| First Author | Golec DP | Year | 2013 |
| Journal | PLoS One | Volume | 8 |
| Issue | 1 | Pages | e53300 |
| PubMed ID | 23308188 | Mgi Jnum | J:195716 |
| Mgi Id | MGI:5485100 | Doi | 10.1371/journal.pone.0053300 |
| Citation | Golec DP, et al. (2013) RasGRP1, but not RasGRP3, is required for efficient thymic beta-selection and ERK activation downstream of CXCR4. PLoS One 8(1):e53300 |
| abstractText | T cell development is a highly dynamic process that is driven by interactions between developing thymocytes and the thymic microenvironment. Upon entering the thymus, the earliest thymic progenitors, called CD4(-)CD8(-) 'double negative' (DN) thymocytes, pass through a checkpoint termed "beta-selection" before maturing into CD4(+)CD8(+) 'double positive' (DP) thymocytes. beta-selection is an important developmental checkpoint during thymopoiesis where developing DN thymocytes that successfully express the pre-T cell receptor (TCR) undergo extensive proliferation and differentiation towards the DP stage. Signals transduced through the pre-TCR, chemokine receptor CXCR4 and Notch are thought to drive beta-selection. Additionally, it has long been known that ERK is activated during beta-selection; however the pathways regulating ERK activation remain unknown. Here, we performed a detailed analysis of the beta-selection events in mice lacking RasGRP1, RasGRP3 and RasGRP1 and 3. We report that RasGRP1 KO and RasGRP1/3 DKO deficient thymi show a partial developmental block at the early DN3 stage of development. Furthermore, DN3 thymocytes from RasGRP1 and RasGRP1/3 double knock-out thymi show significantly reduced proliferation, despite expression of the TCRbeta chain. As a result of impaired beta-selection, the pool of TCRbeta(+) DN4 is significantly diminished, resulting in inefficient DN to DP development. Also, we report that RasGRP1 is required for ERK activation downstream of CXCR4 signaling, which we hypothesize represents a potential mechanism of RasGRP1 regulation of beta-selection. Our results demonstrate that RasGRP1 is an important regulator of proliferation and differentiation at the beta-selection checkpoint and functions downstream of CXCR4 to activate the Ras/MAPK pathway. |
