Essentials of Noncoding RNA in Neuroscience

Ontogenetics, Plasticity of the Vertebrate Brain

Davide De Pietri Tonelli

• Publisher: Academic Press
• Year: 2017
• ISBN:
  9780128498996
• Topic: Ciencias biológicas
• Subtopic: Neurociencia

Essentials of Noncoding RNA in Neuroscience: Ontogenetics, Plasticity of the Vertebrate Brain focuses on the role of miRNAs in neurogenesis, gliogenesis, neuronal network formation, and the cell biology of forebrain development. The important role miRNAs play in neuronal maturation, neocortex function, and in some neurodevelopmental disorders is discussed, as are the computational challenges and methods used in the identification of miRNA targets.

This book is a valuable reference for neuroscientists who wish to better understand the role of miRNAs in complex processes. It is of strong interest to those working to develop enabling technologies to detect and monitor miRNA expression and function, and to evaluate its roles in neural progenitor proliferation/differentiation, neuronal plasticity, and learning and memory.

• Discusses the unique features of neural miRNAs
• Details functional investigation of miRNA actions and current experimental approaches
• Includes extensive coverage of miRNA biology, developmental and postnatal neurogenesis, and computational challenges for miRNA target identification
• Contains thorough discussion of the transcriptional control of miRNA expression in forebrain development and in specific neuronal subtypes, as well as miRNA function in neurogenesis, neuronal network maturation, plasticity, gliogenesis, and dysfunction
• Provides an overview of miRNA roles in neurodevelopmental disorders and their possible role in the evolution of the neocortex

Chapter 1

Making and Maintaining microRNAs in Animals

William P. Schreiner and Amy E. Pasquinelli, University of California at San Diego, La Jolla, CA, United States

Abstract

MicroRNAs (miRNAs) are small RNA molecules with important roles in the specification and function of animal cells. Perturbations in miRNA expression or function have been associated with a broad range of abnormalities in model animals and pathological outcomes in humans. Development and activity of neuronal cells are particularly reliant on the miRNA pathway, as mis-regulation of miRNA expression can lead to neurodegeneration and a variety of cognitive defects. The final 22 nucleotide form of the miRNA is the product of multiple processing steps, all of which are subject to regulation. Once mature, miRNAs use base-pairing interactions to guide an Argonaute protein complex to messenger RNA targets, resulting in translational inhibition and destabilization of the mRNA. Given the importance of producing the precise sequence and appropriate level of miRNA, miRNA biogenesis involves multiple layers of control from the initial transcription, to stepwise processing, to stabilization of the miRNA in its effector complex. This review will focus on the key steps of miRNA maturation and explore how each phase is orchestrated to ensure proper miRNA synthesis.

Keywords

miRNAs; Drosha; Dicer; Argonaute; target mRNA

Introduction

It has now been over 20 years since the first microRNA (miRNA) genes were discovered as critical regulators of developmental transitions in Caenorhabditis elegans worms (Lee et al., 1993; Wightman et al., 1993). Since then, thousands of miRNA genes have been documented in plants and animals (Griffiths-Jones, 2004; Kozomara and Griffiths-Jones, 2014). As a class, miRNAs are essential regulators of gene expression in multicellular organisms, and mis-regulation of specific miRNAs can result in abnormal phenotypes in model organisms and disease in humans (Hammond, 2015; Lin and Gregory, 2015; Tuna et al., 2016). Thus understanding how miRNAs are produced and maintained in the endogenous context is paramount for realizing their full biological functions.

MiRNAs are approximately 22 nucleotides (nt) in length and function by guiding Argonaute (AGO) and associated proteins, called the miRNA-induced silencing complex (miRISC), to their messenger RNA (mRNA) targets. Once there, miRISC generally represses gene expression through translational inhibition and mRNA degradation (Jonas and Izaurralde, 2015). In animals, miRNAs use partial base-pairing to recognize their targets (Ha and Kim, 2014). This property allows one miRNA to bind a variety of target site sequences. In fact, it has been estimated that over 50% of the human genome is regulated by miRNAs (Friedman et al., 2009).

The mature, 22 nt form of the miRNA is a product of multiple processing steps (Fig. 1.1). Most animal miRNAs share a common, well-conserved biogenesis pathway, although there are also noncanonical routes for specific miRNAs (Finnegan and Pasquinelli, 2013; Ha and Kim, 2014; Xie and Steitz, 2014). In the most common pathway, RNA polymerase II transcribes much longer primary miRNAs (pri-miRNAs) that contain 5′m7G caps and 3′polyadenosine (polyA) tails. The microprocessor, consisting of Drosha and Digeorge syndrome critical region gene 8 (DGCR8; also known as Pasha), then cleaves the pri-miRNA into a 70 nt precursor miRNA (pre-miRNA). This pre-miRNA is exported from the nucleus to the cytoplasm by Exportin 5. In the cytoplasm, Dicer cleaves the terminal loop generating a 22 nt double stranded miRNA. Only one strand of the duplex is used for targeting (guide) while the other strand (passenger) is discarded.

Figure 1.1 The general miRNA biogenesis pathway in animals
MiRNAs are transcribed in the nucleus by RNA polymerase II. The resulting primary transcript (pri-miRNA) is processed by the microprocessor complex comprised of Drosha and DGCR8. The excised precursor miRNA (pre-miRNA) is then exported from the nucleus by Exportin 5. Once in the cytoplasm the pre-miRNA is cleaved by Dicer. The guide strand of the transient 22 nt double stranded Dicer product is selected for incorporation into AGO, forming the miRISC. Typically miRISC binds the 3′UTR of a target mRNA and triggers translational inhibition and mRNA destabilization.

While each tissue of a multicellular animal expresses its own set of miRNAs, neuronal cells seem particularly reliant on the miRNA pathway. Of the hundreds of miRNAs discovered, nearly half are expressed to some degree in the mammalian brain (Shao et al., 2010). Early miRNA studies in model systems pointed to the functional importance of this pathway in neuronal development and function. For example, brain morphogenesis fails in Zebrafish defective for general miRNA biogenesis (Giraldez et al., 2005). In C. elegans, specific miRNAs were found to be essential for controlling the fate of two asymmetric chemosensory neurons (Chang et al., 2004; Johnston and Hobert, 2003). A wide body of research has now shown that miRNAs are important for a variety of neuronal processes, such as neurogenesis, axon guidance, and mature neuron functioning (Schratt, 2009; Shi et al., 2010).

MiRNAs biogenesis is an essential process for effective miRNA-mediated gene silencing. Small perturbations in miRNA biogenesis can alter the mature miRNA sequence or levels and, thus, affect gene expression. Here we provide an overview of the miRNA biogenesis pathway in animals, with an emphasis on examples relevant to neurogenesis.

Genomic Organization

MiRNAs genes reside in a variety of genomic arrangements that differ in frequency across organisms. In mammals the majority of miRNAs are located within the intronic regions of genes (Chang et al., 2015; Kim and Kim, 2007; Monteys et al., 2010; Rodriguez et al., 2004; Saini et al., 2008). There are also rare examples of exonic sequences, usually 3′ untranslated regions (UTRs), within mRNAs that encode miRNAs (Chang et al., 2015; Kim and Kim, 2007; Rodriguez et al., 2004). MiRNAs that are found in host genes, whether they are exonic or intronic, are often cotranscribed with their protein-coding counterpart (Baskerville and Bartel, 2005; Rodriguez et al., 2004). However, this is not always the case, and some miRNAs that are located within host genes have their own transcriptional regulatory elements (Corcoran et al., 2009; Monteys et al., 2010; Ozsolak et al., 2008). In C. elegans, most miRNA genes are intragenic but even the ones located within protein-coding genes typically have their own promoters (Martinez et al., 2008).

MiRNAs are often arranged in clusters, where closely spaced miRNAs are cotranscribed as part of a common primary transcript (Bartel, 2009; Lau et al., 2001; Lee et al., 2002). miRNA clusters sometimes encode members of the same family of miRNAs, where each miRNA has identical 5′ end sequences (Bartel, 2009). This arrangement is thought to facilitate the expression of related miRNAs that are capable of regulating shared targets. However, not all clusters include related miRNAs and some contain multiple family members. For example, the miR-17–92 cluster in humans consists of six miRNAs that belong to four different miRNA families: miR-17 and miR-20a are part of the miR-17 family, miR-19a and miR-19b-1 are part of the miR-19 family, and miR-18 and miR-92a-1 are each part of their own distinct families (Ota et al., 2004). This cluster is often perturbed in cancers, and may also be important for regulating the expression of genes involved in neurodegenerative diseases (He et al., 2005; Mogilyansky and Rigoutsos, 2013).

MicroRNA Transcription

The biogenesis of most miRNAs initiates with transcription by RNA polymerase II (Bracht et al., 2004; Cai et al., 2004; Lee et al., 2004). The resulting pri-miRNAs vary widely in size from hundreds to thousands of nts long (Chang et al., 2015; Saini et al., 2008). For details on the identification of miRNA transcription start sites see Chapter 3, Computational and -Omics Approaches for the Identification of miRNAs and Targets, of this book by Hatzigeorgiou and colleagues. In general the transcription of miRNAs is controlled by the same mechanisms that govern the synthesis of protein coding mRNAs. In addition to regulation by chromatin and DNA modifications, specific transcription factors have been shown to control the expression of particular miRNAs during development and in response to various extrinsic conditions (Liu et al., 2013; Marson et al., 2008; Schanen and Li, 2011). For instance, the well-studied p53 transcriptional regulator not only controls the expression of numerous protein coding genes but also stimulates the transcription of specific miRNAs, including members of the miR-34 family, upon DNA damage (Bommer et al., 2007; Chang et al., 2007; Corney et al., 2007; He et al., 2007; Raver-Shapira et al., 2007; Tarasov et al., 2007; Tazawa et al., 2007). Up-regulation of miR-34 family miRNAs is critical for the tumor suppressive function of p53 because these miRNAs repress the expression of cell proliferation genes and promote apoptosis (Bommer et al., 2007; Chang et al., 2007; Corney et al., 2007; He et al., 2007; Raver-Shapira et al., 2007; Tarasov et al., 2007; Tazawa et al., 2007). Interestingly, miR-34 levels also increase during adulthood in mammals, flies, and worms (Cao et al., 2010; de Lencastre et al., 2010; Ibanez-Ventoso et al., 2006; Li et al., 2011a,b; Liu et al., 2012), and in Drosophila this has been shown to have a neuroprotective role (Liu et al., 2012). Whether this induction is also mediated by p53 or other transcription factors is yet to be determined.

A recurring motif in the miRNA pathway is transcriptional regulation through negative feedback loops. One striking example of such regulation involves miR-133b and pituitary homeobox 3 (PITX3) in mouse dopaminergic neurons (Kim et al., 2007). PITX3, a homeodomain transcription factor, promotes the expression of miR-133b. However, PITX3 contains miR-133b binding sites in its 3′UTR. Thus rising levels of miR-133b lead to repression of PITX3, halting its own transcription (Kim et al., 2007). An even more intricate loop exists for miR-273 and lsy-6 in a pair of worm che...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• List of Contributors
• Preface
• Acknowledgments
• Chapter 1. Making and Maintaining microRNAs in Animals
• Chapter 2. Essentials of miRNA-dependent Control of mRNA Translation and decay, miRNA Targeting Principles, and Methods for Target Identification
• Chapter 3. Computational Challenges and -omics Approaches for the Identification of microRNAs and Targets
• Chapter 4. Methodological Challenges in Functional Investigation and Therapeutic Use of microRNAs
• Chapter 5. The Cell Biology of Neural Stem and Progenitor Cells and Neocortex Expansion in Development and Evolution
• Chapter 6. miRNA-Dependent and Independent Functions of the Microprocessor in the Regulation of Neural Stem Cell Biology
• Chapter 7. Epigenetic Regulation of Neurogenesis by microRNAs
• Chapter 8. miRNAs in Mammalian Adult Olfactory Neurogenesis
• Chapter 9. microRNA-Mediated Regulation of Adult Hippocampal Neurogenesis; Implications for Hippocampus-dependent Cognition and Related Disorders?
• Chapter 10. Transcriptional and Epigenetic Control of Astrogliogenesis
• Chapter 11. microRNAs in Oligodendrocyte Myelination and Repair in the Central Nervous System
• Chapter 12. miRNA in Neuronal Networks Maturation and Plasticity
• Chapter 13. Small RNA Dysregulation in Neurocognitive and Neuropsychiatric Disorders
• Chapter 14. Circular RNAs Expression, Function, and Regulation in Neural Systems
• Chapter 15. Comparative Functions of miRNAs in Embryonic Neurogenesis and Neuronal Network Formation
• Chapter 16. microRNA and Neocortical Evolution
• Index