Besides transcription, post-transcriptional mechanisms, such as RNA processing, mRNA stability and local translation, are also important for controlling the expression of many nervous system-specific genes. For a large number of neuronal genes, expression levels are controlled by changes in mRNA stability. These processes are regulated by specific interactions between RNA-binding proteins and instability- conferring sequences in the mRNAs. One of the best characterized post-transcriptionally regulated genes in neurons is that for GAP-43. Work done under our previous grants demonstrated that GAP-43 gene expression is regulated by selective changes in the stability of its mRNA, and that this process depends on the interaction of a highly conserved regulatory element in the 3'untranslated region (3'UTR) of the mRNA with the neuronal-specific RNA-binding protein HuD. Not only is HuD capable of stabilizing GAP-43 mRNA in developing neurons in culture, but also overexpression of this protein in transgenic mice increases GAP-43 gene expression in the hippocampus and neocortex. We have recently found that the pro-destabilizing RNA-binding protein KSRP also binds to the GAP-43 mRNA, suggesting that this protein may be responsible for the fast degradation of the GAP-43 mRNA observed in mature dentate granule cells. Based upon our preliminary studies, we propose that the stability of GAP-43 and other post- transcriptionally-regulated neuronal genes is controlled by the interplay of pro-stabilization factors such as HuD and pro-degradation factors such as KSRP. To test this hypothesis, we plan to perform the studies under the following two specific aims:
Aim 1. To explore the mechanism by which HuD and KSRP control the stability of neuronal mRNAs.
Aim 2. To define the function of HuD and KSRP in the post-transcriptional control of neuronal gene expression in vivo during developmental and adult plasticity. Although the aims are focused on GAP-43, our studies will include other targets of HuD such as neuroserpin and tau. These mRNAs were chosen because they are axonally-localized, developmentally- regulated, upregulated in response to injury and thus, likely to be controlled by similar mechanisms. The proposed studies will characterize the mechanisms of control of GAP-43 and other post- transcriptionally-regulated neuronal mRNAs. Given the role of these proteins in nervous system development, synaptic plasticity, and nerve regeneration, the elucidation of regulatory mechanisms controlling their mRNAs has a broad range of potential applications, from the treatment of neurodevelopmental disorders to the recovery from brain trauma and spinal cord injury.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS030255-17
Application #
7752477
Study Section
Neurogenesis and Cell Fate Study Section (NCF)
Program Officer
Riddle, Robert D
Project Start
1991-06-01
Project End
2011-12-31
Budget Start
2010-01-01
Budget End
2010-12-31
Support Year
17
Fiscal Year
2010
Total Cost
$290,244
Indirect Cost
Name
University of New Mexico
Department
Neurosciences
Type
Schools of Medicine
DUNS #
868853094
City
Albuquerque
State
NM
Country
United States
Zip Code
87131
Briata, Paola; Bordo, Domenico; Puppo, Margherita et al. (2016) Diverse roles of the nucleic acid-binding protein KHSRP in cell differentiation and disease. Wiley Interdiscip Rev RNA 7:227-40
Sosanya, Natasha M; Cacheaux, Luisa P; Workman, Emily R et al. (2015) Mammalian Target of Rapamycin (mTOR) Tagging Promotes Dendritic Branch Variability through the Capture of Ca2+/Calmodulin-dependent Protein Kinase II α (CaMKIIα) mRNAs by the RNA-binding Protein HuD. J Biol Chem 290:16357-71
Gardiner, Amy S; Twiss, Jeffery L; Perrone-Bizzozero, Nora I (2015) Competing Interactions of RNA-Binding Proteins, MicroRNAs, and Their Targets Control Neuronal Development and Function. Biomolecules 5:2903-18
Wang, Feifei; Tidei, Joseph J; Polich, Eric D et al. (2015) Positive feedback between RNA-binding protein HuD and transcription factor SATB1 promotes neurogenesis. Proc Natl Acad Sci U S A 112:E4995-5004
Yoo, Soonmoon; Kim, Hak H; Kim, Paul et al. (2013) A HuD-ZBP1 ribonucleoprotein complex localizes GAP-43 mRNA into axons through its 3' untranslated region AU-rich regulatory element. J Neurochem 126:792-804
Allen, Megan; Bird, Clark; Feng, Wei et al. (2013) HuD promotes BDNF expression in brain neurons via selective stabilization of the BDNF long 3'UTR mRNA. PLoS One 8:e55718
Bird, Clark W; Gardiner, Amy S; Bolognani, Federico et al. (2013) KSRP modulation of GAP-43 mRNA stability restricts axonal outgrowth in embryonic hippocampal neurons. PLoS One 8:e79255
Sosanya, Natasha M; Huang, Peggy P C; Cacheaux, Luisa P et al. (2013) Degradation of high affinity HuD targets releases Kv1.1 mRNA from miR-129 repression by mTORC1. J Cell Biol 202:53-69
Perrone-Bizzozero, Nora; Bird, Clark W (2013) Role of HuD in nervous system function and pathology. Front Biosci (Schol Ed) 5:554-63
Perrone-Bizzozero, Nora I; Tanner, Daniel C; Mounce, Joanna et al. (2011) Increased expression of axogenesis-related genes and mossy fibre length in dentate granule cells from adult HuD overexpressor mice. ASN Neuro 3:259-70

Showing the most recent 10 out of 14 publications