Mattick' Review
Non-coding RNAs may provide the key... Dysregulation of miRNAs..in a mouse knockout of presenilin (Alzheimer's), miR-175 implicated.. in early-onset Parkinson's disease

Sharp
"It's a revolution in how we understand the genome and how the cell functions," says MIT Nobel laureate Phillip Sharp. "There's a whole new frontier there." Sharp and a few microRNA researchers have founded Alnylam Pharmaceuticals to invent RNA-based drugs to treat Parkinson's, cystic fibrosis and spinal injury. The firm has development deals with Merck and Novartis, and such rivals as San Francisco's Sirna Therapeutics are in pursuit.

"What genetic researchers used to call junk DNA may conceal the most important medical secrets of all"

"This will revolutionize human genetics over the next few decades, says David Haussler, a Howard Hughes investigator at UC, Santa Cruz who was on the government team that decoded the human genome. He predicts that most disease-causing genetic flaws will be found lurking in our junk DNA."

"It's a revolution in how we understand the genome and how the cell functions," says MIT Nobel laureate Phillip Sharp.

"PostGenetic Medicine": Personalized Medicine, focusing on PostGenetic Diseases

The Big Picture

AS BIOLOGISTS SIFT more and more novel kinds of active RNA genes out of the long-neglected introns and intergenic stretches of DNA, they are realizing that science is still far from having a complete parts list for humans or any other higher species. Unlike protein-making genes, which have standard "start" and "stop" codes, RNA-only genes vary so much that computer programs cannot reliably pick them out of DNA sequences. To spur the technology on, the NHGRI is launching this autumn an ambitious $36-million project to produce an "Encyclopedia of DNA Elements." The goal is to catalogue every kind of RNA and protein made from a select 1 percent of the human genome in three years.

No one knows yet just what the big picture of genetics will look like once this hidden layer of information is made visible, "Indeed, what was damned as junk because it was not understood may, in fact, turn out to be the very basis of human complexity,'' Mattick suggests. Pseudogenes, riboswitches and all the rest aside, there is a good reason to suspect that is true. Active RNA, it is now coming out, helps to control the large-scale structure of the chromosomes and some crucial chemical modifications to them--an entirely different, epigenetic layer of information in the genome.

The exploration of that epigenetic layer is answering old conundrums: How do human beings survive with a genome horribly cluttered by seemingly useless, parasitic bits of DNA? Why is it so hard to clone an adult animal yet so easy to clone an embryo? Why do certain traits skip generations in an apparently unpredictable way?

DNA sequences long considered genomic garbage are finally getting a little respect. Researchers have figured out how short stretches of DNA that do not normally code for proteins worm their way into genes.

This can result in the production of abnormal proteins and lead to genetic diseases, such as Alport Syndrome, a rare kidney disease.

A growing number of hereditary neurodegenerative disorders have been found to be caused by expansion of trinucleotide repeats. A smaller number of diseases such as fragile X syndrome, myotonic dystrophy, and Friedreich's ataxia, have been found to be due to expansions in non-coding DNA.

^ back to top ^

RNA regulation: a new genetics? (Mattick, 2004)

... Non-coding transcripts. An increasing number of ncRNA genes are being identified, several of which have links to human diseases such as B-cell lymphoma, lung cancer, prostate cancer, cartilage-hair hypoplasia, spinocerebellar ataxia type 8, DiGeorge syndrome, autism and schizophrenia, among others14,25,26,29,42–44.

---

^ back to top ^

Non-coding RNA in the nervous system

Mark F. Mehler and John S. Mattick

Abstract

Increasing evidence suggests that the development and function of the nervous system is heavily dependent on RNA editing and the intricate spatiotemporal expression of a wide repertoire of non-coding RNAs, including micro RNAs, small nucleolar RNAs and longer non-coding RNAs. Non-coding RNAs may provide the key to understanding the multi-tiered links between neural development, nervous system function, and neurological diseases.

Introduction

The nervous system is unique among organs in its precise and sophisticated patterns of regional cellular morphogenesis, cellular diversity, membrane electrical properties, responses to changing environmental inputs and perturbations, neural network connections, and dynamic activity-dependent alterations in synaptic strength underlying higher order cognitive functions including learning and memory (Abrous et al., 2005).

These functional properties are, in turn, orchestrated by a corresponding set of multilayered developmental mechanisms (Mehler, 2002a, b), including neural induction, neural patterning and axis formation within the evolving neural plate and neural tube, elaboration of stem cell generative zones throughout the neuraxis and the evolution of connections between specialized regional neuronal and glial cell types.

Alterations of specific components of these developmental stages and maturational processes result in a broad spectrum of neurodevelopmental disorders and predispose to an equally complex array of adult neurological and neuropsychiatric disorders of unknown aetiology, underscoring the levels of complexity in developmental and mature brain-behaviour relationships. However, we have little understanding of the genetic programs and molecular mechanisms that orchestrate nervous system development, plasticity and function, or how these programs and mechanisms are perturbed in disease.

Although only about 1.2% of the mammalian genome encodes proteins, most of the genome is transcribed, in complex patterns of interlacing and overlapping transcripts from both strands (Carninci et al., 2005; Cheng et al., 2005a; Frith et al., 2005;

Katayama et al., 2005; Engstrom et al., 2006; Mattick & Makunin, 2006), at least some of which are processed to form small regulatory RNAs such as microRNAs and small nucleolar RNAs (reviewed in (Mattick & Makunin, 2005). A range of evidence suggests that these RNAs form complex networks that direct the trajectories of differentiation and development, via regulation of chromatin modification, transcription, RNA modification, splicing, mRNA translation, and RNA stability (Mattick & Gagen, 2001; Mattick, 2003, 2004a) as well as other mechanisms (Prasanth et al., 2005; Willingham et al., 2005). It is also clear that multiple classes of non-coding RNAs (ncRNAs) are overly represented in the central and peripheral nervous system (Hsieh & Gage, 2004; Kim et al., 2004; Rogelj & Giese, 2004; Cheng et al., 2005b; Davies et al., 2005; Klein et al., 2005; Rogaev, 2005; Cao et al., 2006; Ravasi et al., 2006), underscoring the likelihood that nervous system development and function is heavily dependent on RNA regulatory networks, and that perturbations of these networks underlie many neurological diseases.

MicroRNAs

MicroRNAs (miRNAs) are short 21-23 nucleotide regulatory sequences that inhibit the translation or stability of target RNAs (reviewed in (Mattick & Makunin, 2005; Zamore & Haley, 2005). In mice, there are numerous brain-specific miRNAs (Krichevsky et al., 2003; Cheng et al., 2005b; Lim et al., 2005; Xie et al., 2005), a significant subset of which have been directly implicated in neural development and neural cell differentiation (Kawasaki & Taira, 2003; Smirnova et al., 2005). A wide variety of miRNAs are localized to neuronal subtypes with the highest concentration in the cerebral cortex and the cerebellum (Kosik & Krichevsky, 2005; Krichevsky et al., 2006). Additional miRNAs are present within glial cell subtypes with others exhibiting more ubiquitous or neural progenitor cell-specific patterns of expression (Krichevsky et al., 2003; Klein et al., 2005; Smirnova et al., 2005). In zebrafish, the miRNA miR-430 rescues defects of neurulation, neural tube formation, segmental morphogenesis, neural stem cell maintenance and axonal pathfinding observed in dicer mutants that are defective in miRNA processing - although not completely, indicating that that other miRNAs are involved in later stages of neural development (Giraldez et al., 2005).

miRNAs are also abundantly expressed in the adult brain and appear to regulate the maintenance of mature neural traits and synaptic plasticity (Krichevsky et al., 2003; Jin et al., 2004; Sempere et al., 2004; Cheng et al., 2005b; Kosik & Krichevsky, 2005; Smirnova et al., 2005; Conaco et al., 2006; Schratt et al., 2006). Numerous studies suggest that miRNAs are intimately involved in synaptic function and input specificity during memory formation (Martin & Kosik, 2002; Schaeffer et al., 2003; Kim et al., 2004; Lugli et al., 2005; Ashraf et al., 2006; Schratt et al., 2006). Moreover, transcripts encoding synapse-associated proteins also comprise the largest subgroup of predicted miRNA targets, including synapsin 1 and the fragile X mental retardation protein (FMRP) (John et al., 2004).

A novel RNA called dsNRSE (double-stranded neuron-restrictive silencing element) that resembles a miRNA in structure and length acts as a transcriptional activator of neuronal differentiation genes by converting the neuronal silencer factor (REST/NRSF) from a transcriptional repressor in undifferentiated and non-neuronal cells to a transcriptional activator during neuroblast differentiation (Kuwabara et al., 2004). Interestingly, recent studies have revealed that REST modulates the expression of a family of miRNAs including the CNS-specific miR-124a (Conaco et al., 2006).

Perturbations in miRNAs are associated with a number of neural diseases. Deletion of DGCR8, which encodes a component of the complex that processes miRNAs (Gregory et al., 2004; Landthaler et al., 2004), results in DiGeorge syndrome, a multi-system disorder associated with significant learning disabilities (Shiohama et al., 2003).

Dysregulation of miRNAs also occurs in a mouse knockout of presenilin 1, the gene mutated in a subset of early familial forms of Alzheimer’s disease (AD) (Krichevsky et al., 2003). Further, miR-175 has been implicated in a form of X-linked mental retardation (MRX3) and in a type of early-onset Parkinson’s disease (Waisman syndrome) (Dostie et al., 2003). Other studies have implicated miRNAs in diverse neuropsychiatric conditions, particularly those associated with developmental pathogenesis (Rogaev, 2005). In addition, predicted miRNA targets include numerous proteins implicated in neurodevelopmental and neurodegenerative diseases (Rogaev, 2005). Sequence variations in the binding site for miR-189 in the SLIT and Trk-like family member1 (SLITRK1) mRNA have been associated with Tourette’s syndrome (Abelson et al., 2005). SLITRK1 is essential for neuronal growth, guidance and neurite branching and is also differentially expressed in many different neural tumours (Aruga & Mikoshiba, 2003; Aruga et al., 2003). Profound over-expression of miR-21 is seen in glioblastoma multiforme, a highly malignant tumour of the brain, whereas less dramatic degrees of miR-21 over-expression are seen in other neural-specific tumour types (Chan et al., 2005).

In mammals, ADARs are differentially expressed during organogenesis with ADAR3 restricted to brain and ADAR2 preferentially expressed in the nervous system (Chen et al., 2000; Bass, 2002). RNA editing also exhibits precise CNS regional specificity and essential regulatory roles during neuronal maturation (Lai et al., 1997; Kohr et al., 1998; Bernard et al., 1999; Paupard et al., 2000). RNA editing can also affect multiple sites on the same RNA with diverse functional outcomes catalyzed by different ADARs (Valente & Nishikura, 2005). ADAR mutants exhibit complex behavioural defects in C. elegans, Drosophila and mice (Reenan, 2001; Tonkin et al., 2002). Moreover, abnormalities in RNA editing have been implicated in a spectrum of nervous system disorders including Alzheimer’s and Huntington’s diseases, amyotrophic lateral sclerosis, epilepsy, schizophrenia, depression, suicidal ideation, autosomal dominant episodic ataxia type I and Prader-Willi and Angelman syndromes (reviewed in (Valente & Nishikura, 2005).

Intriguingly, in humans, A-I editing occurs far more frequently in transcripts than had been previously appreciated, with the vast majority of the editing occurring in inverted Alu repeats predicted to form intra-molecular duplexes in non-coding RNA sequences in introns, intergenic transcripts and UTRs (Athanasiadis et al., 2004; Blow et al., 2004; Kim et al., 2004; Levanon et al., 2004). These observations raise the intriguing possibility that the predominance of Alu elements in the human genome (10.5% of which is comprised of Alu elements) may not be simply an accident of history, [anybody said it was? - AJP] but the result of positive selection for these sequences as a natural substrate for A-I editing, in turn driven by selection for increased cognitive capacity in the primate lineage (Mattick, 2004b).

It is also worth noting that other small brain-specific trans-acting RNAs such as the primate-specific dendritic BC200 RNA and the analogous rodent dendritic BC1 RNA are both descended from retrotransposed sequences (Martignetti & Brosius, 1993; Ohashi et al., 2000), and it appears likely that many, if not most, transposon-derived sequences in our genome have been exapted into function, primarily at the regulatory level (Brosius,1999).

Longer non-coding RNAs

There are tens of thousands of larger ncRNAs, both polyadenylated and nonpolyadenylated, that are transcribed from the mammalian genome (Carninci et al., 2005; Cheng et al., 2005a; Kapranov et al., 2005; Engstrom et al., 2006), many of which MBII-78 and MBII-85 (Cavaille et al., 2000; Huttenhofer et al., 2001; Rogelj & Giese, 2004). At least some of these miRNAs show differential expression in different areas of the brain, such as the hippocampus and amygdala, areas associated with learning and memory, and are transiently modulated during contextual memory consolidation (fear conditioning) (Rogelj et al., 2003). Human homologs of these snoRNAs are also highly enriched in brain (Cavaille et al., 2000). Certain snoRNAs (RBI-36) exhibit genusspecific functions in rat brain, further attesting to the potential complexity of nonhousekeeping snoRNA functions in the nervous system (Cavaille et al., 2001).

In addition it has recently been shown that HBII-52 modifies the A-I RNA editing and alternative splicing of the serotonin 5-HT (2C) receptor subunit (Kishore & Stamm, 2006). HBII-52 is not expressed in the Prader-Willi developmental syndrome and 5-HT (2C) receptor isoforms distinct from the normal expression pattern are present, suggesting that anomalous splicing may contribute to disease pathogenesis (Cavaille et al., 2000; Kishore & Stamm, 2006). In humans, HBII-13, HBII-52 and HBII-85 map to the Prader-Willi syndrome locus suggesting that snoRNAs may be involved in, or regulated by, genomic imprinting (Rogelj & Giese, 2004). Many larger non-coding RNAs are also imprinted and also implicated in the genetic transactions which underlie imprinting, which clearly affects brain development and function in a variety of ways (see below).

RNA editing

Adenosine to inosine (A-I) RNA editing catalyzed by ADARs is particularly active in the brain, especially in transcripts encoding proteins involved in nerve cell function (Bass, 2002), such as voltage-gated ion channels, ligand-gated receptors, intracellular transduction molecules, apoptosis and cell cycle arrest proteins and modulators of presynaptic terminal integrity (Morse et al., 2002; Hoopengardner et al., 2003; Maas et al., 2003; Athanasiadis et al., 2004; Gelbard, 2004; Levanon et al., 2004; Wang et al., 2004a; Valente & Nishikura, 2005). A-I editing has the capacity to change the coding capacity of mRNA (Bass, 2002), to modulate splice site choice (Laurencikiene et al., 2006), miRNA and miRNA target diversity (Blow et al., 2006), miRNA processing (Yang et al., 2006), and perhaps other targets including chromatin architecture (Fernandez et al., 2005; Valente & Nishikura, 2005), as well as to be inhibited by snoRNAs (Vitali et al., 2005), further evidence of the complexity of RNA regulatory networks.

Regulatory actions are only beginning to be understood (reviewed in (Korneev & O'Shea, 2005). These antisense RNAs exhibit dynamic developmentally regulated and spatially discrete expression profiles, and modulate the expression of genes involved in brain morphogenesis, stem cell renewal and proliferation, stress responses, cell polarity and cytoskeletal functions, and neuronal survival, maturation and synaptic plasticity (Korneev & O'Shea, 2005).

In both schizophrenia and bipolar illness, susceptibility loci are present within the disabled in schizophrenia 1 (DISC1) gene and in the large antisense DISC2 RNA that modulates its expression (Millar et al., 2000; Millar et al., 2004). DISC1 is involved in intracellular transport, cell polarity and neuronal migration and disruption of function during cortical developmental may, in part, underlie the developmental pathogenesis of these heterogeneous neuropsychiatric diseases (Kamiya et al., 2005).

Non-coding RNAs and brain imprinting

Imprinted genes have essential roles in both neural development and adult CNS functioning, and alterations in their expression profiles are associated with a spectrum of complex neurodevelopmental and neuropsychiatric disorders (Costa, 2005; Davies et al., 2005; Davies et al., 2006). These allele-selective genes exhibit preferential and exquisite cell-specific patterns of expression within the brain, and are frequently processed from larger transcriptional units encompassing multiple tandemly repeated snoRNAs and miRNAs (Sleutels et al., 2000; Seitz et al., 2004; Davies et al., 2005; Lewis & Reik, 2006). These imprinted loci also generate a complex spectrum of spliced and unspliced larger ncRNAs of presently unknown function (Sleutels et al., 2000; Davies et al., 2005; O'Neill, 2005; Furuno, 2006). Additional ncRNAs associated with imprinted loci include the production of antisense RNAs to reciprocally imprinted neighbouring protein-coding genes (Sleutels et al., 2000; Davies et al., 2005). The seminal role of imprinted genes in regulating distinct brain signalling systems and in mediating brain-behaviour relationships is illustrated by the spectrum of neurological diseases associated with parent of origin effects and caused by disruptions in imprinted loci: autism, schizophrenia, attention deficit hyperactivity disorder, bipolar disorder and Tourette’s syndrome (see Davies et al., 2004; Wang et al., 2004b; Davies et al., 2005; Davies et al., 2006).

Transfer RNAs and ribosomal RNAs

Transfer RNAs (tRNAs) and ribosomal RNAs (rRNAs) have recently been implicated in a broad array of neural developmental and mature CNS functions as indicated by the effects of mutations in these two classes of ncRNAs which underlie a range of neurodevelopmental, neurodegenerative and neuropsychiatric diseases, including chronic progressive external ophthalmoplegia (CPEO), Kearn-Sayre syndrome (KSS: CPEO with retinal degeneration), MELAS syndrome (mitochondrial encephalopathy with stroke-like syndromes and migraine headaches), MERRF syndrome (myoclonus epilepsy, mitochondrial myopathy, cerebellar ataxia and less commonly dementia, hearing loss and peripheral neuropathy) (reviewed in Dimauro, 2004; Dimauro & Davidzon, 2005; Fattal et al., 2006) and motor neuron disease (Borthwick et al., 2006). MELAS syndrome and other tRNA-mediated diseases are also associated with prominent neuropsychiatric diseases including schizophrenia, psychosis, delirium, personality disorders, major depressive disorders, and anxiety disorders (Fattal et al., 2006).

RNA trinucleotide expansions

A range of neurodevelopmental and neurodegenerative diseases associated with trinucleotide repeat expansion appear to be caused by RNA-mediated mechanisms (reviewed in Gallo et al., 2005; Gatchel & Zoghbi, 2005). These include fragile X syndrome which results from dramatically expanded (>200) CGG repeats in the 5’ UTR of the Fmr1 gene and the related disease associated with smaller (60-200) trinucleotide repeat expansions called FXTAS (fragile X tremor/ataxia syndrome) (FXTAS) associated with tremor, cerebellar ataxia, cognitive decline, peripheral neuropathy, Parkinson’s disease, autonomic dysfunction, proximal muscle weakness, multisystem atrophy and dementia (Hagerman et al., 2005; Van Esch, 2006). Trinucleotide repeat expansions also underlie myotonic dystrophy, which is predominantly a muscle disorder but exists in two forms with associated CNS pathology: DM1 with mental retardation, memory and visuo-spatial and executive dysfunction and DM2 with preferential executive dysfunction (D'Angelo & Bresolin, 2006). DM1 is associated with CTG expansion within the 3’ UTR of the dystrophia myotonica protein kinase gene, DMPK, and DM2 is linked to CCTG expansion in intron 1 of the zinc finger protein gene, ZNF9 (Brook et al., 1992; Fu et al., 1992; Mahadevan et al., 1992; Ranum et al., 1998; Liquori et al., 2001). These mutant RNAs orchestrate different forms of pathogenesis through the degree and type of repeat length expansion and their molecular interactions with RNAbinding proteins of the muscleblind-like (MBNL) family (Jiang et al., 2004; Pascual et al., 2006).

Several forms of spinocerebellar ataxia (SCA) may also be caused by different RNAmediated pathological mechanisms. SCA8 results from CTG expansion of the 3’ UTR of an untranslated antisense RNA with partial overlap with the Kelch-like 1 (KLHL1) gene (Koob et al., 1999; Nemes et al., 2000; Mutsuddi et al., 2004; Gatchel & Zoghbi, 2005).

Moreover, using SCA8 as a sensitized background in a modifier screen resulted in the identification of four novel ncRNAs with preferential neuronal expression (Mutsuddi et al., 2004). SCA10 is mediated by an unstable ATTCT repeat expansion in the 3’ end of a large intron of a gene of presently unknown function that may result in transcriptional silencing or in a different RNA-associated toxic mechanism (Matsuura et al., 2000). SCA12 is caused by CAG expansion in the non-coding 5’ promoter/5’ UTR of the PPP2R2B gene, which encodes a brain specific regulatory subunit of protein phosphatase 2A (Holmes et al., 1999). Depending on the precise location of the expanded trinucleotide repeat, disease pathogenesis may be mediated by distinct trans-dominant RNA or alternate toxic gain of function mechanisms (Holmes et al., 2003).

Conclusion

The known list of both small and large ncRNAs that are involved in the nervous system almost certainly represents only a tiny fraction of the total transcriptome devoted to RNA-mediated mechanisms underlying the development, functional complexity and plasticity of the mammalian brain. Indeed, it appears that the majority of human genomic programming is devoted to RNA-based regulatory circuitry (Mattick, 2003; Mattick & Makunin, 2006). It also appears that the traditional presumption that most genetic information is transacted by proteins has led to a fundamental misunderstanding of the genetic programming of human differentiation and development, both generally and specifically in the brain, where RNA transactions appear to be at their most complex.

References

Abelson JF, Kwan KY, O'Roak BJ, Baek DY, Stillman AA, Morgan TM, Mathews CA,

Pauls DL, Rasin MR, Gunel M, et al. (2005). Sequence variants in SLITRK1 are

associated with Tourette's syndrome. Science 310, 317-320.

Abrous DN, Koehl M & Le Moal M (2005). Adult neurogenesis: from precursors to

network and physiology. Physiol Rev 85, 523-569.

Aruga J & Mikoshiba K (2003). Identification and characterization of Slitrk, a novel

neuronal transmembrane protein family controlling neurite outgrowth. Mol Cell

Neurosci 24, 117-129.

Aruga J, Yokota N & Mikoshiba K (2003). Human SLITRK family genes: genomic

organization and expression profiling in normal brain and brain tumor tissue. Gene

315, 87-94.

Ashraf SI, McLoon AL, Sclarsic SM & Kunes S (2006). Synaptic protein synthesis

associated with memory is regulated by the RISC pathway in Drosophila. Cell 124,

191-205.

Athanasiadis A, Rich A & Maas S (2004). Widespread A-to-I RNA editing of Alucontaining

mRNAs in the human transcriptome. PLoS Biol 2, e391.

Bachellerie JP, Cavaille J & Huttenhofer A (2002). The expanding snoRNA world.

Biochimie 84, 775-790.

Bass BL (2002). RNA editing by adenosine deaminases that act on RNA. Annu Rev

Biochem 71, 817-846.

Bentwich I, Avniel A, Karov Y, Aharonov R, Gilad S, Barad O, Barzilai A, Einat P,

Einav U, Meiri E, et al. (2005). Identification of hundreds of conserved and

nonconserved human microRNAs. Nat Genet 37, 766-770.

Bernard A, Ferhat L, Dessi F, Charton G, Represa A, Ben-Ari Y & Khrestchatisky M

(1999). Q/R editing of the rat GluR5 and GluR6 kainate receptors in vivo and in

vitro: evidence for independent developmental, pathological and cellular

regulation. Eur J Neurosci 11, 604-616.

Blow M, Futreal PA, Wooster R & Stratton MR (2004). A survey of RNA editing in

human brain. Genome Res 14, 2379-2387.

Blow MJ, Grocock RJ, van Dongen S, Enright AJ, Dicks E, Futreal PA, Wooster R &

Stratton MR (2006). RNA editing of human microRNAs. Genome Biol 7, R27.

Borthwick GM, Taylor RW, Walls TJ, Tonska K, Taylor GA, Shaw PJ, Ince PG &

Turnbull DM. (2006). Motor neuron disease in a patient with a mitochondrial

tRNAIle mutation. Ann Neurol 59, 570-574.

Brook JD, McCurrach ME, Harley HG, Buckler AJ, Church D, Aburatani H, Hunter K,

Stanton VP, Thirion JP, Hudson T, et al. (1992). Molecular basis of myotonic

dystrophy: expansion of a trinucleotide (CTG) repeat at the 3' end of a transcript

encoding a protein kinase family member. Cell 68, 799-808.

Brosius J (1999). RNAs from all categories generate retrosequences that may be exapted

as novel genes or regulatory elements. Gene 238, 115-134.

Brosius J & Tiedge H (2001). Neuronal BC1 RNA: intracellular transport and activitydependent

modulation. Results Probl Cell Differ 34, 129-138.

Cao X, Yeo G, Muotri AR, Kuwabara T & Gage FH (2006). Noncoding RNAs in the

mammalian central nervous system. Annu Rev Neurosci 29, in press.

Carninci P, Kasukawa T, Katayama S, Gough J, Frith MC, Maeda N, Oyama R, Ravasi

T, Lenhard B, Wells C, et al. (2005). The transcriptional landscape of the

mammalian genome. Science 309, 1559-1563.

Cavaille J, Buiting K, Kiefmann M, Lalande M, Brannan CI, Horsthemke B, Bachellerie

JP, Brosius J & Huttenhofer A (2000). Identification of brain-specific and

imprinted small nucleolar RNA genes exhibiting an unusual genomic organization.

Proc Natl Acad Sci U S A 97, 14311-14316.

Cavaille J, Vitali P, Basyuk E, Huttenhofer A & Bachellerie JP (2001). A novel brainspecific

box C/D small nucleolar RNA processed from tandemly repeated introns

of a noncoding RNA gene in rats. J Biol Chem 276, 26374-26383.

Ceman S, Brown V & Warren ST (1999). Isolation of an FMRP-associated messenger

ribonucleoprotein particle and identification of nucleolin and the fragile X-related

proteins as components of the complex. Mol Cell Biol 19, 7925-7932.

Ceman S, Nelson R & Warren ST (2000). Identification of mouse YB1/p50 as a

component of the FMRP-associated mRNP particle. Biochem Biophys Res

Commun 279, 904-908.

Chan JA, Krichevsky AM & Kosik KS (2005). MicroRNA-21 is an antiapoptotic factor

in human glioblastoma cells. Cancer Res 65, 6029-6033.

Chang S, Johnston RJ, Jr., Frokjaer-Jensen C, Lockery S & Hobert O (2004).

MicroRNAs act sequentially and asymmetrically to control chemosensory laterality

in the nematode. Nature 430, 785-789.

Chen CX, Cho DS, Wang Q, Lai F, Carter KC & Nishikura K (2000). A third member of

the RNA-specific adenosine deaminase gene family, ADAR3, contains both singleand

double-stranded RNA binding domains. Rna 6, 755-767.

Cheng J, Kapranov P, Drenkow J, Dike S, Brubaker S, Patel S, Long J, Stern D,

Tammana H, Helt G, et al. (2005a). Transcriptional maps of 10 human

chromosomes at 5-nucleotide resolution. Science 308, 1149-1154.

Cheng LC, Tavazoie M & Doetsch F (2005b). Stem cells: from epigenetics to

microRNAs. Neuron 46, 363-367.

Conaco C, Otto S, Han JJ & Mandel G (2006). Reciprocal actions of REST and a

microRNA promote neuronal identity. Proc Natl Acad Sci U S A 103, 2422-2427.

Costa FF. (2005). Non-coding RNAs: new players in eukaryotic biology. Gene 357, 83-

94.

Cummins JM, He Y, Leary RJ, Pagliarini R, Diaz LA, Jr., Sjoblom T, Barad O,

Bentwich Z, Szafranska AE, Labourier E, et al. (2006). The colorectal

microRNAome. Proc Natl Acad Sci U S A 103, 3687-3692.

D'Angelo MG & Bresolin N (2006). Cognitive impairment in neuromuscular disorders.

Muscle Nerve; DOI: 10.1002/mus.20535.

Davies W, Isles AR, Burgoyne PS & Wilkinson LS (2006). X-linked imprinting: effects

on brain and behaviour. Bioessays 28, 35-44.

Davies W, Isles AR & Wilkinson LS (2005). Imprinted gene expression in the brain.

Neurosci Biobehav Rev 29, 421-430.

Davies W, Smith RJ, Kelsey G & Wilkinson LS (2004). Expression patterns of the novel

imprinted genes Nap1l5 and Peg13 and their non-imprinted host genes in the adult

mouse brain. Gene Expr Patterns 4, 741-747.

Dimauro S (2004). Mitochondrial medicine. Biochim Biophys Acta 1659, 107-114.

Dimauro S & Davidzon G (2005). Mitochondrial DNA and disease. Ann Med 37, 222-

232.

Dostie J, Mourelatos Z, Yang M, Sharma A & Dreyfuss G (2003). Numerous microRNPs

in neuronal cells containing novel microRNAs. Rna 9, 180-186.

Engstrom PG, Suzuki H, Ninomiya N, Akalin A, Sessa L, Lavorgna G, Brozzi A, Luzi L,

Tan SL, Yang L, et al. (2006). Complex Loci in human and mouse genomes. PLoS

Genet 2, e47.

Fattal O, Budur K, Vaughan AJ & Franco K (2006). Review of the literature on major

mental disorders in adult patients with mitochondrial diseases. Psychosomatics 47,

1-7.

Fernandez HR, Kavi HH, Xie W & Birchler JA (2005). Heterochromatin: on the ADAR

radar? Curr Biol 15, R132-R134.

Frith MC, Pheasant M & Mattick JS (2005). The amazing complexity of the human

transcriptome. Eur J Hum Genet 13, 894-897.

Fu YH, Pizzuti A, Fenwick RG, Jr., King J, Rajnarayan S, Dunne PW, Dubel J, Nasser

GA, Ashizawa T, de Jong P, et al. (1992). An unstable triplet repeat in a gene

related to myotonic muscular dystrophy. Science 255, 1256-1258.

Furuno M, Pang KC, Ninomiya N, Fukuda S, Frith MC, Bult C, Kai C, Kawai J,

Carninci P, Hayashizaki Y, et al. (2006). Clusters of internally-primed transcripts

reveal novel long noncoding RNAs. PLoS Genet 2, e37.

Gallo JM, Jin P, Thornton CA, Lin H, Robertson J, D'Souza I & Schlaepfer WW (2005).

The role of RNA and RNA processing in neurodegeneration. J Neurosci 25, 10372-

10375.

Gatchel JR & Zoghbi HY (2005). Diseases of unstable repeat expansion: mechanisms

and common principles. Nat Rev Genet 6, 743-755.

Gelbard HA. (2004). Synapses and Sisyphus: life without paraplegin. J Clin Invest 113,

185-187.

Giraldez AJ, Cinalli RM, Glasner ME, Enright AJ, Thomson JM, Baskerville S,

Hammond SM, Bartel DP & Schier AF (2005). MicroRNAs regulate brain

morphogenesis in zebrafish. Science 308, 833-838.

Gregory RI, Yan KP, Amuthan G, Chendrimada T, Doratotaj B, Cooch N & Shiekhattar

R (2004). The Microprocessor complex mediates the genesis of microRNAs.

Nature 432, 235-240.

Hagerman RJ, Ono MY & Hagerman PJ (2005). Recent advances in fragile X: a model

for autism and neurodegeneration. Curr Opin Psychiatry 18, 490-496.

Hardiman KE, Brewster R, Khan SM, Deo M & Bodmer R (2002). The bereft gene, a

potential target of the neural selector gene cut, contributes to bristle

morphogenesis. Genetics 161, 231-247.

Holmes SE, O'Hearn E & Margolis RL (2003). Why is SCA12 different from other

SCAs? Cytogenet Genome Res 100, 189-197.

Holmes SE, O'Hearn EE, McInnis MG, Gorelick-Feldman DA, Kleiderlein JJ, Callahan

C, Kwak NG, Ingersoll-Ashworth RG, Sherr M, Sumner AJ, et al. (1999).

Expansion of a novel CAG trinucleotide repeat in the 5' region of PPP2R2B is

associated with SCA12. Nat Genet 23, 391-392.

Hoopengardner B, Bhalla T, Staber C & Reenan R (2003). Nervous system targets of

RNA editing identified by comparative genomics. Science 301, 832-836.

Hsieh J & Gage FH (2004). Epigenetic control of neural stem cell fate. Curr Opin Genet

Dev 14, 461-469.

Huttenhofer A, Brosius J & Bachellerie JP (2002). RNomics: identification and function

of small, non-messenger RNAs. Curr Opin Chem Biol 6, 835-843.

Huttenhofer A, Kiefmann M, Meier-Ewert S, O'Brien J, Lehrach H, Bachellerie JP &

Brosius J (2001). RNomics: an experimental approach that identifies 201

candidates for novel, small, non-messenger RNAs in mouse. Embo J 20, 2943-

2953.

Inagaki S, Numata K, Kondo T, Tomita M, Yasuda K, Kanai A & Kageyama Y (2005).

Identification and expression analysis of putative mRNA-like non-coding RNA in

Drosophila. Genes Cells 10, 1163-1173.

Jiang H, Mankodi A, Swanson MS, Moxley RT & Thornton CA (2004). Myotonic

dystrophy type 1 is associated with nuclear foci of mutant RNA, sequestration of

muscleblind proteins and deregulated alternative splicing in neurons. Hum Mol

Genet 13, 3079-3088.

Jin P, Alisch RS & Warren ST (2004). RNA and microRNAs in fragile X mental

retardation. Nat Cell Biol 6, 1048-1053.

John B, Enright AJ, Aravin A, Tuschl T, Sander C & Marks DS (2004). Human

microRNA targets. PLoS Biol 2, e363.

Johnson EM, Kinoshita Y, Weinreb DB, Wortman MJ, Simon R, Khalili K, Winckler B

& Gordon J (2006). Role of Puralpha in targeting mRNA to sites of translation in

hippocampal neuronal dendrites. J Neurosci Res 83, 929-943.

Johnston RJ & Hobert O (2003). A microRNA controlling left/right neuronal asymmetry

in Caenorhabditis elegans. Nature 426, 845-849.

Kamiya A, Kubo K, Tomoda T, Takaki M, Youn R, Ozeki Y, Sawamura N, Park U,

Kudo C, Okawa M, et al. (2005). A schizophrenia-associated mutation of DISC1

perturbs cerebral cortex development. Nat Cell Biol 7, 1167-1178.

Kanai Y, Dohmae N & Hirokawa N (2004). Kinesin transports RNA: isolation and

characterization of an RNA-transporting granule. Neuron 43, 513-525.

Kapranov P, Drenkow J, Cheng J, Long J, Helt G, Dike S & Gingeras TR (2005).

Examples of the complex architecture of the human transcriptome revealed by

RACE and high-density tiling arrays. Genome Res 15, 987-997.

Katayama S, Tomaru Y, Kasukawa T, Waki K, Nakanishi M, Nakamura M, Nishida H,

Yap CC, Suzuki M, Kawai J, et al. (2005). Antisense transcription in the

mammalian transcriptome. Science 309, 1564-1566.

Kawasaki H & Taira K (2003). Functional analysis of microRNAs during the retinoic

acid-induced neuronal differentiation of human NT2 cells. Nucleic Acids Res Suppl

3, 243-244.

Kim J, Krichevsky A, Grad Y, Hayes GD, Kosik KS, Church GM & Ruvkun G (2004).

Identification of many microRNAs that copurify with polyribosomes in

mammalian neurons. Proc Natl Acad Sci U S A 101, 360-365.

Kishore S & Stamm S (2006). The snoRNA HBII-52 regulates alternative splicing of the

serotonin receptor 2C. Science 311, 230-232.

Klein ME, Impey S & Goodman RH (2005). Role reversal: the regulation of neuronal

gene expression by microRNAs. Curr Opin Neurobiol 15, 507-513.

Kobayashi S, Takashima A & Anzai K (1998). The dendritic translocation of translin

protein in the form of BC1 RNA protein particles in developing rat hippocampal

neurons in primary culture. Biochem Biophys Res Commun 253, 448-453.

Kohr G, Melcher T & Seeburg PH (1998). Candidate editases for GluR channels in

single neurons of rat hippocampus and cerebellum. Neuropharmacology 37, 1411-

1417.

Koob MD, Moseley ML, Schut LJ, Benzow KA, Bird TD, Day JW & Ranum LP (1999).

An untranslated CTG expansion causes a novel form of spinocerebellar ataxia

(SCA8). Nat Genet 21, 379-384.

Korneev S & O'Shea M (2005). Natural antisense RNAs in the nervous system. Rev

Neurosci 16, 213-222.

Kosik KS & Krichevsky AM (2005). The elegance of the microRNAs: a neuronal

perspective. Neuron 47, 779-782.

Krichevsky AM, King KS, Donahue CP, Khrapko K & Kosik KS (2003). A microRNA

array reveals extensive regulation of microRNAs during brain development. Rna 9,

1274-1281.

Krichevsky AM, Sonntag KC, Isacson O & Kosik KS (2006). Specific microRNAs

modulate embryonic stem cell-derived neurogenesis. Stem Cells 24, 857-864.

Kuwabara T, Hsieh J, Nakashima K, Taira K & Gage FH (2004). A small modulatory

dsRNA specifies the fate of adult neural stem cells. Cell 116, 779-793.

Lai F, Chen CX, Lee VM & Nishikura K (1997). Dramatic increase of the RNA editing

for glutamate receptor subunits during terminal differentiation of clonal human

neurons. J Neurochem 69, 43-52.

Landthaler M, Yalcin A & Tuschl T (2004). The human DiGeorge syndrome critical

region gene 8 and Its D. melanogaster homolog are required for miRNA

biogenesis. Curr Biol 14, 2162-2167.

Laurencikiene J, Kallman AM, Fong N, Bentley DL & Ohman M (2006). RNA editing

and alternative splicing: the importance of co-transcriptional coordination. EMBO

Rep 7, 303-307.

Lestrade L & Weber MJ (2006). snoRNA-LBME-db, a comprehensive database of

human H/ACA and C/D box snoRNAs. Nucleic Acids Res 34, D158-162.

Levanon EY, Eisenberg E, Yelin R, Nemzer S, Hallegger M, Shemesh R, Fligelman ZY,

Shoshan A, Pollock SR, Sztybel D, et al. (2004). Systematic identification of

abundant A-to-I editing sites in the human transcriptome. Nat Biotechnol 22, 1001-

1005.

Lewis A & Reik W (2006). How imprinting centres work. Cytogenet Genome Res 113,

81-89.

Lim LP, Lau NC, Garrett-Engele P, Grimson A, Schelter JM, Castle J, Bartel DP,

Linsley PS & Johnson JM (2005). Microarray analysis shows that some

microRNAs downregulate large numbers of target mRNAs. Nature 433, 769-773.

Liquori CL, Ricker K, Moseley ML, Jacobsen JF, Kress W, Naylor SL, Day JW &

Ranum LP (2001). Myotonic dystrophy type 2 caused by a CCTG expansion in

intron 1 of ZNF9. Science 293, 864-867.

Luciano DJ, Mirsky H, Vendetti NJ & Maas S (2004). RNA editing of a miRNA

precursor. Rna 10, 1174-1177.

Lugli G, Larson J, Martone ME, Jones Y & Smalheiser NR (2005). Dicer and eIF2c are

enriched at postsynaptic densities in adult mouse brain and are modified by

neuronal activity in a calpain-dependent manner. J Neurochem 94, 896-905.

Maas S, Rich A & Nishikura K (2003). A-to-I RNA editing: recent news and residual

mysteries. J Biol Chem 278, 1391-1394.

Mahadevan M, Tsilfidis C, Sabourin L, Shutler G, Amemiya C, Jansen G, Neville C,

Narang M, Barcelo J, O'Hoy K, et al. (1992). Myotonic dystrophy mutation: an

unstable CTG repeat in the 3' untranslated region of the gene. Science 255, 1253-

1255.

Martignetti JA & Brosius J (1993). BC200 RNA: a neural RNA polymerase III product

encoded by a monomeric Alu element. Proc Natl Acad Sci U S A 90, 11563-11567.

Martin KC & Kosik KS (2002). Synaptic tagging -- who's it? Nat Rev Neurosci 3, 813-

820.

Matsuura T, Yamagata T, Burgess DL, Rasmussen A, Grewal RP, Watase K, Khajavi M,

McCall AE, Davis CF, Zu L, Achari M, Pulst SM, Alonso E, Noebels JL, Nelson

DL, Zoghbi HY & Ashizawa T (2000). Large expansion of the ATTCT

pentanucleotide repeat in spinocerebellar ataxia type 10. Nat Genet 26, 191-194.

Mattick JS (2003). Challenging the dogma: the hidden layer of non-protein-coding RNAs

in complex organisms. Bioessays 25, 930-939.

Mattick JS (2004a). RNA regulation: a new genetics? Nat Rev Genet 5, 316-323.

Mattick JS (2004b). The hidden genetic program of complex organisms. Scientific

American 291, 60-67.

Kapranov P, Drenkow J, Cheng J, Long J, Helt G, Dike S & Gingeras TR (2005).

Examples of the complex architecture of the human transcriptome revealed by

RACE and high-density tiling arrays. Genome Res 15, 987-997.

Katayama S, Tomaru Y, Kasukawa T, Waki K, Nakanishi M, Nakamura M, Nishida H,

Yap CC, Suzuki M, Kawai J, et al. (2005). Antisense transcription in the

mammalian transcriptome. Science 309, 1564-1566.

Kawasaki H & Taira K (2003). Functional analysis of microRNAs during the retinoic

acid-induced neuronal differentiation of human NT2 cells. Nucleic Acids Res Suppl

3, 243-244.

Kim J, Krichevsky A, Grad Y, Hayes GD, Kosik KS, Church GM & Ruvkun G (2004).

Identification of many microRNAs that copurify with polyribosomes in

mammalian neurons. Proc Natl Acad Sci U S A 101, 360-365.

Kishore S & Stamm S (2006). The snoRNA HBII-52 regulates alternative splicing of the

serotonin receptor 2C. Science 311, 230-232.

Klein ME, Impey S & Goodman RH (2005). Role reversal: the regulation of neuronal

gene expression by microRNAs. Curr Opin Neurobiol 15, 507-513.

Kobayashi S, Takashima A & Anzai K (1998). The dendritic translocation of translin

protein in the form of BC1 RNA protein particles in developing rat hippocampal

neurons in primary culture. Biochem Biophys Res Commun 253, 448-453.

Kohr G, Melcher T & Seeburg PH (1998). Candidate editases for GluR channels in

single neurons of rat hippocampus and cerebellum. Neuropharmacology 37, 1411-

1417.

Koob MD, Moseley ML, Schut LJ, Benzow KA, Bird TD, Day JW & Ranum LP (1999).

An untranslated CTG expansion causes a novel form of spinocerebellar ataxia

(SCA8). Nat Genet 21, 379-384.

Korneev S & O'Shea M (2005). Natural antisense RNAs in the nervous system. Rev

Neurosci 16, 213-222.

Kosik KS & Krichevsky AM (2005). The elegance of the microRNAs: a neuronal

perspective. Neuron 47, 779-782.

Krichevsky AM, King KS, Donahue CP, Khrapko K & Kosik KS (2003). A microRNA

array reveals extensive regulation of microRNAs during brain development. Rna 9,

1274-1281.

Krichevsky AM, Sonntag KC, Isacson O & Kosik KS (2006). Specific microRNAs

modulate embryonic stem cell-derived neurogenesis. Stem Cells 24, 857-864.

Kuwabara T, Hsieh J, Nakashima K, Taira K & Gage FH (2004). A small modulatory

dsRNA specifies the fate of adult neural stem cells. Cell 116, 779-793.

Lai F, Chen CX, Lee VM & Nishikura K (1997). Dramatic increase of the RNA editing

for glutamate receptor subunits during terminal differentiation of clonal human

neurons. J Neurochem 69, 43-52.

Landthaler M, Yalcin A & Tuschl T (2004). The human DiGeorge syndrome critical

region gene 8 and Its D. melanogaster homolog are required for miRNA

biogenesis. Curr Biol 14, 2162-2167.

Laurencikiene J, Kallman AM, Fong N, Bentley DL & Ohman M (2006). RNA editing

and alternative splicing: the importance of co-transcriptional coordination. EMBO

Rep 7, 303-307.

Lestrade L & Weber MJ (2006). snoRNA-LBME-db, a comprehensive database of

human H/ACA and C/D box snoRNAs. Nucleic Acids Res 34, D158-162.

Levanon EY, Eisenberg E, Yelin R, Nemzer S, Hallegger M, Shemesh R, Fligelman ZY,

Shoshan A, Pollock SR, Sztybel D, et al. (2004). Systematic identification of

abundant A-to-I editing sites in the human transcriptome. Nat Biotechnol 22, 1001-

1005.

Lewis A & Reik W (2006). How imprinting centres work. Cytogenet Genome Res 113,

81-89.

Lim LP, Lau NC, Garrett-Engele P, Grimson A, Schelter JM, Castle J, Bartel DP,

Linsley PS & Johnson JM (2005). Microarray analysis shows that some

microRNAs downregulate large numbers of target mRNAs. Nature 433, 769-773.

Liquori CL, Ricker K, Moseley ML, Jacobsen JF, Kress W, Naylor SL, Day JW &

Ranum LP (2001). Myotonic dystrophy type 2 caused by a CCTG expansion in

intron 1 of ZNF9. Science 293, 864-867.

Luciano DJ, Mirsky H, Vendetti NJ & Maas S (2004). RNA editing of a miRNA

precursor. Rna 10, 1174-1177.

Lugli G, Larson J, Martone ME, Jones Y & Smalheiser NR (2005). Dicer and eIF2c are

enriched at postsynaptic densities in adult mouse brain and are modified by

neuronal activity in a calpain-dependent manner. J Neurochem 94, 896-905.

Maas S, Rich A & Nishikura K (2003). A-to-I RNA editing: recent news and residual

mysteries. J Biol Chem 278, 1391-1394.

Mahadevan M, Tsilfidis C, Sabourin L, Shutler G, Amemiya C, Jansen G, Neville C,

Narang M, Barcelo J, O'Hoy K, et al. (1992). Myotonic dystrophy mutation: an

unstable CTG repeat in the 3' untranslated region of the gene. Science 255, 1253-

1255.

Martignetti JA & Brosius J (1993). BC200 RNA: a neural RNA polymerase III product

encoded by a monomeric Alu element. Proc Natl Acad Sci U S A 90, 11563-11567.

Martin KC & Kosik KS (2002). Synaptic tagging -- who's it? Nat Rev Neurosci 3, 813-

820.

Matsuura T, Yamagata T, Burgess DL, Rasmussen A, Grewal RP, Watase K, Khajavi M,

McCall AE, Davis CF, Zu L, Achari M, Pulst SM, Alonso E, Noebels JL, Nelson

DL, Zoghbi HY & Ashizawa T (2000). Large expansion of the ATTCT

pentanucleotide repeat in spinocerebellar ataxia type 10. Nat Genet 26, 191-194.

Mattick JS (2003). Challenging the dogma: the hidden layer of non-protein-coding RNAs

in complex organisms. Bioessays 25, 930-939.

Mattick JS (2004a). RNA regulation: a new genetics? Nat Rev Genet 5, 316-323.

Mattick JS (2004b). The hidden genetic program of complex organisms. Scientific

American 291, 60-67.

Kapranov P, Drenkow J, Cheng J, Long J, Helt G, Dike S & Gingeras TR (2005).

Examples of the complex architecture of the human transcriptome revealed by

RACE and high-density tiling arrays. Genome Res 15, 987-997.

Katayama S, Tomaru Y, Kasukawa T, Waki K, Nakanishi M, Nakamura M, Nishida H,

Yap CC, Suzuki M, Kawai J, et al. (2005). Antisense transcription in the

mammalian transcriptome. Science 309, 1564-1566.

Kawasaki H & Taira K (2003). Functional analysis of microRNAs during the retinoic

acid-induced neuronal differentiation of human NT2 cells. Nucleic Acids Res Suppl

3, 243-244.

Kim J, Krichevsky A, Grad Y, Hayes GD, Kosik KS, Church GM & Ruvkun G (2004).

Identification of many microRNAs that copurify with polyribosomes in

mammalian neurons. Proc Natl Acad Sci U S A 101, 360-365.

Kishore S & Stamm S (2006). The snoRNA HBII-52 regulates alternative splicing of the

serotonin receptor 2C. Science 311, 230-232.

Klein ME, Impey S & Goodman RH (2005). Role reversal: the regulation of neuronal

gene expression by microRNAs. Curr Opin Neurobiol 15, 507-513.

Kobayashi S, Takashima A & Anzai K (1998). The dendritic translocation of translin

protein in the form of BC1 RNA protein particles in developing rat hippocampal

neurons in primary culture. Biochem Biophys Res Commun 253, 448-453.

Kohr G, Melcher T & Seeburg PH (1998). Candidate editases for GluR channels in

single neurons of rat hippocampus and cerebellum. Neuropharmacology 37, 1411-

1417.

Koob MD, Moseley ML, Schut LJ, Benzow KA, Bird TD, Day JW & Ranum LP (1999).

An untranslated CTG expansion causes a novel form of spinocerebellar ataxia

(SCA8). Nat Genet 21, 379-384.

Korneev S & O'Shea M (2005). Natural antisense RNAs in the nervous system. Rev

Neurosci 16, 213-222.

Kosik KS & Krichevsky AM (2005). The elegance of the microRNAs: a neuronal

perspective. Neuron 47, 779-782.

Krichevsky AM, King KS, Donahue CP, Khrapko K & Kosik KS (2003). A microRNA

array reveals extensive regulation of microRNAs during brain development. Rna 9,

1274-1281.

Krichevsky AM, Sonntag KC, Isacson O & Kosik KS (2006). Specific microRNAs

modulate embryonic stem cell-derived neurogenesis. Stem Cells 24, 857-864.

Kuwabara T, Hsieh J, Nakashima K, Taira K & Gage FH (2004). A small modulatory

dsRNA specifies the fate of adult neural stem cells. Cell 116, 779-793.

Lai F, Chen CX, Lee VM & Nishikura K (1997). Dramatic increase of the RNA editing

for glutamate receptor subunits during terminal differentiation of clonal human

neurons. J Neurochem 69, 43-52.

Landthaler M, Yalcin A & Tuschl T (2004). The human DiGeorge syndrome critical

region gene 8 and Its D. melanogaster homolog are required for miRNA

biogenesis. Curr Biol 14, 2162-2167.

Paupard MC, O'Connell MA, Gerber AP & Zukin RS (2000). Patterns of developmental

expression of the RNA editing enzyme rADAR2. Neuroscience 95, 869-879.

Prasanth KV, Prasanth SG, Xuan Z, Hearn S, Freier SM, Bennett CF, Zhang MQ &

Spector DL (2005). Regulating gene expression through RNA nuclear retention.

Cell 123, 249-263.

Rackham O & Brown CM (2004). Visualization of RNA-protein interactions in living

cells: FMRP and IMP1 interact on mRNAs. Embo J 23, 3346-3355.

Ranum LP, Rasmussen PF, Benzow KA, Koob MD & Day JW (1998). Genetic mapping

of a second myotonic dystrophy locus. Nat Genet 19, 196-198.

Ravasi T, Suzuki H, Pang KC, Katayama S, Furuno M, Okunishi R, Fukuda S, Ru K,

Frith MC, Gongora MM, et al. (2006). Experimental validation of the regulated

expression of large numbers of non-coding RNAs from the mouse genome.

Genome Res 16, 11-19.

Reenan RA (2001). The RNA world meets behavior: A-->I pre-mRNA editing in

animals. Trends Genet 17, 53-56.

Rogaev EI (2005). Small RNAs in human brain development and disorders. Biochemistry

(Mosc) 70, 1404-1407.

Rogelj B & Giese KP (2004). Expression and function of brain specific small RNAs. Rev

Neurosci 15, 185-198.

Rogelj B, Hartmann CE, Yeo CH, Hunt SP & Giese KP (2003). Contextual fear

conditioning regulates the expression of brain-specific small nucleolar RNAs in

hippocampus. Eur J Neurosci 18, 3089-3096.

Royo H, Bortolin ML, Seitz H & Cavaille J (2006). Small non-coding RNAs and

genomic imprinting. Cytogenet Genome Res 113, 99-108.

Schaeffer C, Beaulande M, Ehresmann C, Ehresmann B & Moine H (2003). The RNA

binding protein FMRP: new connections and missing links. Biol Cell 95, 221-228.

Schratt GM, Tuebing F, Nigh EA, Kane CG, Sabatini ME, Kiebler M & Greenberg ME

(2006). A brain-specific microRNA regulates dendritic spine development. Nature

439, 283-289.

Seitz H, Royo H, Bortolin ML, Lin SP, Ferguson-Smith AC & Cavaille J (2004). A large

imprinted microRNA gene cluster at the mouse Dlk1-Gtl2 domain. Genome Res

14, 1741-1748.

Sempere LF, Freemantle S, Pitha-Rowe I, Moss E, Dmitrovsky E & Ambros V (2004).

Expression profiling of mammalian microRNAs uncovers a subset of brainexpressed

microRNAs with possible roles in murine and human neuronal

differentiation. Genome Biol 5, R13.

Shiohama A, Sasaki T, Noda S, Minoshima S & Shimizu N (2003). Molecular cloning

and expression analysis of a novel gene DGCR8 located in the DiGeorge syndrome

chromosomal region. Biochem Biophys Res Commun 304, 184-190.

Sleutels F, Barlow DP & Lyle R (2000). The uniqueness of the imprinting mechanism.

Curr Opin Genet Dev 10, 229-233.

Smirnova L, Grafe A, Seiler A, Schumacher S, Nitsch R & Wulczyn FG (2005).

Regulation of miRNA expression during neural cell specification. Eur J Neurosci

21, 1469-1477.

Tonkin LA, Saccomanno L, Morse DP, Brodigan T, Krause M & Bass BL (2002). RNA

editing by ADARs is important for normal behavior in Caenorhabditis elegans.

Embo J 21, 6025-6035.

Valente L & Nishikura K (2005). ADAR gene family and A-to-I RNA editing: diverse

roles in posttranscriptional gene regulation. Prog Nucleic Acid Res Mol Biol 79,

299-338.

Van Esch H (2006). The Fragile X premutation: new insights and clinical consequences.

Eur J Med Genet 49, 1-8.

Vitali P, Basyuk E, Le Meur E, Bertrand E, Muscatelli F, Cavaille J & Huttenhofer A

(2005). ADAR2-mediated editing of RNA substrates in the nucleolus is inhibited

by C/D small nucleolar RNAs. J Cell Biol 169, 745-753.

Wang Q, Miyakoda M, Yang W, Khillan J, Stachura DL, Weiss MJ & Nishikura K

(2004a). Stress-induced apoptosis associated with null mutation of ADAR1 RNA

editing deaminase gene. J Biol Chem 279, 4952-4961.

Wang Y, Joh K, Masuko S, Yatsuki H, Soejima H, Nabetani A, Beechey CV, Okinami S

& Mukai T (2004b). The mouse Murr1 gene is imprinted in the adult brain,

presumably due to transcriptional interference by the antisense-oriented U2af1-rs1

gene. Mol Cell Biol 24, 270-279.

Willingham AT, Orth AP, Batalov S, Peters EC, Wen BG, Aza-Blanc P, Hogenesch JB

& Schultz PG (2005). A strategy for probing the function of noncoding RNAs finds

a repressor of NFAT. Science 309, 1570-1573.

Wu XQ & Hecht NB (2000). Mouse testis brain ribonucleic acid-binding protein/translin

colocalizes with microtubules and is immunoprecipitated with messenger

ribonucleic acids encoding myelin basic protein, alpha calmodulin kinase II, and

protamines 1 and 2. Biol Reprod 62, 720-725.

Xie X, Lu J, Kulbokas EJ, Golub TR, Mootha V, Lindblad-Toh K, Lander ES & Kellis

M (2005). Systematic discovery of regulatory motifs in human promoters and 3'

UTRs by comparison of several mammals. Nature 434, 338-345.

Xu NL, Ye CQ, Poo MM & Zhang XH (2006). Coincidence detection of synaptic inputs

is facilitated at the distal dendrites after long-term potentiation induction. J

Neurosci 26, 3002-3009.

Yang W, Chendrimada TP, Wang Q, Higuchi M, Seeburg PH, Shiekhattar R & Nishikura

K (2006). Modulation of microRNA processing and expression through RNA

editing by ADAR deaminases. Nat Struct Mol Biol 13, 13-21.

Zamore PD & Haley B (2005). Ribo-gnome: the big world of small RNAs. Science 309,

1519-1524.

^ back to top ^