Macro Roles for MicroRNAs in the Life and Death of Neurons (eBook)

1: Profiling the microRNAs 10
Introduction 10
The first miRNA profiling 11
miRNA profiling by multiplex real time PCR 12
In situ hybridization for miRNAs 15
Profiling by deep sequencing 16
References 16
2: The Wide Variety of miRNA Expression Profiles in the Developing and Mature CNS 18
Introduction 18
miRNAs can be widely expressed in proliferating and/or differentiated cells throughout the brain 19
miRNAs can show spatially restricted expression in the larval brain 20
Is miRNA expression conserved between larval and adult brain? 21
miRNAs of the same family or cluster can show subtle differences in brain expression 22
What do the miRNA expression profiles predict about the role of miRNAs in the brain? 23
Conclusion 24
References 24
3: Interactions between microRNAs and Transcription Factors in the Development and Function of the Nervous System 27
Introduction 27
MicroRNA-Transcription Factor Interactions at the Synapse 30
The mechanisms of microRNA/transcription factor interaction 30
Further identification of microRNA-transcription factor interactions 31
Concluding Remarks 32
References 33
4: A microRNA Feedback Circuit in Midbrain Dopamine Neurons 35
References 40
5: Fine-tuning mRNA Translation at Synapses with microRNAs 42
Introduction 42
Results 44
The prototypic dendritic microRNA: miR-134 44
The tip of the iceberg: miR-138 and beyond 45
Regulating the regulators: miRNAs under the control of neural activity 47
Activity-dependent transcription 47
Activity-dependent regulation of miRNA-associated complexes 48
Local vs. global: are miRNAs involved in synaptic homeostasis? 49
Concluding remarks 49
References 50
6: Neuronal P-bodies and Transport of microRNA-Repressed mRNAs 52
Introduction 52
MicroRNA: tiny molecules for huge challenges 53
Local translation and mRNA transport to synapses 53
P-bodies: properties and function in human cells 54
P-bodies are sites of storage for miRNA- repressed mRNAs 54
P-bodies are sites of degradation for aberrant mRNAs 55
P-bodies form a distinct class of dendritic granules 56
Neuronal P-bodies are present in dendrites and are involved in the miRNA pathway 56
dlP-bodies are transported along dendrites by motors 58
dlP-bodies become dynamic upon synaptic stimulation 59
Conclusion and perspectives 59
References 61
7: Crosstalk between microRNA and Epigenetic Regulation in Stem Cells 64
Introduction 64
Adult Neural Stem Cells and Neurogenesis 65
Epigenetic Regulation in Stem Cells 66
DNA methylation 66
MBD protein family 66
Mbd1 may regulate adult neural stem/progenitor cells 67
Histone modifications regulate adult NSCs and neurogenesis 68
MiRNA function in NSCs and Neurogenesis 68
Conclusion 72
References 72
8: microRNAs in CNS Development and Neurodegeneration: Insights from Drosophila Genetics 76
Introduction 76
microRNAs, the brain and disease 77
Approaches to the study of microRNA functions 79
microRNAs and neurodegenerative disease 80
A genome-wide screen for Drosophila microRNAs linked to normal CNS function and neurodegeneration 81
Prospects 81
References 82
9: Drosophila as a Model for Neurodegenerative Disease: Roles of RNA Pathways in Pathogenesis 85
Introduction 86
A role of microRNAs in polyglutamine toxicity 88
A pathogenic role for the CAG-repeat encoding mRNA in polyglutamine disease 91
Conclusions 94
References 94
10: microRNAs in Sporadic Alzheimer´s Disease and Related Dementias 97
Introduction 97
Gene dosage effects in neurodegenerative disorders: a role for miRNAs? 98
microRNAs in sporadic AD 99
Clinical relevance for miRNAs in neurodegenerative disease 102
Conclusion and Perspectives 102
References 102
11: microRNA Dysregulation in Psychiatric Disorders 105
Introduction 105
miRNA Biogenesis 106
miRNA biogenesis and RNAinduced silencing complex (RISC) pathway 106
Regulation of miRNA expression and maturation 106
Mode of action 108
Target control 108
Regulatory network control 109
Characteristics of miRNA Action 110
The impact of disrupting miRNA biogenesis and RISC pathways 110
The impact of disrupting individual miRNAs 111
MiR-134 cluster on dendritic morphology and synaptic plasticity 111
MiR-219 and NMDA receptor-mediated neurobehavioral dysfunction 112
miRNA Dysregulation in Neuropsychiatric Disorders 112
Schizophrenia 112
22q11.2 microdeletion and risk for SCZ 113
Generation of the 22q11.2 microdeletion mouse model(Df(16)A+/-) 113
Df(16)A+/- mice: altered synaptic connectivity and cognitive function 114
Abnormal miRNA processing in Df(16)A+/- mice 115
Dgcr8 deficiency affects neuronal development and cognitive function 116
Dgcr8 haploinsufficiency interacts with haploinsufficiency of other 22q11.2 genes 117
miRNAs and SCZ 117
Tourette's syndrome 118
Autism spectrum disorders 119
References 119
: Index 124