Zhang, Ping
(2011)
SIGNALING FROM DEPOLARIZATION TO ALTERNATIVE SPLICING: IDENTIFICATION OF MOLECULAR LINKS MEDIATING INDUCIBLE EXON SKIPPING.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Alternative pre-mRNA splicing is one of main contributors to protein diversity. A fundamental unanswered question is how splicing decision is altered by signal transduction. The C1 exon of the glutamate NMDA receptor NR1 subunit is alternatively spliced in a tissue-specific manner. It is predominantly included in the forebrain, and predominantly skipped in the hindbrain. Importantly, the C1 exon encodes the C1 protein cassette containing an ER retention signal that regulates the surface delivery rate of assembled receptors, and a calmodulin binding site that plays critical roles in learning and memory via regulating Ca2+ flux. Recently, it has been reported C1 exon skipping can be induced by cell depolarization. However, the molecular links mediating the depolarization on the cell membrane and alternative splicing in the nucleus largely remain unclear. Here I have investigated the roles of Ca2+ signaling, PKA and hnRNP A1 in mediating depolarization induced C1 splicing silencing. Specifically, using Ca2+ imaging, I have found the KCl induced sustained Ca2+ influx is associated with C1 splicing silencing. In addition, I have demonstrated that CaMK IV and PKA regulate C1 splicing in a hnRNP A1 dependent manner. Finally, I have shown that hnRNP A1 is recruited to the C1 splicing site upon depolarization in neurons. The results here have demonstrated signal transduction from depolarization to splicing factors, showing how splicing decision can be altered by external stimuli.
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Details
| Item Type: |
University of Pittsburgh ETD
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| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
30 September 2011 |
| Date Type: |
Completion |
| Defense Date: |
2 August 2011 |
| Approval Date: |
30 September 2011 |
| Submission Date: |
18 August 2011 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
Dietrich School of Arts and Sciences > Biological Sciences |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
alternative splicing; C1 casseette; NMDA receptor |
| Other ID: |
http://etd.library.pitt.edu/ETD/available/etd-08182011-103915/, etd-08182011-103915 |
| Date Deposited: |
10 Nov 2011 20:00 |
| Last Modified: |
15 Nov 2016 13:49 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/9183 |
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