PPAR gamma is required for placental, cardiac, and adipose tissue development.
The nuclear hormone receptor PPAR gamma promotes adipogenesis and macrophage differentiation and is a primary pharmacological target in the treatment of type II diabetes. Here, we show that PPAR gamma gene knockout results in two independent lethal phases. Initially, PPAR gamma deficiency interferes with terminal differentiation of the trophoblast and placental vascularization, leading to severe myocardial thinning and death by E10.0. Supplementing PPAR gamma null embryos with wild-type placentas via aggregation with tetraploid embryos corrects the cardiac defect, implicating a previously unrecognized dependence of the developing heart on a functional placenta. A tetraploid-rescued mutant surviving to term exhibited another lethal combination of pathologies, including lipodystrophy and multiple hemorrhages. These findings both confirm and expand the current known spectrum of physiological functions regulated by PPAR gamma.
Barak
Y
Y
Gene Expression Laboratory, The Salk Institute, La Jolla, California 92037, USA.
Nelson
M C
MC
Ong
E S
ES
Jones
Y Z
YZ
Ruiz-Lozano
P
P
Chien
K R
KR
Koder
A
A
Evans
R M
RM
D000273:Adipose Tissue / Q000254:growth & development*; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D005328:Fetal Viability / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D018390:Gene Targeting / Q000379:methods; D017930:Genes, Reporter; D006321:Heart / Q000254:growth & development*; D017403:In Situ Hybridization; D008060:Lipodystrophy / Q000235:genetics; D008099:Liver / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000166:cytology / Q000648:ultrastructure; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010920:Placenta / Q000166:cytology / Q000648:ultrastructure; D010929:Placentation; D011003:Ploidies; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000235:genetics; D047488:Retinoid X Receptors; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
D009687:Nuclear Proteins; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D014157:Transcription Factors