Placental but not heart defects are associated with elevated hypoxia-inducible factor α levels in mice lacking prolyl hydroxylase domain protein 2

被引:337
作者
Takeda, Kotaro
Ho, Vivienne C.
Takeda, Hiromi
Duan, Li-Juan
Nagy, Andras
Fong, Guo-Hua
机构
[1] Univ Connecticut, Ctr Hlth, Ctr Vasc Biol, Farmington, CT 06030 USA
[2] Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada
关键词
D O I
10.1128/MCB.00425-06
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
PHD1, PHD2, and PHD3 are prolyl hydroxylase domain proteins that regulate the stability of hypoxia-inducible factor alpha subunits (HIF-alpha). To determine the roles of individual PHDs during mouse development, we disrupted all three Phd genes and found that Phd2(-/-) embryos died between embryonic days 12.5 and 14.5 whereas Phd1(-/-) or Phd3(-/-) mice were apparently normal. In Phd2(-/-) mice, severe placental and heart defects preceded embryonic death. Placental defects included significantly reduced labyrinthine branching morphogenesis, widespread penetration of the labyrinth by spongiotrophoblasts, and abnormal distribution of trophoblast giant cells. The expression of several trophoblast markers was also altered, including an increase in the spongiotrophoblast marker Mash2 and decreases in the labyrinthine markers Tfeb and Gem]. In the heart, trabeculae were poorly developed, the myocardium was remarkably thinner, and interventricular septum was incompletely formed. Surprisingly, while there were significant global increases in HIF-alpha protein levels in the placenta and the embryo proper, there was no specific HIF-alpha increase in the heart. Taken together, these data indicate that among all three PHD proteins, PHD2 is uniquely essential during mouse embryogenesis.
引用
收藏
页码:8336 / 8346
页数:11
相关论文
共 39 条
[1]   Placental cell fates are regulated in vivo by HIF-mediated hypoxia responses [J].
Adelman, DM ;
Gertsenstein, M ;
Nagy, A ;
Simon, MC ;
Maltepe, E .
GENES & DEVELOPMENT, 2000, 14 (24) :3191-3203
[2]   Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3 in the regulation of hypoxia-inducible factor [J].
Appelhoff, RJ ;
Tian, YM ;
Raval, RR ;
Turley, H ;
Harris, AL ;
Pugh, CW ;
Ratcliffe, PJ ;
Gleadle, JM .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (37) :38458-38465
[3]   HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1α in normoxia [J].
Berra, E ;
Benizri, E ;
Ginouvès, A ;
Volmat, V ;
Roux, D ;
Pouysségur, J .
EMBO JOURNAL, 2003, 22 (16) :4082-4090
[4]   A conserved family of prolyl-4-hydroxylases that modify HIF [J].
Bruick, RK ;
McKnight, SL .
SCIENCE, 2001, 294 (5545) :1337-1340
[5]   Hypoxia up-regulates prolyl hydroxylase activity - A feedback mechansim that limits HIF-1 responses during reoxygenation [J].
D'Angelo, G ;
Duplan, E ;
Boyer, N ;
Vigne, P ;
Frelin, C .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (40) :38183-38187
[6]   Hypoxia-indulcible factors 1α and 2α regulate trophoblast differentiation [J].
Dahl, KDC ;
Fryer, BH ;
Mack, FA ;
Compernolle, V ;
Maltepe, E ;
Adelman, DM ;
Carmeliet, P ;
Simon, MC .
MOLECULAR AND CELLULAR BIOLOGY, 2005, 25 (23) :10479-10491
[7]   C-elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation [J].
Epstein, ACR ;
Gleadle, JM ;
McNeill, LA ;
Hewitson, KS ;
O'Rourke, J ;
Mole, DR ;
Mukherji, M ;
Metzen, E ;
Wilson, MI ;
Dhanda, A ;
Tian, YM ;
Masson, N ;
Hamilton, DL ;
Jaakkola, P ;
Barstead, R ;
Hodgkin, J ;
Maxwell, PH ;
Pugh, CW ;
Schofield, CJ ;
Ratcliffe, PJ .
CELL, 2001, 107 (01) :43-54
[8]  
Forsythe JA, 1996, MOL CELL BIOL, V16, P4604
[9]   Defective placental vasculogenesis causes embryonic lethality in VHL-deficient mice [J].
Gnarra, JR ;
Ward, JM ;
Porter, FD ;
Wagner, JR ;
Devor, DE ;
Grinberg, A ;
EmmertBuck, MR ;
Westphal, H ;
Klausner, RD ;
Linehan, WM .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1997, 94 (17) :9102-9107
[10]   Characterization of the human prolyl 4-hydroxylases that modify the hypoxia-inducible factor [J].
Hirsilä, M ;
Koivunen, P ;
Günzler, V ;
Kivirikko, KI ;
Myllyharju, J .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (33) :30772-30780