Invited Review: HXB/BXH rat recombinant inbred strain platform: a newly enhanced tool for cardiovascular, behavioral, and developmental genetics and genomics

Abstract

This review deals with the largest set of rat recombinant inbred (RI) strains and summarizes past and recent accomplishments with this platform for genetic mapping and analyses of divergent and complex traits. This strain, derived by crossing the spontaneously hypertensive rat, SHR/Ola, with a Brown Norway congenic, BN-Lx, carrying polydactyly-luxate syndrome, is referred to as HXB/BXH. The RI strain set has been used for linkage and association studies to identify quantitative trait loci for numerous cardiovascular phenotypes, including arterial pressure, stress-elicited heart rate, and pressor response, and metabolic traits, including insulin resistance, dyslipidemia and glucose handling, and left ventricular hypertrophy. The strain's utility has been enhanced with development of a new framework marker-based map and strain distribution patterns of polymorphic markers. Quantitative trait loci for behavioral traits mapped include loci for startle motor response and habituation, anxiety and locomotion traits associated with elevated plus maze, and conditioned taste aversion. The polydactyly-luxate syndrome Lx mutation has allowed the study of alleles important to limb development and malformation phenotypes as well as teratogens. The RI strains have guided development of numerous congenic strains to test locus assignments and to study the effect of genetic background. Although these strains were originally developed to aid in studies of rat genetic hypertension and morphogenetic abnormalities, this rodent platform has been shown to be equally powerful for a wide spectrum of traits and endophenotypes. These strains provide a ready and available vehicle for many physiological and pharmacological studies.

Deletion of a conserved noncoding sequence in Plzf intron leads to Plzf down‐regulation in limb bud and polydactyly in the rat

“…Therefore, the phenotype of the Lx/Lx homozygotes may be stabilized at a certain severity by the uniform genetic background. Indeed, gross phenotype of other strains containing the Lx allele (Printz et al, 2003) supports this hypothesis. In BN.Lx, another congenic strain (with genetic background different from PD5, albeit also uniform), we observed 6-toed hindlimbs, shortening of the hindlimb zeugopod with distal bending and fibula thickening.…”

“…In particular the medial cuneiform (labeled "c") lost its elongated shape and widened to accommodate the extra finger ray, accompanied by similar widening of the communicating navicular bone (labeled "n"). Zeugopods are comparable in Lx/Lx and ϩ/Lx animals and do not differ from ϩ/ϩ animals (data not shown; for detailed morphometric analysis of zeugopods, see Printz et al, 2003).…”

“…This does not change the fact that, in the experimental setting of this study, using SHR genetic background, Lx behaves as strictly recessive. Moreover, Lx mutation segregates in the largest rat recombinant inbred (RI) strain panel HXB and BXH (Printz et al, 2003). Each RI strain, derived by inbreeding of a F2 progeny, represents a unique, but reproducible, combination of the parental genomes (for BXH and HXB panels, parents are SHR and BN.Lx).…”

Chromosome-substituted rat strains provide insights into the genetics of placentation

“…Earlier research efforts using recombinant inbred strains of rats (29) sought to identify genetic contributions to litter size and placental and fetal weight regulation (6, 47). These recombinant rat strains were originally established to elucidate the genetics of hypertension and involved analyses of BN and spontaneous hypertensive rat strain recombinants (29).…”

Homer expression in the hippocampus of an animal model of attention-deficit/hyperactivity disorder

“…In particular, these rats show impaired sustained attention without notable sensory problems, as well as motor impulsiveness and hyperactivity, relative to control Wistar-Kyoto (WKY) rats (3,(6)(7)(8)(9)(10)(11)(12). In addition, SHRs exhibit brain pathology similar to ADHD, including reduced brain volumes relative to controls, specifically in the prefrontal cortex, occipital cortex and hippocampus (13). Therefore, this model has been widely used to investigate the neural basis of ADHD.…”