Liang Huiling, Coles Andrew H, Zhu Zhiqing, Zayas Jennifer, Jurecic Roland, Kang Joonsoo, Jones Stephen N
Department of Cell Biology, University of Massachusetts Medical School, Worcester, MA 01545, USA.
J Exp Med. 2007 Dec 24;204(13):3077-84. doi: 10.1084/jem.20062692. Epub 2007 Dec 10.
The Wnt-beta-catenin signaling pathway has been shown to govern T cell development by regulating the growth and survival of progenitor T cells and immature thymocytes. We explore the role of noncanonical, Wnt-Ca(2+) signaling in fetal T cell development by analyzing mice deficient for Wnt5a. Our findings reveal that Wnt5a produced in the thymic stromal epithelium does not alter the development of progenitor thymocytes, but regulates the survival of alphabeta lineage thymocytes. Loss of Wnt5a down-regulates Bax expression, promotes Bcl-2 expression, and inhibits apoptosis of CD4(+)CD8(+) thymocytes, whereas exogenous Wnt5a increases apoptosis of fetal thymocytes in culture. Furthermore, Wnt5a overexpression increases apoptosis in T cells in vitro and increases protein kinase C (PKC) and calmodulin-dependent kinase II (CamKII) activity while inhibiting beta-catenin expression and activity. Conversely, Wnt5a deficiency results in the inhibition of PKC activation, decreased CamKII activity, and elevation of beta-catenin amounts in thymocytes. These results indicate that Wnt5a induction of the noncanonical Wnt-Ca(2+) pathway alters canonical Wnt signaling and is critical for normal T cell development.
Wnt-β-连环蛋白信号通路已被证明可通过调节祖细胞T细胞和未成熟胸腺细胞的生长与存活来控制T细胞发育。我们通过分析Wnt5a基因缺陷小鼠来探究非经典Wnt-Ca(2+)信号在胎儿T细胞发育中的作用。我们的研究结果表明，胸腺基质上皮细胞产生的Wnt5a不会改变祖细胞胸腺细胞的发育，但会调节αβ谱系胸腺细胞的存活。Wnt5a的缺失会下调Bax表达，促进Bcl-2表达，并抑制CD4(+)CD8(+)胸腺细胞的凋亡，而外源性Wnt5a会增加培养的胎儿胸腺细胞的凋亡。此外，Wnt5a的过表达会增加体外T细胞的凋亡，并增加蛋白激酶C（PKC）和钙调蛋白依赖性激酶II（CamKII）的活性，同时抑制β-连环蛋白的表达和活性。相反，Wnt5a的缺乏会导致PKC激活的抑制、CamKII活性的降低以及胸腺细胞中β-连环蛋白含量的升高。这些结果表明，非经典Wnt-Ca(2+)通路的Wnt5a诱导会改变经典Wnt信号，并且对正常T细胞发育至关重要。
