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| Status |
Public on Apr 24, 2012 |
| Title |
Alternative splicing controlled by heterogeneous nuclear ribonucleoprotein L (hnRNP L) regulates development, proliferation and migration of thymic pre-T cells |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
|
| Summary |
The regulation of post-transcriptional modifications of pre-mRNA by alternative splicing is important for cellular function, development and immunity The receptor tyrosine phosphatase CD45, which is expressed on all hematopoietic cells, is known for its role in the development and activation of T cells. To investigate the role of hnRNP L further, we have generated conditional hnRNP L knockout mice carrying floxed alleles and the T-cell specific Lck-Cre recombinase transgene. The Lck-Cre transgene is active in DN3, DN4 as well as in DP and SP cells. We found that deletion of hnRNP L results in a decreased thymic cellularity caused by a partial block at the transition stage between DN4 and DP cells. In addition, hnRNP L-/- thymocytes express aberrant levels of the CD45RA splice isoform and show high levels of phosphorylated Lck at the activator tyrosine Y394 but lacking phosphorylation of the inhibitory tyrosine Y505. This is indicative of an increased basal Lck activation and correlated with a higher proliferation rate of DN4 cells in hnRNP L-/- mice. Deletion of hnRNP L also blocked egress of SP cells to peripheral lymphoid organs and the migration of SP thymocytes in response to the chemokines CCL21 and SDF-1a. Since we found that actin polymerization was also compromised in hnRNP L-/- SP cells, we propose that a defect in the signal transduction cascade downstream of the chemokine receptors CCR7 and CXCR4 caused by the absence of hnRNP L is responsible for this phenotype. Our results indicate that hnRNPL regulates pre-T cell development and migration by regulating CD45 pre-mRNA splicing and chemokine receptor signaling.
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| Overall design |
RNA-seq from Thymocytes from WT mice compared to KO (hnRNP L) mice
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| |
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| Contributor(s) |
Moroy T, Gaudreau M, Wilhelm BT |
| Citation(s) |
22523384 |
| |
| Submission date |
Oct 27, 2011 |
| Last update date |
May 15, 2019 |
| Contact name |
Brian Wilhelm |
| E-mail(s) |
brian.wilhelm@umontreal.ca
|
| Organization name |
University of Montreal
|
| Street address |
2950 Chemin Polytechnique
|
| City |
Montreal |
| ZIP/Postal code |
H1J 3R4 |
| Country |
Canada |
| |
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| Platforms (1) |
| GPL9318 |
AB SOLiD System 3.0 (Mus musculus) |
|
| Samples (4)
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| Relations |
| SRA |
SRP009271 |
| BioProject |
PRJNA149309 |
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