K-ras/PI3K-Akt signaling is essential for zebrafish hematopoiesis and angiogenesis.
The RAS small GTPases orchestrate multiple cellular processes. Studies on knock-out mice showed the essential and sufficient role of K-RAS, but not N-RAS and H-RAS in embryonic development. However, many physiological functions of K-RAS in vivo remain unclear. Using wild-type and fli1:GFP transgenic zebrafish, we showed that K-ras-knockdown resulted in specific hematopoietic and angiogenic defects, including the impaired expression of erythroid-specific gene gata1 and sse3-hemoglobin, reduced blood circulation and disorganized blood vessels. Expression of either K-rasC40 that links to phosphoinositide 3-kinase (PI3K) activation, or Akt2 that acts downstream of PI3K, could rescue both hematopoietic and angiogenic defects in the K-ras knockdown. Consistently, the functional rescue by k-ras mRNA was significantly suppressed by wortmannin, a PI3K-specific inhibitor. Our results provide direct evidence that PI3K-Akt plays a crucial role in mediating K-ras signaling during hematopoiesis and angiogenesis in vivo, thus offering new targets and alternative vertebrate model for studying these processes and their related diseases.
Liu
Lihui
L
Department of Biological Sciences, Cell Signaling and Developmental Biology Laboratory, The National University of Singapore, Singapore, The Republic of Singapore.
Zhu
Shizhen
S
Gong
Zhiyuan
Z
Low
Boon Chuan
BC
D000818:Animals; D006410:Hematopoiesis / Q000502:physiology*; D018919:Neovascularization, Physiologic / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D015398:Signal Transduction; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000502:physiology*; D018631:ras Proteins / Q000502:physiology*
D029961:Zebrafish Proteins; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D018631:ras Proteins