The hypodactylous (hd) locus impairs limb development and spermatogenesis, leading to male infertility in rats. We show that the hd mutation is caused

The spontaneously hypertensive rat (SHR), one of the most widely used model of essential hypertension, is predisposed to left ventricular hypertrophy, myocardial fibrosis, and metabolic disturbances. Recently, quantitative trait loci influencing blood pressure, left ventricular mass, and heart interstitial fibrosis were genetically isolated within a minimal congenic subline that contains only 7 genes, including mutantPlzf(promyelocytic leukemia zinc finger) candidate gene. To identifyPlzfas a quantitative trait gene, we targetedPlzfin the SHR using the transcription activator-like effector nuclease technique and obtained SHR line harboring targetedPlzfgene with a premature stop codon. Because thePlzftargeted allele is semilethal, morphologically normal heterozygous rats were used for metabolic and hemodynamic analyses. SHR-Plzf^+/−heterozygotes versus SHR wild-type controls exhibited reduced body weight and relative weight of epididymal fat, lower serum and liver triglycerides and cholesterol, and better glucose tolerance. In addition, SHR-Plzf^+/−rats exhibited significantly increased sensitivity of adipose and muscle tissue to insulin action when compared with wild-type controls. Blood pressure was comparable in SHR versus SHR-Plzf^+/−; however, there was significant amelioration of cardiomyocyte hypertrophy and cardiac fibrosis in SHR-Plzf^+/−rats. Gene expression profiles in the liver and expression of selected genes in the heart revealed differentially expressed genes that play a role in metabolic pathways, PPAR (peroxisome proliferator-activated receptor) signaling, and cell cycle regulation. These results provide evidence for an important role ofPlzfin regulation of metabolic and cardiac traits in the rat and suggest a cross talk between cell cycle regulators, metabolism, cardiac hypertrophy, and fibrosis.

In human cells, ribosomal DNA (rDNA) is arranged in ten clusters of multiple tandem repeats. Each repeat is usually described as consisting of two parts: the 13 kb long ribosomal part, containing three genes coding for 18S, 5.8S and 28S RNAs of the ribosomal particles, and the 30 kb long intergenic spacer (IGS). However, this standard scheme is, amazingly, often altered as a result of the peculiar instability of the locus, so that the sequence of each repeat and the number of the repeats in each cluster are highly variable. In the present review, we discuss the causes and types of human rDNA instability, the methods of its detection, its distribution within the locus, the ways in which it is prevented or reversed, and its biological significance. The data of the literature suggest that the variability of the rDNA is not only a potential cause of pathology, but also an important, though still poorly understood, aspect of the normal cell physiology.

The spontaneously hypertensive rat (SHR) is the most widely used model of essential hypertension and is susceptible to left ventricular hypertrophy (LVH) and myocardial fibrosis. Recently, a quantitative trait locus (QTL) that influences heart interstitial fibrosis was mapped to chromosome 8. Our aim was to dissect the genetic basis of this QTL(s) predisposing SHR to hypertension, LVH, and interstitial fibrosis. Hemodynamic and histomorphometric analyses were performed in genetically defined SHR.PD-chr.8 minimal congenic strain (PD5 subline) rats. The differential segment, genetically isolated within the PD5 subline, spans 788kb and contains 7 genes, including the promyelocytic leukemia zinc finger (Plzf) gene that has been implicated in hypertrophy and cardiac fibrosis. Mutant Plzf allele contains a 2,964-bp deletion in intron 2. The PD5 congenic strain, when compared with the SHR, showed significantly reduced systolic blood pressure by approximately 15mm Hg (P = 0.002), amelioration of LVH (0.23±0.02 vs. 0.39±0.02g/100g body weight; P < 0.00001), and reduced interstitial fibrosis (17,478±1,035 vs. 41,530±3,499 μm²; P < 0.0001). The extent of amelioration of LVH and interstitial fibrosis was disproportionate to blood pressure decrease in congenic rats, suggesting an important role for genetic factors. Cardiac expression of Plzf was significantly reduced in prehypertensive (8 and 21 days) congenic animals compared with controls. These results provide compelling evidence of a significant role for genetic factors in regulating blood pressure, LVH, and cardiac fibrosis and identify mutant Plzf as a prominent candidate gene.

The polydactylous rat strain (PD/Cub) is a highly inbred (F > 90) genetic model of metabolic syndrome. The aim of this study was to analyze the genetic architecture of the metabolic derangements found in the PD/Cub strain and to assess its dynamics in time and in response to diet and medication. We derived a PD/Cub × BN/Cub (Brown Norway) F2 intercross population of 149 male rats and performed metabolic profiling and genotyping and multiple levels of genetic linkage and statistical analyses at five different stages of ontogenesis and after high-sucrose diet feeding and dexamethasone administration challenges. The interval mapping analysis of 83 metabolic and morphometric traits revealed over 50 regions genomewide with significant or suggestive linkage to one or more of the traits in the segregating PD/Cub × BN/Cub population. The multiple interval mapping showed that, in addition to “single” quantitative train loci, there are more than 30 pairs of loci across the whole genome significantly influencing the variation of particular traits in an epistatic fashion. This study represents the first whole genome analysis of metabolic syndrome in the PD/Cub model and reveals several new loci previously not connected to the genetics of insulin resistance and dyslipidemia. In addition, it attempts to present the concept of “dynamic genetic architecture” of metabolic syndrome attributes, evidenced by shifts in the genetic determination of syndrome features during ontogenesis and during adaptation to the dietary and pharmacological influences.