miRNAs and Other Non-coding RNAs in Nervous System Development and Function

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miRNAs and Other Non-coding RNAs in Nervous System Development and Function

Monday, November 2, 2009

The New York Academy of Sciences

Presented By

 

From the initial specification of neuronal cell types to the formation and plasticity of synaptic connections, non-protein coding small regulatory RNAs, in particular the microRNAs (miRNAs), are emerging as important regulators of nervous system development and function. Moreover, their role in controlling pathogenesis of neurological disease and their potential as disease biomarkers and targets for therapeutic intervention are becoming increasingly apparent. This 1-day symposium will explore the role of non-coding RNAs in nervous system development, gene expression, function and etiology of disease.

Agenda


8:30 AM

Registration and Continental Breakfast

9:00 AM

Opening Remarks

9:15 AM

miRNAs in the Drosophila Nervous System
Eric Lai, Memorial Sloan-Kettering Cancer Center

10:00 AM

RNA Regulatory Circuitry in Nervous System Development
Mark F. Mehler, Albert Einstein College of Medicine

10:45 AM

Coffee Break

11:15 AM

A Polyq-repeat Protein Promotes The Novel, Morphologically Conserved
Death of the Linker Cell in C. elegans

Shai Shaham, The Rockefeller University

12:00 PM

microRNAs: A Role in Neuronal Plasticity
Kenneth S. Kosik, University of California, Santa Barbara

12:45 PM

Lunch

1:45 PM

MicroRNA Regulation of Adult Neurogenesis
Fiona Doetsch, Columbia University

2:30 PM

The Role of Small RNAs in Synaptic Plasticity
Priya Rajasethupathy, College of Physicians and Surgeons of Columbia University

3:15 PM

Epigenetic Control of Transcriptional Homeostasis in the Brain
Anne Schaefer, The Rockefeller University

4:00 PM

Coffee Break

4:30 PM

miRNA Expression and Target Sequence Variation in the Human Central Nervous System
Neil Renwick, The Rockefeller University

4:50 PM

Transcriptome-wide Determination of miRNA-binding Sites by PURE-CLIP
Markus Hafner, The Rockefeller University

5:10 PM

Networking Reception

Speakers

Organizers

Eric Lai

Memorial Sloan-Kettering Cancer Center

Thomas Tuschl

The Rockefeller University

Speakers

Fiona Doetsch

Columbia University

Markus Hafner

The Rockefeller University

Markus Hafner obtained his Diplom in chemistry from the University of Bonn, Germany in 2002. In 2007 he obtained a PhD in biochemistry under the supervision of Prof. Michael Famulok at the University of Bonn, working on the identification of small-molecule inhibitors for cytohesins, a class of small guanosine exchange factors. Since 2007 he is a postdoctoral fellow in the lab of Prof. Thomas Tuschl at the Rockefeller University in New York.

Kenneth S. Kosik

University of California, Santa Barbara

Dr. Kosik is Harriman Professor of Neuroscience Research of the Department of Molecular, Cellular, and Developmental Biology and Co-Director of the Neuroscience Research Institute at the University of California, Santa Barbara. Dr. Kosik’s research focuses on both the mechanisms of neuronal plasticity and its impairment in neurodegeneration.

Eric Lai

Memorial Sloan-Kettering Cancer Center

Eric Lai received his BA from Harvard University and performed thesis work in the laboratory of Gary Ruvkun, where he learned about developmental gene regulation in C. elegans. He did his PhD at UC San Diego with James Posakony on Drosophila neural patterning and Notch signaling, and continued to study these topics as a postdoc with Gerald Rubin at UC Berkeley. He joined the faculty of Sloan-Kettering Institute in 2005.

Mark F. Mehler

Albert Einstein College of Medicine

Dr. Mark F. Mehler is the Alpern Professor and University Chairman of the Saul R. Korey Department of Neurology, Director of the Institute for Brain Disorders and Neural Regeneration, Professor of Neurology, Neuroscience and Psychiatry and Behavioral Sciences and Neurologist-in-Chief at the Albert Einstein College of Medicine. His recent research focus has included molecular mechanisms mediating mammalian forebrain development, neural stem cell biology, the pathogenesis of nervous system disorders, with a particular emphasis on neurodegenerative diseases, and epigenetics and epigenomic and regenerative medicine with special emphasis on the roles of different classes of non-coding RNAs and RNA editing and DNA recoding in neural lineage specification, maturation, maintenance, plasticity and neural connectivity and in dynamic interactions with other components of the epigenome.

Priya Rajasethupathy

College of Physicians and Surgeons of Columbia University

Priya Rajasethupathy attended Cornell University for her undergraduate studies, and majored in Biological Sciences. She received her B.A degree and graduated Suma Cum Laude from Cornell in 2004. She then traveled to India and spent one year as a research student at the National Center for Biological Sciences in Bangalore, India. Upon returning, she joined the MD-PhD program at Columbia University, where she is currently pursuing her PhD in neuroscience with Eric Kandel.

Neil Renwick

The Rockefeller University

Neil Renwick is an Instructor in Clinical Investigation in the Laboratory of RNA Molecular Biology (Tuschl Lab), Rockefeller University. His research focuses on defective post-transcriptional regulation of gene expression in neurological diseases. He received his MBChB from the University of Otago, New Zealand, PhD in Virology from the University of Amsterdam, The Netherlands, and is a diplomate of the American Board of Pathology.

Anne Schaefer

The Rockefeller University

Dr. Anne Schaefer is a Research Associate in the Laboratory of Molecular and Cellular Neuroscience, headed by Dr. Paul Greengard, Vincent Astor Professor and Nobel Laureate 2000, at The Rockefeller University. Dr. Schaefer did her graduate work in Berlin/Germany and New York City, receiving her M.D./ Ph.D. from the Charite Berlin in 2004. Dr. Schaefer began her postdoctoral fellowship in the Greengard Laboratory at the end of 2004 studying the role of miRNAs in adult brain function. She has received a number of awards including the German National Merit Foundation scholarship, the Hans-Hench award, a German Research Foundation (DFG) scholarship, and a Robert Leet and Clara Guthrie Patterson Trust Research Grant Award.

Shai Shaham

The Rockefeller University

Shai Shaham is an Associate Professor at the Rockefeller University in New York. After completing doctoral studies at the Massachusetts Institute of Technology with H. Robert Horvitz, and postdoctoral studies at the University of California, San Francisco with Ira Herskowitz and Cori Bargmann, Shaham joined Rockefeller as an Assistant Professor in 2001. Since then, his lab has continued studies of programmed cell death, initiated during his graduate studies, uncovering a novel morphologically conserved pathway for cellular demise. His lab has also developed the model organism C. elegans as a unique setting to study glial cells, the major components of vertebrate nervous systems. These studies have revealed that glia play essential and dynamic roles in the development and function of the nervous system.

Abstracts

miRNAs in the Drosophila Nervous System

Eric Lai, Memorial Sloan-Kettering Cancer Center

miRNAs are ~21-24 nucleotide RNAs with pervasive and fundamental roles in post-transcriptional gene regulation. Neurons have especial requirements for post-transcriptional regulation, and are known to express a diversity of miRNAs. Still, relatively little is known about the functional impact of neural miRNAs. We are using molecular and genetic techniques to study this topic in the Drosophila system. I will present our studies on the function of individual miRNAs and targets during neural development and physiology.

RNA Regulatory Circuitry in Nervous System Development

Mark F. Mehler, Albert Einstein College of Medicine

RNA plays a central role in mediating the explosive and asymmetric evolutionary advances in mammalian nervous system form and function. It serves as an exquisitely environmentally responsive dual interface between the sequence-specific digital-mediated genome and analogue-based protein signaling networks, safeguards CNS bioenergetic reserves, actively modulates other components of the epigenetic hierarchy, participates in dynamic intracellular as well as intercellular transport and local, systemic and germ line targeting, epigenetic memory states, accelerated evolution and multigenerational heritability. These unique properties of RNA molecules mediate multifaceted aspects of genome regulation, essential cellular functions and a diverse array of neural developmental and adult brain functions. In this talk, we will focus on the evolving roles of long non-coding RNAs in orchestrating seminal neural developmental fate decisions and adult homeostatic processes as well as interactions with other site-specific epigenetic remodeling complexes. This will allow us to begin to generate a series of testable hypotheses regarding the roles of non-coding RNAs and their complex post-transcriptional processing in promoting neural cell identity, plasticity, connectivity and higher-order cognitive and behavioral functions in health and in neuropsychiatric disease states.

A Polyq-repeat Protein Promotes The Novel, Morphologically Conserved Death of the Linker Cell in C. elegans

Shai Shaham, The Rockefeller University

Programmed cell death is an essential process during metazoan development. During wild type C. elegans development, nearly all cells slated to die activate caspases and undergo stereotypical morphological changes including chromatin compaction and cell shrinkage. The male-specific linker cell (LC), however, is an exception. The LC leads the migration of the developing gonad, and once migration is complete at the L4-Adult transition, the LC dies. LC death is independent of ced-3 caspase, ced-4/Apaf-1, ced-9/Bcl2, and egl-1/BH3-only protein, indicating that LC death is controlled by a novel program. Indeed, electron micrographs of dying LCs reveal non-apoptotic features, including nuclear crenellation and organelle swelling. Remarkably similar features are also seen in normally dying cells of the vertebrate spinal cord and ciliary ganglion, suggesting that LC death is morphologically conserved. To understand the molecular mechanism of LC death, we performed a genome-wide RNAi screen to identify genes whose loss prevents LC death. RNAi against pqn-41, a gene predicted to encode a polyQ-repeat protein, blocks LC death in 20% of animals examined. Similar defects are seen in pqn-41(ns294) mutants we generated. A transgene containing pqn-41 genomic DNA fused to GFP is expressed in many cells in the animal. Strikingly, expression in the LC is only visible as the cell begins to die, and we identified a pqn-41 promoter region required for LC expression. PQN-41 protein is localized to nuclei and nuclear puncta in all cells, except for the dying LC, where PQN-41 is also cytoplasmic. Previous studies revealed that LC death requires the heterochronic genes let-7, a microRNA, and lin-29, a Zn-finger transcription factor, and that these genes act within the LC to promote its death. We have now shown that a MAPK module containing the TIR-1 adapter protein and the SEK-1 MAPKK also regulate LC death: 30% of tir-1(RNAi) and 49% sek-1(ag1) adult males exhibit LC survival. Epistasis analysis suggests that the heterochronic and MAPK pathways likely function in parallel to regulate LC death. Since both pathways impinge on transcriptional regulators, it is possible that both pathways converge on the promoters of key LC death genes. We are testing this hypothesis with regard to pqn-41. Several human neurodegenerative disorders result from polyQ expansions within endogenous proteins, however, the mechanisms promoting cell death in these diseases is not known. Our studies raise the intriguing possibility that these aberrant proteins activate an endogenous cell death program similar to that driving the death of the LC.

The Role of Small RNAs in Synaptic Plasticity

Priya Rajasethupathy, College of Physicians and Surgeons of Columbia University

To explore the role of small RNAs in learning-related synaptic plasticity, we profiled the small RNAs of Aplysia Californica by massive parallel sequencing. We identified two classes of neuronally expressed small RNAs that are bi-directionally regulated, miRNAs and piRNAs. We here present our progress in understanding the function of these small RNAs during learning-related synaptic-plasticity.

Epigenetic Control of Transcriptional Homeostasis in the Brain

Anne Schaefer, The Rockefeller University

The maintenance of stable patterns and levels of gene expression (transcriptional homeostasis) in functionally distinct neurons is essential for normal brain function. Alteration of the transcriptional homeostasis is associated with numerous neurological diseases such as mental retardation or autism. We will discuss the role of epigenetic regulators, such as histone modifying enzymes and miRNAs, in regulation of gene expression in adult neurons. We will show how changes in the neuronal transcriptional homeostasis in the postnatal brain lead to diseases such a neurodegeneration, mental retardation or epilepsy.

miRNA Expression and Target Site Variation in the Human Central Nervous System

Neil Renwick, The Rockefeller University

Defective post-transcriptional regulation of gene expression, mediated through the actions of RNA-binding proteins (RBPs) and microRNAs (miRNAs), causes or underlies several neurodegenerative and other neurological disorders. To characterize these disorders, we have developed several methods, including small RNA sequencing, miRNA in situ hybridization, photoreactive-uridine enhanced cross-linking and immunoprecipitation (PURE-CLIP) and nested, multiplexed PCR in the Tuschl Lab. Here, I will focus on (1) small RNA profiling of brain regions from persons with neurodegenerative disorders and unaffected controls and (2) genetic variation in RBP and miRNA target sites in the NF1 gene in persons with autism. Our goal is to find disease-related molecular alterations that can be used for diagnostics and/or therapeutic intervention.

Transcriptome-wide Determination of miRNA-binding Sites by PURE-CLIP

Markus Hafner, The Rockefeller University

miRNAs are key mediators of post-transcriptional gene regulation. Their function as parts of larger miRNA-containing ribonucleoproteins (miRNPs), as well as their biogenesis requires a number of different RNA binding proteins (RBPs). We have used PURE-CLIP to map at nucleotide resolution and on a transcriptome-wide scale the RNA-binding sites of the Argonaute proteins (AGO1-4) and TNRC6A-C, RBPs making up the effector miRNPs. PURE-CLIP relies on feeding the nucleoside analog 4-thiouridine (4SU) to cultured cells. 4SU is readily incorporated into newly synthesized RNAs and efficiently crosslinked to RNA-binding proteins (RBPs) by long-wavelength UV irradiation of live cells. The precise position of the crosslink and the RNA recognition site of the protein can be deduced from a characteristic T to C transition in the reverse transcribed cDNA from the crosslinked segments, separating these sequences efficiently from the always present background sequences derived from fragments of abundant cellular RNAs. We could show by AGO1-4-PURE-CLIP that the endogenous miRNAs target approximately 20% of the 22,000 transcripts expressed in HEK293-cells. Surprisingly, more than 50% of the identified miRNA-binding sites were located in the coding sequences (CDS). miRNA-binding at these sites led to a much smaller destabilization effect on the target RNA compared to binding in the 3’UTR. In general, our data are in good agreement with the current knowledge on mRNA-regulation by miRNAs gained by overexpression and inhibition of individual miRNAs. TNRC6A-C PURE-CLIP revealed that the TNRC6 proteins not only bind a closely related set of transcripts as the AGO proteins, but that they also share same binding site – more than 50% of the TNRC6 binding sites were found within 25 nt of an AGO-binding site.

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