3 Paramutation, first observed in maize 1 and subsequently in a variety of plants 2 , is a heritable epigenetic change of the phenotype of a "paramutable" allele, initiated by interaction in heterozygotes with a "paramutagenic" form of the locus. Often referred to as an exception to the law of Mendel, which states that genetic factors segregate unchanged from heterozygotes, paramutation is meiotically stable and inherited in the absence of the inducing allele. To date, the closest observations in an animal species were changes in the DNA methylation profiles directed by the allelic locus in the mouse that we and others described as "transvection" or "paramutation-like" effects 3,4 . We now report a modification in the phenotypic expression of the wild type allele of the Kit receptor gene in the progeny of heterozygotes with a null insertion mutant. The "paramutated (Kit*)", genotypically wild type animals, maintain the white-spotted phenotype characteristic of Kit mutants in the absence of the mutant allele. The efficient paternal and maternal inheritance of the paramutated state raises the question of a possible molecular support of the epigenetic information. Non-Mendelian phenotype distributionThe tm1Alf mutation (MGI:2449782, initially designated Kit W-LacZ ) was engineered 5 by inserting a 3 kb Neo-LacZ cassette downstream of the initiator ATG. A unique mRNA of the same size with the ß-galactosidase coding sequence is expressed under control of the Kit promoter and regulatory sequences. The mutation abrogates the synthesis of the Kit tyrosine kinase receptor, which plays a critical role in several developmental processes including germinal differentiation, hematopoiesis and melanogenesis. Accordingly, Kit tm1Alf homozygotes die shortly after birth and heterozygotes show a white tail tip and white feet (Fig. 1). We initially observed an abnormal segregation of phenotypes in the progeny of crosses between two heterozygous parents. Wild type genotypes were identified by the absence of both LacZ sequences determined by genomic PCR analysis and ß-galactosidase expression by in situ X-Gal staining (not shown), and further confirmed by Southern blot analysis (Fig. 1c).However, it was striking that most of these genetically Kit +/+ mice maintained the white patches characteristic of the parental heterozygotes ( Fig. 1 and Table 1). The occurrence of this modified, "paramutated" form of the Kit + allele (Kit* phenotype) was not restricted to the progeny of heterozygote intercrossing, but also observed in Kit tm1Alf / + crosses with wild type partners, 4 independently of the gender combination (Table 1). It was not dependent on the genetic background of the mice since the same phenotypes were found with the original 129/Sv Kit tm1Alf / + heterozygotes and after at least 6 generations of back-crosses of the mutation onto the C57Bl/6 and B6D2 genetic backgrounds (Supplementary Table 1). The paramutated phenotype was inherited, with a variable phenotypic extent depending on the crosses (Supplementary Fig. 1). It was mos...

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors exerting several functions in development and metabolism. The physiological functions of PPARdelta remain elusive. By using a CRE-Lox recombination approach, we generated an animal model for muscle-specific PPARdelta overexpression to investigate the role of PPARdelta in this tissue. Muscle-specific PPARdelta overexpression results in a profound change in fiber composition due to hyperplasia and/or shift to more oxidative fiber and, as a consequence, leads to the increase of both enzymatic activities and genes implicated in oxidative metabolism. These changes in muscle are accompanied by a reduction of body fat mass, mainly due to a large reduction of adipose cell size. Furthermore, we demonstrate that endurance exercise promotes an accumulation of PPARdelta protein in muscle of wild-type animals. Collectively, these results suggest that PPARdelta plays an important role in muscle development and adaptive response to environmental changes, such as training exercise. They strongly support the idea that activation of PPARdelta could be beneficial in prevention of metabolic disorders, such as obesity or type 2 diabetes.

WT1 is a tumor suppressor gene with a key role in urogenital development and the pathogenesis of Wilms' tumor. Two alternative splice sites in the WT1 transcript allow the gene to encode four proteins. These carry four Krüppel-type zinc fingers and to date have primarily been implicated in transcriptional control of genes involved in growth regulation. However, here we demonstrate colocalization of WT1 with splicing factors in the fetal kidney and testis and in expressing cell lines. Using immunoprecipitation, we show that two WT1 isoforms directly associate with one or a limited number of components in the spliceosomes and coiled bodies. Moreover, COS cell expression studies suggest that alternative splicing within the WT1 zinc finger region determines whether the protein localizes mainly with splicing factors or with DNA in transcription factor domains in the nucleus. We propose that WT1 plays roles in posttranscriptional processing of RNA as well as in transcription.