Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor involved in diverse biological processes including adipocyte differentiation, glucose homeostasis, and inflammatory responses. Analyses of PPARγ knockout animals have been so far preempted by the early embryonic death of PPARγ-/- embryos as a consequence of the severe alteration of their placental vasculature. Using Sox2Cre/PPARγL2/L2 mice, we obtained fully viable PPARγ-null mice through specific and total epiblastic gene deletion, thereby demonstrating that the placental defect is the unique cause of PPARγ-/- embryonic lethality. The vasculature defects observed in PPARγ-/- placentas at embryonic d 9.5 correlated with an unsettled balance of pro- and antiangiogenic factors as demonstrated by increased levels of proliferin (Prl2c2, PLF) and decreased levels of proliferin-related protein (Prl7d1, PRP), respectively. To analyze the role of PPARγ in the later stage of placental development, when its expression peaks, we treated pregnant wild-type mice with the PPARγ agonist rosiglitazone. This treatment resulted in a disorganization of the placental layers and an altered placental microvasculature, accompanied by the decreased expression of proangiogenic genes such as Prl2c2, vascular endothelial growth factor, and Pecam1. Together our data demonstrate that PPARγ plays a pivotal role in controlling placental vascular proliferation and contributes to its termination in late pregnancy.

Thyroid hormones act directly on transcription by binding to TRalpha1, TRbeta1, and TRbeta2 nuclear receptors, regulating many aspects of postnatal development and homeostasis. To analyze precisely the implication of the widely expressed TRalpha1 isoform in this pleiotropic action, we have generated transgenic mice with a point mutation in the TRalpha1 coding sequence, which is expressed only after CRE/loxP-mediated DNA recombination. The amino acid change prevents interaction between TRalpha1 and histone acetyltransferase coactivators and the release of corepressors. Early expression of this dominant-negative receptor deeply affects postnatal development and adult homeostasis, recapitulating many aspects of congenital and adult hypothyroidism, except in tissues and cells where TRbeta1 and TRbeta2 are predominantly expressed. Both respective abundance and intrinsic properties of TRalpha1 and TRbeta1/2 seem to govern specificity of action.

Thyroid hormones are involved in the regulation of many physiological processes and regulate gene transcription by binding to their nuclear receptors TR␣ and TR␤. In the absence of triiodothyronine (T3), the unliganded receptors (aporeceptors) do bind DNA and repress the transcription of target genes. The role of thyroid hormone aporeceptors as repressors was observed in hypothyroid adult mice, but its physiological relevance in nonpathological hypothyroid conditions remained to be determined. Here we show that, in the normal mouse fetus, TR␣ aporeceptors repress heart rate as well as the expression of TR␤ and several genes encoding ion channels involved in cardiac contractile activity. Right after birth, when T3 concentration sharply increases, liganded TR␣ (holoreceptors) turn on the expression of some of these same genes concomitantly with heart rate increase. These data describe a physiological situation under which conversion of TR␣ from apo-receptors into holo-receptors, upon changes in T3 availability, plays a determinant role in a developmental process.