Development of the Cerebellum from Molecular Aspects to Diseases

Preface
Contents
The Development of the Cerebellum: From the Beginnings
The Origin of the Cerebellum
Histogenesis
Development of the Cerebellar Nuclei
Development of Longitudinal Purkinje Cell Zones
Development of Connections
Development of the Folial Pattern
References
The Embryology and Anatomy of the Cerebellum
Introduction
Embryology of the Cerebellum
Anatomy and Histology of the Human Cerebellum
Gross Anatomy and Internal Structure of the Cerebellum
Subdivisions of the Cerebellum
Cerebellar Cortex
Cerebellar Nuclei (CN)
Cerebellar Peduncles
Blood Supply of the Cerebellum
References
Cellular and Genetic Programs Underlying Cerebellum Development
Introduction
Early Patterning of the Neural Tube and Specification of the Cerebellar Territory
Ventricular Zone Lineage
Postnatal Cerebellar Cortex Progenitor Populations and Lineages
Rhombic Lip Lineage
Granule Cell Precursor Cell Behaviors
Development of Cerebellar Afferents
Development of Cerebellar Foliation and Relationship to Afferent and Efferent Circuitry
References
Early Purkinje Cell Development and the Origins of Cerebellar Patterning
Purkinje Cells as Project Managers of Cerebellar Cytoarchitecture and Connectivity
Cerebellar Anlagen and Germinal Zones
Establishment of Neurogenic Microdomains for GABAergic Progenitors
The Regulation of PC Progenitor Specification and Commitment
Ebf2 and PC Subtype Specification
The First Formation of PC Afferent Projections
Embryonic PC Cluster Formation
From Clusters to Zones and Stripes
Conclusions
References
Cerebellar Developmental Disorders and Cerebellar Nuclei
What Are Cerebellar Nuclei?
Cellular Anatomy and Diversity
Outputs of the Cerebellar Nuclei
Inputs to Cerebellar Nuclei
Development of Cerebellar Nuclei
Origin of Glutamatergic Neurons
Origin of GABAergic Projection Neurons
Other GABAergic Neurons
Nucleogenesis and Cell Migration
Evolution and the Diversification of Cerebellar Nuclei
Cerebellar Nuclei and Disease
Future Perspectives on Cerebellar Nucleus Development
References
The Role of Non-coding RNAs in Cerebellar Development
Introduction
Enhancer RNAs
Long Non-coding RNAs
The Universe of MicroRNAs
miRNAs in Cerebellar Development
miRNAs Expression in Cerebellar-Related Disorders
References
Motor Circuit Abnormalities During Cerebellar Development
Introduction
Structure of the Cerebellum
Development of the Cerebellar Circuit
The Role of Cerebellar Development in Ataxia, a Classical Cerebellar Movement Disorder
SCA1 (Spinocerebellar Ataxia Type 1)
SCA6 (Spinocerebellar Ataxia Type 6)
Car8wdl (The Waddles Spontaneous Mutant Mouse)
L7Cre;Vgatflox/flox (Conditional Genetic Silencing of Purkinje Cell Neurotransmission)
Cerebellar Development and Non-motor Disorders
References
A Comparative View of Cerebellar Morphology and Diversity in Fishes
Introduction
Development of the Fish Cerebellum and Its Structural Organization
Morphological Diversity of the Fish Cerebellum
Neurogenesis and Lifelong Cerebellar Development in Fishes
Closing Remarks
References
The Role of nNOS/NO on Cerebellar Development in Health and Disease
Introduction
Murine Cerebellar Development: A Brief Overview
Purkinje Neuron Development and Synaptic Innervation
Bergmann Glia Development
Nitric Oxide Synthase Isoforms: Synthesis and Physiological Functions
NO/nNOS in the Cerebellum
Nitric Oxide Signaling Pathways in the Cerebellum
Protein Kinase-G Signaling Cascade
Regulation via S-Nitrosylation
NO and Synaptic Plasticity in the Cerebellum
PF–PN Synapse, LTD, and NO
Synapse Morphology
NO, Bergmann Glia, and Cerebellar Development
NO and GLAST Regulation
Cerebellar Disorders and Implications
Spinocerebellar Ataxia
Episodic Ataxia
NO as a Therapeutic: Good or Bad?
References
Developmental Disorders of the Cerebellum and Neurotrophic Factors
Introduction
Neurotrophic Factors
Neurotrophins
Transforming Growth Factor-Beta Superfamily
Neurotrophic Cytokines
Neurotrophic Factors and Cerebellar Development
Cerebellum and Neurodevelopmental Disorders
Attention Deficit Hyperactivity Disorder
Autism Spectrum Disorders
Ataxia
Ethanol Neurotoxicity
Medulloblastoma
Schizophrenia
Williams Syndrome
Other Cerebellar Neurodevelopmental Disorders
References
Apoptosis, Autophagy, and Unfolded Protein Response and Cerebellar Development
Introduction
Introduction to Programmed Cell Death (Apoptosis)
Caspases Are Central Initiators and Executioners of Apoptosis
Molecular Pathways of Apoptosis
Cell Death Receptor Pathway
Mitochondrial Pathway
Apoptosis in Development
Autophagy and Its Role During Development
Autophagy
Role of Autophagy in Development
Endoplasmic Reticulum Stress and Unfolded Protein Response
UPR and General Development
Apoptosis and Cerebellum Development
Apoptosis of Stellate and Basket Cells
Apoptosis of Purkinje Cells
Apoptosis of Granule Cells
Apoptosis of Cerebellar Nuclei Neurons
Autophagy and Cerebellum Development
COVID-19, Cerebellum, and Autophagy
Involvement of UPR in Cerebellum Development
Conclusion
References
The Ubiquitin–Proteasome System and Cerebellar Developmental Disease
Introduction
The Ubiquitin–Proteasome System
Ataxia and Spinocerebellar Ataxia
Spinocerebellar Ataxia Type 1 (SCA1)
Spinocerebellar Ataxia Type 2 (SCA2)
Spinocerebellar Ataxia Type 3 (SCA3)/Machado–Joseph Disease and Ataxin 3
Spinocerebellar Ataxia 5 (SCA5)
Spinocerebellar Ataxia 6 (SCA6)
Spinocerebellar Ataxia 7 (SCA7)
Spinocerebellar Ataxia 8 (SCA8)
Spinocerebellar Ataxia 15 (SCA15)
Spinocerebellar Ataxia 17 (SCA17)
Spinocerebellar Ataxia Type 19 (SCA19) and Type 22 (SCA22)
CHIP and Gordon Homes Syndrome
Dentatorubropallidoluysian Atrophy
Friedrich’s Ataxia and Ubiquitin-Competing Molecules
Episodic Ataxia and Ubiquitin Ligases
Ataxia Telangiectasia (AT) and the ATM Protein
Cerebellar Hemangioblastoma and the Von Hippel–Lindau Protein
Autism-Associated Genes
Medulloblastoma and Ubiquitin–Proteasome Components
Prospective Expectations
References
Epigenetic Control and Cerebellar Neurodevelopmental Disorders
Introduction
Epigenetics
DNA Methylation
DNA Methyl Writers
DNA Methyl Readers and MeCP2
DNA Methyl Erasers
Histone Modifications
Other Epigenetic Regulatory Mechanisms
Epigenetics in Development and Bivalent Marks
Epigenetics and Cerebellum
Epigenetics and Neurodevelopmental Cerebellar Disorders
Conclusions
References
Hormonal Regulation of Cerebellar Development and Its Disorders
Hormone and Cerebellar Development: A General Overview
Cerebellar Disorders Induced by Aberrant TH Systems
Cerebellar Disorders and Gonadal Steroids
Cerebellar Disorders Induced by Corticosteroids
Environmental Chemicals That May Disrupt Cerebellar Development Through Disruption of Hormone Actions
Conclusion
References
Infections of the Cerebellum
General Virology
General Nature of Viruses
Virus Morphology
Virus Classification
Virus Replication
Cell Tropism
Virus Infections of the Brain and Cerebellum
Enteroviruses
Arboviruses
Alphatogaviridae
Flaviviridae
Coronaviruses
Herpesviruses
Myxoviruses
Prions
Other Viral Agents
Bacterial and Fungal Infections of the Cerebellum
Bacteria
Fungi
References
Interrelation Between the Immune and the Nervous Systems in the Context of Cerebellar Development and Developmental Disorders
Introduction
Anatomy of the Cerebellum and Interconnection with Other Central Centers Implicated in Neuroimmune Regulation
The Immune System in the Cerebellum
Pattern Recognition Receptors
Innate Immune Responses in the Cerebellum
Adaptive Immune T and B Cells in Cerebellum
Cerebellum and Immune Response Interactions in Cerebellar Diseases
Neurological Disorders Associated with Coronavirus Disease 2019
Diagnostic Tests and Managements of Immune-Mediated Cerebellar Disorders
Conclusion
References
Teratogenic Influences on Cerebellar Development
Introduction
Intrauterine Infections
Congenital Rubella
Congenital Zika Infection
Congenital Anticonvulsant Syndrome
Valproic Acid
Prenatal Alcohol Effects and Fetal Alcohol Spectrum Disorder
Mechanisms for Alcohol Teratogenesis
Molecular Pathways and Genetic Factors
Epigenetics
FASD and the Cerebellum
Clinical Consequences to Cerebellar Dysfunction in PAE and FASD
Summary
References
Primary Pediatric Brain Tumors of the Posterior Fossa: Part I
Introduction
Atypical Teratoid/Rhabdoid Tumor (ATRT)
Epidemiology
Clinical Presentation
Diagnostic Imaging (Fig. 1)
Tumor Pathology (Fig. 2)
Molecular Genetics and Biology
Therapy and Prognosis
Future Considerations
Pilocytic Astrocytoma
Epidemiology
Clinical Presentation
Diagnostic Imaging (Fig. 3)
Tumor Pathology (Fig. 4)
Molecular Genetics and Biology
Therapy and Prognosis
Current and Future Considerations
Ependymoma
Epidemiology
Clinical Presentation
Diagnostic Imaging (Fig. 5)
Tumor Pathology (Fig. 6)
Molecular Genetics and Biology
Therapy and Prognosis
Future Considerations
References
Primary Pediatric Brain Tumors of the Posterior Fossa: Part II A Comprehensive Overview of Medulloblastoma
Medulloblastoma (MB)
Clinical Presentation
Current Treatment and Traditional Therapies
Proton Versus Photon Radiotherapy – The Emerging Standard of Care for MB
Histological Classification
Emergence of the MB Molecular Subtypes
WNT-Activated MB
Demographics
Genetic and Molecular Alterations
Cell of Origin and Mouse Models of WNT-Activated MB
Treatment
SHH-Activated MB
Demographics
Genetic and Molecular Alterations
Cell of Origin and Mouse Models of SHH-Activated MB
Treatment
Group 3 and Group 4 MB
Demographics
Genetic and Molecular Alterations
Cell of Origin and Mouse Models of Group 3 and 4 MB
Treatment
Diagnostic Imaging in the Molecular Era
Cancer Stem Cells and Their Contribution to MB Tumor Heterogeneity
MB in the Molecular Era
Conclusions
References
Can Cerebellar Neurodevelopmental Disorders Affect Behavioral Disorders or Vice Versa?
Introduction
Contribution of the Cerebellum in Neurodevelopment
Role of the Cerebellum in Adaptive Behaviors, Autism Spectrum, and Neuropsychiatric Disorders
Cerebellum Plays a Role in ASD
Cerebellum Plays a Role in ADHD
Cerebellum Plays a Role in Behavioral Despair and Neuropsychiatric Illnesses
Conclusion
References
Neurodevelopmental Disorders of the Cerebellum: Autism Spectrum Disorder
Introduction
Autism Spectrum Disorder Pathogenesis
Genetic Factors
The Role of Glia
Environmental Factors
Covid-19 and ASD
Functional Gastrointestinal Disorders and ASD
Air Pollution and ASD
Diagnosis of ASD
The Cerebellum and ASD
ASD and Cerebellar Structure Abnormalities
Assessment and Treatment
Summary
References
Clinical Aspects of the Inherited Cerebellar Malformations
Introduction
Cerebellar Hypoplasia
Cerebellar Dysplasia
Dandy–Walker Malformation
Joubert Syndrome and Related Disorders
Pontocerebellar Hypoplasia
Rhombencephalosynapsis
Lissencephaly with Cerebellar Hypoplasia
Dysplastic Cerebellar Gangliocytoma or Lhermitte–Duclos Disease
Summary
References
Clinical Features, Assessment, and Management of Patients with Developmental and Other Cerebellar Disorders
Introduction
Limbs Motor Control
Ocular Motor Control
Speech Control
Nonmotor Impairments in Cerebellar Disorders
Language
Cognition
Affect and Behavior
Assessment of Pediatric Patients with Developmental and Other Cerebellar Disorders
History
Physical Examination
Pitfalls in the Assessment of Ataxia
Formulating a Clinical Impression and a Plan of Investigations
Management
Conclusions
References
Rehabilitation in Cerebellar Ataxia
Introduction
Motor Learning Principles
Evidence in the Literature
Evaluation
Examination
Clinical Outcomes
Functional Outcomes
Patient Reported Outcomes
Rehabilitation Interventions
Intensive Balance and Gait Training
Aerobic Exercise Training
Compensatory Strategies
Education for Lifelong Self-Management
Controversial Interventions
Conclusion
References
Epidemiology of Cerebellar Disorders
Introduction
Selection of Studies
Results
Ataxia
Hereditary Cerebellar Ataxias
Autosomal Recessive Ataxias
Autosomal Dominant Ataxia
X-Linked Ataxia and Ataxia Due to Mitochondrial Mutations
Acquired Ataxias
Autism Spectrum Disorder and the Cerebellum
Cerebellar Tumors
Medulloblastoma
Fetal Alcohol Spectrum Disorders
Cerebellar Malformations
Cerebellar Agenesis
Dandy-Walker Malformation
Joubert Syndrome and Related Disorders
Lissencephaly and Cerebellar Hypoplasia
Pontocerebellar Hypoplasia
Gómez-López-Hernández Syndrome
Rhombencephalosynapsis
Chiari Malformations
Tectocerebellar Dysraphia
Other
Cerebellitis
Cerebellar Stroke
Conclusions
References
Cerebellar Transplantation: A Potential Model to Study Repair and Development of Neurons and Circuits in the Cerebellum
Introduction and History
The Neuron Doctrine: Plasticity of Adult Circuits, But Absence of Neuronal Regeneration
Changing Bizzozero’s Classification: Not All Neurons Are Perennial Cells – The Discovery of the Existence of Adult Neurogenesis, and Neural Stem Cells Even in Mammalian Brains
Neuronal Transplantation
Neuronal Replacement in “Point-to-Point” Cerebellar Circuits
Positive Results in Favor of the PC Replacement in Mutant Mice with Heredodegenerative Ataxia
Morphologic Results
Electrophysiological Results
Parasagittal Compartmentation of Grafted PCs
The Difficulties in Restoring the Corticonuclear Projections Argue Against the Possibility of Successful Complete PC Replacement by Embryonic Cerebellar Transplants
Embryonic and Adult Cells Interactions
Molecular Mechanisms Underlying the Interactions Between Adult Host Bergmann Fibers and Grafted Embryonic PCs Migration, a New Type of Neural Plasticity Which is Called “Adaptive Rejuvenation”
Neural Grafting and the Balance Between Neuronal Intrinsic Growth Regulatory Mechanisms and Extrinsic Environmental Stimuli for Central Axon Regeneration
The Transplantation of Stem Cells: A New Approach
Origins of the Cells: Embryonic and Adult Multipotent Stem Cells and Immortalized Cell Lines
Neural Stem Cells from the Postnatal Cerebellum
The Reprogramming of Somatic Cells into Induced Stem Cells, or Directly into Precise Neuronal Fates, to Provide an Autologous Source of Transplantable Cells
Historical Introduction
Cerebellar Transplantation of Granule Cells
Cerebellar Transplantation of Purkinje Cells
Future Prospects
References
Index