Phosphoinositide 3-Kinase (PI3K) Subunit p110δ Is Essential for Trophoblast Cell Differentiation and Placental Development in Mouse.
Maternal PI3K p110δ has been implicated in smaller litter sizes in mice, but its underlying mechanism remains unclear. The placenta is an indispensable chimeric organ that supports mammalian embryonic development. Using a mouse model of genetic inactivation of PI3K p110δ (p110δ(D910A/D910A)), we show that fetuses carried by p110δ(D910A/D910A) females were growth retarded and showed increased mortality in utero mainly during placentation. The placentas in p110δ(D910A/D910A) females were anomalously anemic, exhibited thinner spongiotrophoblast layer and looser labyrinth zone, which indicate defective placental vasculogenesis. In addition, p110δ was detected in primary trophoblast giant cells (P-TGC) at early placentation. Maternal PI3K p110δ inactivation affected normal TGCs generation and expansion, impeded the branching of chorioallantoic placenta but enhanced the expression of matrix metalloproteinases (MMP-2, MMP-12). Poor vasculature support for the developing fetoplacental unit resulted in fetal death or gross growth retardation. These data, taken together, provide the first in vivo evidence that p110δ may play an important role in placental vascularization through manipulating trophoblast giant cell.
Vascular Biology Research Institute, Guangdong Pharmaceutical University, Guangzhou 510006, China.
Xiwen
X
Hu
Vascular Biology Research Institute, Guangdong Pharmaceutical University, Guangzhou 510006, China.
Jiangchao
J
Li
Vascular Biology Research Institute, Guangdong Pharmaceutical University, Guangzhou 510006, China.
Qianqian
Q
Zhang
School of Basic Courses, Guangdong Pharmaceutical University, Guangzhou, 510006, Guangdong, China.
Lingyun
L
Zheng
Key Laboratory for Regenerative Medicine of the Ministry of Education, Division of Histology &Embryology, Medical College, Jinan University, Guangzhou 510632, China.
Guang
G
Wang
Vascular Biology Research Institute, Guangdong Pharmaceutical University, Guangzhou 510006, China.
Xiaohan
X
Zhang
Vascular Biology Research Institute, Guangdong Pharmaceutical University, Guangzhou 510006, China.
Jingli
J
Zhang
Vascular Biology Research Institute, Guangdong Pharmaceutical University, Guangzhou 510006, China.
Quliang
Q
Gu
Vascular Biology Research Institute, Guangdong Pharmaceutical University, Guangzhou 510006, China.
Yuxiang
Y
Ye
Shanghai OB/GYN Hospital, Fudan University, Shanghai 200011, China.|Shanghai Key Laboratory of Female Reproductive Endocrine-Related Diseases, Fudan University, Shanghai, China.
Sun-Wei
SW
Guo
Key Laboratory for Regenerative Medicine of the Ministry of Education, Division of Histology &Embryology, Medical College, Jinan University, Guangzhou 510632, China.
Xuesong
X
Yang
Vascular Biology Research Institute, Guangdong Pharmaceutical University, Guangzhou 510006, China.
Lijing
L
Wang
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D058534:Class I Phosphatidylinositol 3-Kinases; D004195:Disease Models, Animal; D005260:Female; D005317:Fetal Growth Retardation / Q000235:genetics*; D008098:Litter Size / Q000235:genetics; D008297:Male; D053508:Matrix Metalloproteinase 12 / Q000096:biosynthesis; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D010920:Placenta / Q000098:blood supply*; D010929:Placentation / Q000235:genetics*; D011247:Pregnancy; D014327:Trophoblasts / Q000166:cytology*
D058534:Class I Phosphatidylinositol 3-Kinases; D053508:Matrix Metalloproteinase 12; D020778:Matrix Metalloproteinase 2; D019869:Phosphatidylinositol 3-Kinases; C421683:Pik3cd protein, mouse; C522362:Mmp2 protein, mouse; C000602031:matrix metallopeptidase 12, mouse