Specific Gene Expression

5.1. Cooperation between the Mrfs and other transcription factors

5.2. Mrfs and chromatin remodeling

6. Genome-Wide Studies and the Paradox of Excess Binding Sites for the Mrfs

6.1. Myod binding through the genome: productivity or remodeling?

6.2. Private versus shared E-boxes and lineage-determined chromatin accessibility

6.3. Lessons learned from Pax3/7 genome-wide studies

7. Molecular Evolution and Conservation in Other Species

8. Conclusions and Perspectives

Acknowledgments

References

Chapter Two: Proneural bHLH Genes in Development and Disease

1. Introduction to Proneural Genes

1.1. Identification and functional characterization of proneural genes in Drosophila

1.2. Introduction to vertebrate proneural genes

2. Proneural Functions of the Neurogenin Genes in Development

2.1. Neurog1 and Neurog2 identification and functions in the developing PNS

2.1.1. Neurog1 and Neurog2 specify distinct neuronal phenotypes in dorsal root ganglia

2.1.2. Neurog1 and Neurog2 function similar to Drosophila proneural genes in the cranial placodes

2.2. Neurog1 and Neurog2 function in the developing CNS

2.2.1. Neurog2 specifies distinct neuronal phenotypes in different regions of the neural tube

2.2.2. Neurog2 proneural functions are tightly regulated in the developing neocortex via multiple mechanisms

2.2.3. Neurog1 and Neurog2 have distinct and overlapping functions in the neocortex

2.3. Neurog3 identification and function in the developing CNS

2.4. Neurog3 function in the developing pancreas

2.5. Neurog3 function in the enteroendocrine system

3. Atoh1/Atoh7 Proneural Functions in Development

3.1. Introduction to Atoh family proneural genes

3.2. Atoh1 function in rhombic lip derivatives

3.3. Atoh1 function in inner ear development

3.4. Atoh1 function in the intestinal epithelium

3.5. Atoh7 function in the retina

4. Ascl1 Proneural Functions in Development

4.1. Ascl1 identification and function in the developing PNS

4.2. Ascl1 proneural functions in the developing CNS

4.2.1. Ascl1s ability to specify more than one cell fate is regulated by target gene selection and posttranslational modi...

4.3. Ascl1 and neuronal reprogramming

5. Proneural Genes in Human Disease (Table 2.1)

5.1. Human developmental disorders

5.2. Neurologic and neuropsychiatric disease

5.3. Proneural genes in cancer

5.3.1. Atoh1 in nervous system and gastrointestinal cancer

5.3.2. ASCL1 in nervous system cancers

5.3.3. ASCL1 in neuroendocrine cancers

5.4. Proneural genes in diabetes and enteroendocrine disorders

References

Chapter Three: The Hand2 Gene Dosage Effect in Developmental Defects and Human Congenital Disorders

1. Introduction

2. Cloning of Hand Genes and Their Expression Patterns

3. Developmental Functions of Hand2

4. Gene Dosage Effect of Hand2 in Mouse Embryogenesis

5. Disruption of Hand2 Dosage Causes Human Diseases

6. Future Perspectives

Acknowledgments

References

Chapter Four: E Proteins in Lymphocyte Development and Lymphoid Diseases

1. Introduction

2. E Proteins

2.1. E proteins and cell-cycle control

3. E Proteins in Lymphocyte Development

3.1. Antigen receptor recombination

3.2. Lymphocyte selection

4. E Proteins in B Cell Development

5. E Protein Roles in Mature B Cells

6. E Protein Roles in T Cell Development

7. Roles of E Proteins in Mature T Cells

8. E Proteins in Lymphoid Diseases

8.1. E proteins in autoimmunity

8.2. E proteins in cancer

8.2.1. Burkitt Lymphoma

8.2.2. E2A-PBX1 translocation in B cell acute lymphocytic leukemia

8.2.3. E proteins in T cell cancers

9. Conclusion

Acknowledgments

References

Chapter Five: Id Proteins: Small Molecules, Mighty Regulators

1. Introduction

2. The Structure and Function of Id Proteins

3. Regulation of Id Gene Expression

4. Id Proteins in Stem Cell Maintenance

4.1. Hematopoietic stem cells

4.2. Neural stem cells

5. Id Proteins in Vasculogenesis

6. Id Proteins in Cancer

7. Id Proteins in the Immune System

8. Id Proteins in Adipogenesis

9. Concluding Remarks

References

Chapter Six: E(spl): Genetic, Developmental, and Evolutionary Aspects of a Group of Invertebrate Hes Proteins with Close ...

1. E(spl): From a Spontaneous Dominant Mutation to a Group of Core Developmental Regulators

2. E(spl) Proteins-Where Did They All Come From?

3. Regulation of E(spl) Genes

4. Functions of E(spl) Proteins in Drosophila

4.1. Lateral inhibition of neural precursors in the CNS

4.2. Lateral inhibition of neural precursors in the PNS-Inhibition of proneural proteins

4.3. Lateral inhibition of neuronal precursors in the retina-Autoinhibition of E(spl)

4.4. E(spl) in other instances of Notch-mediated lateral inhibition

4.5. Involvement of E(spl) in other developmental processes-Interplay with the RTK/MAPK pathway

4.6. E(spl) in tissue maintenance and regeneration

4.7. E(spl) can synergize with other bHLH-O proteins

5. E(spl) Function in Other Species

6. Closing Remarks

Acknowledgments

References

Chapter Seven: Expression Dynamics and Functions of Hes Factors in Development and Diseases

1. Introduction

2. Hes Family Members and Protein Structures

3. Hes General Functions

4. Roles of Hes Factors in Various Tissues

5. Hes Functions in the Central Nervous System

5.1. Hes genes in NS cells

5.2. Hes genes in brain morphogenesis

6. Hes1 Oscillation and Cell Proliferation in Cultured Cells

7. Hes1 Oscillation in ES and NS Cells

7.1. Hes1 oscillation in ES cells

7.2. Hes1 oscillation in developing mouse brain

7.3. Hes1 oscillation in NS cells and the optogenetic control

8. Conclusions and Perspectives

References

Chapter Eight: Hey bHLH Transcription Factors

1. Introduction

2. Notch Signaling and Crosstalk with Other Pathways

2.1. Tgfβ/Bmp signaling induces Hey genes

2.2. CoupTF-II and Hif1 control cardiovascular Hey expression

3. Interaction Partners of Hey Proteins

3.1. Interaction with cofactors

3.2. Interaction with other transcription factors

4. Downstream Targets of Hey Proteins

5. Hey Proteins in Heart Development and Disease

5.1. Hey genes in adult cardiac disease

6. Hey Proteins in Vascular Development

6.1. Role of Hey2 in smooth muscle cells during vascular injury

7. Control of Myogenesis and Muscle Stem Cells

8. Bone Development and Homeostasis

9. Hey Proteins Control Neural Development

10. Hey Functions in Ear Development

11. Immune Functions of Hey Proteins

12. Hey Genes in Cancer

12.1. An oncogenic HEY1-NCOA2 fusion protein

12.2. Deregulated Hey genes in diverse malignancies

13. Conclusion

References

Chapter Nine: Stra13 and Sharp-1, the Non-Grouchy Regulators of Development and Disease

1. Introduction

2. Mechanisms of Transcriptional Repression

3. Embryonic and Adult Tissue Expression

4. Roles in Differentiation and Development

4.1. Musculoskeletal system

4.2. Metabolism

4.3. Immune system

5. Deregulation of Stra13 and Sharp-1 in Cancer

5.1. Roles in cell cycle arrest senescence

5.2. Apoptosis

5.3. Hypoxia signaling and DNA repair

6. Conclusion

References

Chapter Ten: DEC1/STRA13/SHARP2 and DEC2/SHARP1 Coordinate Physiological Processes, Including Circadian Rhythms in Respon...

1. Introduction

2. Structures of DEC1 and DEC2

2.1. Primary structures of DEC1 and DEC2 proteins

2.2. Genomic structure of Dec1 and Dec2

3. Tissue Distribution and Circadian Expression of Dec1 and Dec2

4. Role of DEC1 and DEC2 in Molecular Clocks

4.1. Molecular clock system

4.2. Molecular mechanisms involved in DEC activity in the clocks

4.3. Resetting of the clocks by DEC

4.4. Effects of DEC deficiency on circadian rhythms

5. Mechanisms of DEC1 and DEC2 Actions

5.1. Transcriptional repression by direct DNA binding

5.2. Transcriptional regulation by protein-protein interaction with other transcription factors

5.2.1. Hypoxia-inducible factor-1α

5.2.2. Myoblast determination protein

5.2.3. Nuclear receptor retinoid X receptor

5.2.4. Specificity protein 1

5.2.5. Other factors

5.3. Structure-function relationship in DEC proteins

6. Regulatory Factors for Dec1 and Dec2 Expression

6.1. Transcription factors

6.1.1. Clock proteins

6.1.2. Hypoxia-inducible factor-1

6.1.3. Nuclear receptors

6.1.4. Other transcription factors

6.2. Growth factors, hormones, and autacoids

6.3. Cytokines

6.4. Nutrients

6.5. Environmental stimuli

7. Perspectives

Acknowledgments

References

Index

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