The discovery that restricted regions of the adult mammalian brain exhibit ongoing neurogenesis promises considerable therapeutic potential, however, there is a current lack of understanding regarding the cellular and molecular mechanisms that control neural stein cell proliferation and fate specification in vivo. Neuronal differentiation is in part controlled by the transcription factor NRSF, which restricts expression of neuron specific genes to neuronal cells. By binding to a ~21 base-pair consensus DNA sequence (NRSE) within their regulatory regions and via recruitment of silencers, NRSF represses these genes. As neural stem cells (NSCs) undergo differentiation into mature neurons, repression is relieved and expression of neuron-specific genes is activated. Recently, a double-stranded RNA (dsRNA) of the same sequence and approximate length as the NRSE was found to mediate this switch. This RNA is necessary and sufficient to specify the neuronal fate of multipotent adult NSCs in vitro and may therefore function as an intrinsic inducer of neuronal differentiation in vivo. Moreover, this finding represents the first example of a novel class of regulatory RNAs, termed small modulatory RNAs (smRNA), whose biogenesis and mode of action is distinct from previously characterized RNAs. The overall goal of this work is to elucidate how NRSE smRNA is expressed and to understand the molecular mechanism by which this RNA regulates adult neurogenesis in vivo. This project is in response to the PAS-04-130 on Collaborative Research in Stem Cell Biology and reflects the collaboration of several scientific groups to address this novel discovery.
Specific Aim 1 will focus on how the NRSE smRNA is regulated in NSCs and Specific Aim 2 will examine the functional consequences of regulating this smRNA in vivo. These are aims directly related to skills and experience in the Gage lab.
Specific Aim 3 focuses on the structural relationships between the NRSE smRNA and NRSF, and with its DNA binding sequence. The Riek lab has skills and expertise in addressing these structural biology questions.
Specific Aim 4 continues the search for new smRNAs by taking advantage of the expertise in ribozyme technology developed by Kuwabara in Japan and applied at the Salk for this project.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS052842-01
Application #
6958184
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Owens, David F
Project Start
2005-05-18
Project End
2009-04-30
Budget Start
2005-05-18
Budget End
2006-04-30
Support Year
1
Fiscal Year
2005
Total Cost
$635,965
Indirect Cost
Name
Salk Institute for Biological Studies
Department
Type
DUNS #
078731668
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Pao, Gerald M; Zhu, Quan; Perez-Garcia, Carlos G et al. (2014) Role of BRCA1 in brain development. Proc Natl Acad Sci U S A 111:E1240-8
Zhao, Chunmei; Jou, Jessica; Wolff, Lisa J et al. (2014) Spine morphogenesis in newborn granule cells is differentially regulated in the outer and middle molecular layers. J Comp Neurol 522:2756-66
Zhao, Chunmei; Warner-Schmidt, Jennifer; Duman, Ronald S et al. (2012) Electroconvulsive seizure promotes spine maturation in newborn dentate granule cells in adult rat. Dev Neurobiol 72:937-42
Zhu, Quan; Pao, Gerald M; Huynh, Alexis M et al. (2011) BRCA1 tumour suppression occurs via heterochromatin-mediated silencing. Nature 477:179-84
Mathews, Emily A; Morgenstern, Nicolas A; Piatti, Veronica C et al. (2010) A distinctive layering pattern of mouse dentate granule cells is generated by developmental and adult neurogenesis. J Comp Neurol 518:4479-90
Qu, Qiuhao; Sun, Guoqiang; Li, Wenwu et al. (2010) Orphan nuclear receptor TLX activates Wnt/beta-catenin signalling to stimulate neural stem cell proliferation and self-renewal. Nat Cell Biol 12:31-40; sup pp 1-9
Deng, Wei; Saxe, Michael D; Gallina, Iryna S et al. (2009) Adult-born hippocampal dentate granule cells undergoing maturation modulate learning and memory in the brain. J Neurosci 29:13532-42
Jessberger, Sebastian; Toni, Nicolas; Clemenson Jr, Gregory D et al. (2008) Directed differentiation of hippocampal stem/progenitor cells in the adult brain. Nat Neurosci 11:888-93
Maji, Samir K; Schubert, David; Rivier, Catherine et al. (2008) Amyloid as a depot for the formulation of long-acting drugs. PLoS Biol 6:e17
Suh, Hoonkyo; Consiglio, Antonella; Ray, Jasodhara et al. (2007) In vivo fate analysis reveals the multipotent and self-renewal capacities of Sox2+ neural stem cells in the adult hippocampus. Cell Stem Cell 1:515-28

Showing the most recent 10 out of 14 publications