PPARδ
PPARδ is the least studied member of the PPAR family. Deficiency for PPARδ is embryonic lethal in most, albeit not all cases. 5-10% of PPARδ null embryos survive to parturition and, although born runt, recover and live long. These PPARδ null mice display a conspicuous phenotype as adults: all of their fat depots - brown, white, and subcutaneous - are 3-fold smaller than those of their wild type counterparts.Using a fat-specific PPARδ knockout, we proved that this reduction in fat mass is adipocyte-nonautonomous, and therefore likely reflects the response of adipose tissue to a defect either in systemic metabolism or in another specific tissue. Detailed studies of the physiological basis of this phenomenon have been encumbered by the scarcity of PPARδ null animals.
Most PPARδ null embryos start dying at the 10th day of gestation, in conjunction with placental defects. These involve breakdown of placental-decidual contact and severe hemorrhage of maternal blood into the fetal side. As trophoblast differentiation continues normally up to the time of death, the placental function of PPARδ is clearly distinct from that of PPARγ, and serves as an independent entry point into placental development. Our current interests span two interrelated themes:
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PPARδ target genes in trophoblasts and their relationship with the phenotype. We adopt an approach similar to the one that we undertake to study trophoblast PPARγ target genes, relying on PPARδ agonists as well as wild type and null placentas and TS cells as differential platforms for target gene identification.
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Genes that modify the severity of PPARδ deficiency. We could not previously find evidence for the involvement of heritability in the incomplete penetrance of the embryonic lethal PPARδ null phenotype. Thus, breeding pairs which parented live null progeny once, did not typically repeat that feat in subsequent litters. Moreover, null mice did not parent more live null progeny than PPARδ -sufficient ones. Backcrossing against a c57Bl/6J background did not improve survival rates. Nevertheless, data from Peters et al., who used a different targeting construct (which acts as a phenotypic hypomorph), suggest that survival of PPARδ null mice might be a genetically modifiable trait. The importance of this observation is two-fold:
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It implies the existence of a gene which modifies the PPARδ pathway. identifying this modifier with the aid of classical genetic tools, such as allele typing, will provide valuable information about PPARδ function.
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It may provide means to generate enough viable PPARδ null mice to study the postnatal functions of the receptor.
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