Noncanonical Wnt signaling promotes apoptosis in thymocyte development.
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.
Liang
Huiling
H
Department of Cell Biology, University of Massachusetts Medical School, Worcester, MA 01545, USA.
Coles
Andrew H
AH
Zhu
Zhiqing
Z
Zayas
Jennifer
J
Jurecic
Roland
R
Kang
Joonsoo
J
Jones
Stephen N
SN
D000818:Animals; D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D049109:Cell Proliferation; D002469:Cell Separation; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D015398:Signal Transduction; D013950:Thymus Gland / Q000166:cytology* / Q000473:pathology*; D051153:Wnt Proteins / Q000378:metabolism* / Q000502:physiology; D000071818:Wnt-5a Protein
D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C438615:Wnt5a protein, mouse; D002118:Calcium