R01NS121223

Beyond Transcription - MicroRNA Regulation of Neuronal Development - Abstract

As the brain matures, each neuronal cell type must execute a specialized developmental program to build a cell with the appropriate features. These programs are composed of waves of gene expression that turn on and off with exquisite precision as the cell goes through sequential developmental stages. In fact, failure of these programs to unfold correctly is linked to several neurodevelopmental disorders.

Modern transcriptomics has allowed us to map developmental trajectories of different neuronal subtypes at increasingly high resolution. However, this information alone is not sufficient. In fact, layers of sophisticated post-transcriptional regulation of gene expression by microRNAs (miRNA) help execute these incredibly complex developmental programs. miRNAs act as post-transcriptional repressors, ensuring that their mRNA targets are not expressed at an inappropriate time or place.

We and others have demonstrated that removal of a single brain-enriched miRNA can have profound consequences for brain development. But because each miRNA represses hundreds of different targets, it is hard to pinpoint precise molecular mechanisms. In light of this information, it is necessary to radically change the way we study miRNAs.

Here, we propose two novel strategies that do not focus on single miRNAs and are designed to immediately identify molecular mechanisms of post-transcriptional regulation of gene expression. The first approach is based on the fact that, at times, de-repression of a single miRNA-target interaction (MTI) can be sufficient to induce a phenotype. Hence, in Aim 1, we establish a pipeline to perform a large-scale test of all MTIs in excitatory principal neurons (PN), independently of which miRNA is binding to them, to identify which ones are critical for their development. To do so, we engineered tools to map and manipulate cell type-specific MTIs, and fluorescent reporters that function as fast readouts of the developmental stage of PNs.

The second approach takes advantage of the fact that, often, multiple miRNAs converge on the same target to ensure tight regulation. If evolution imposed multiple layers of repression on the same target, then controlling its protein levels must be essential to maintain the proper developmental trajectory. Thus, in Aim 2, we establish a pipeline to identify the targets most heavily repressed by miRNAs and study the functional consequences of their complete de-repression on the developmental trajectory of PNs.

For both aims, we propose to investigate how de-repression of a single MTI or of a single miRNA target affects the structure, function, and connectivity of developing cortical PNs both in vitro and in vivo. With this proposal, we expect to greatly expand our understanding of broad post-transcriptional mechanisms of PN development, both at single MTI resolution and at the level of single targets repressed by many miRNAs. Such knowledge will be key not only for basic neurobiology but also to identify how failure in miRNA repression could lead to neurodevelopmental disorders.

Scripps Research Institute

(1) TO SUPPORT EXTRAMURAL RESEARCH FUNDED BY THE NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE (NINDS) INCLUDING: BASIC RESEARCH THAT EXPLORES THE FUNDAMENTAL STRUCTURE AND FUNCTION OF THE BRAIN AND THE NERVOUS SYSTEM, RESEARCH TO UNDERSTAND THE CAUSES AND ORIGINS OF PATHOLOGICAL CONDITIONS OF THE NERVOUS SYSTEM WITH THE GOAL OF PREVENTING THESE DISORDERS, RESEARCH ON THE NATURAL COURSE OF NEUROLOGICAL DISORDERS, IMPROVED METHODS OF DISEASE PREVENTION, NEW METHODS OF DIAGNOSIS AND TREATMENT, DRUG DEVELOPMENT, DEVELOPMENT OF NEURAL DEVICES, CLINICAL TRIALS, AND RESEARCH TRAINING IN BASIC, TRANSLATIONAL AND CLINICAL NEUROSCIENCE. THE INSTITUTE IS THE LARGEST FUNDER OF BASIC NEUROSCIENCE IN THE US AND SUPPORTS RESEARCH ON TOPICS INCLUDING BUT NOT LIMITED TO: DEVELOPMENT OF THE NERVOUS SYSTEM, INCLUDING NEUROGENESIS AND PROGENITOR CELL BIOLOGY, SIGNAL TRANSDUCTION IN DEVELOPMENT AND PLASTICITY, AND PROGRAMMED CELL DEATH, SYNAPSE FORMATION, FUNCTION, AND PLASTICITY, LEARNING AND MEMORY, CHANNELS, TRANSPORTERS, AND PUMPS, CIRCUIT FORMATION AND MODULATION, BEHAVIORAL AND COGNITIVE NEUROSCIENCE, SENSORIMOTOR LEARNING, INTEGRATION AND EXECUTIVE FUNCTION, NEUROENDOCRINE SYSTEMS, SLEEP AND CIRCADIAN RHYTHMS, AND SENSORY AND MOTOR SYSTEMS. IN ADDITION, THE INSTITUTE SUPPORTS BASIC, TRANSLATIONAL AND CLINICAL STUDIES ON A NUMBER OF DISORDERS OF THE NERVOUS SYSTEM INCLUDING (BUT NOT LIMITED TO): STROKE, TRAUMATIC INJURY TO THE BRAIN, SPINAL CORD AND PERIPHERAL NERVOUS SYSTEM, NEURODEGENERATIVE DISORDERS, MOVEMENT DISORDERS, BRAIN TUMORS, CONVULSIVE DISORDERS, INFECTIOUS DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, IMMUNE DISORDERS OF THE BRAIN AND NERVOUS SYSTEM, INCLUDING MULTIPLE SCLEROSIS, DISORDERS RELATED TO SLEEP, AND PAIN. PROGRAMMATIC AREAS, WHICH ARE PRIMARILY SUPPORTED BY THE DIVISION OF NEUROSCIENCE, ARE ALSO SUPPORTED BY THE DIVISION OF EXTRAMURAL ACTIVITIES, THE DIVISION OF TRANSLATIONAL RESEARCH, THE DIVISION OF CLINICAL RESEARCH, THE OFFICE OF TRAINING AND WORKFORCE DEVELOPMENT, THE OFFICE OF PROGRAMS TO ENHANCE NEUROSCIENCE WORKFORCE DEVELOPMENT, AND THE OFFICE OF INTERNATIONAL ACTIVITIES. (2) TO EXPAND AND IMPROVE THE SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. TO UTILIZE THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM, TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.853 - Extramural Research Programs in the Neurosciences and Neurological Disorders

National Institute of Neurological Disorders and Stroke (NNDS) [HHS - NIH]

La Jolla, California 920371000 United States

Single Zip Code

Promoting Research in Basic Neuroscience (R01) (PAS-18-483)

Amendment Since initial award the total obligations have increased 389% from $718,646 to $3,516,775.