Rat Models of Human Diseases and Related Phenotypes: A Novel Inventory of Causative Genes.

The laboratory rat (Rattus norvegicus) has been used for a long time as the model of choice in several biomedical disciplines. In 2020, I made an inventory of rat genes that had been identified as underlying diseases or playing a key role in critical biological processes that are altered in diseases. Over 350 genes could be found, a significant number of which have similar effects in rat and humans (Szpirer in J Biomed Sci 27:84-155, 2020).

Rat models of human diseases and related phenotypes: a systematic inventory of the causative genes.

The laboratory rat has been used for a long time as the model of choice in several biomedical disciplines. Numerous inbred strains have been isolated, displaying a wide range of phenotypes and providing many models of human traits and diseases. Rat genome mapping and genomics was considerably developed in the last decades.

BAC CGH-array identified specific small-scale genomic imbalances in diploid DMBA-induced rat mammary tumors.

Background: Development of breast cancer is a multistage process influenced by hormonal and environmental factors as well as by genetic background. The search for genes underlying this malignancy has recently been highly productive, but the etiology behind this complex disease is still not understood. In studies using animal cancer models, heterogeneity of the genetic background and environmental factors is reduced and thus analysis and identification of genetic aberrations in tumors may become easier.

Cancer research in rat models.

Rat has been the major model species used in several biomedical fields, notably in drug development and toxicology, including carcinogenicity testing. Rat is also a useful model in basic cancer research. Several rat models of monogenic (Mendelian) human hereditary cancers are available.

Contrasting epistatic interactions between rat quantitative trait loci controlling mammary cancer development.

We previously defined quantitative trait loci (QTLs) that control susceptibility to 7,12-dimethylbenz(alpha)anthracene-induced mammary carcinoma in SPRD-Cu3 (susceptible) and WKY (resistant) rats. Two of these QTLs, assigned to chromosomes (Chr) 10 and 18, control tumor growth rate and invasiveness. In this study we characterized a congenic strain in which a large segment of WKY Chr 10 was introduced in the SPRD-Cu3 genetic background and demonstrated that this chromosome segment controls this tumor trait.

A role for Rhesus factor Rhcg in renal ammonium excretion and male fertility.

The kidney has an important role in the regulation of acid-base homeostasis. Renal ammonium production and excretion are essential for net acid excretion under basal conditions and during metabolic acidosis. Ammonium is secreted into the urine by the collecting duct, a distal nephron segment where ammonium transport is believed to occur by non-ionic NH(3) diffusion coupled to H(+) secretion.

Nicotinamide phosphoribosyl transferase/pre-B cell colony-enhancing factor/visfatin is required for lymphocyte development and cellular resistance to genotoxic stress.

Nicotinamide phosphoribosyl transferase (Nampt)/pre-B cell colony-enhancing factor (PBEF)/visfatin is a protein displaying multiple functional properties. Originally described as a cytokine-like protein able to regulate B cell development, apoptosis, and glucose metabolism, this protein also plays an important role in NAD biosynthesis. To gain insight into its physiological role, we have generated a mouse strain expressing a conditional Nampt allele.

Zinc finger protein ZBTB20 is a key repressor of alpha-fetoprotein gene transcription in liver.

The alpha-fetoprotein (AFP) gene is highly activated in fetal liver but is dramatically repressed shortly after birth. The mechanisms that underlie AFP transcriptional repression in postpartum liver are not well understood. AFP enhancer, repressor region, and promoter are implicated to be involved in AFP postnatal repression, but the major transcriptional repressor remains undefined.

Absence of Ras mutations in rat DMBA-induced mammary tumors.

Animal cancer models reduce genetic background heterogeneity and thus, may facilitate identification and analysis of specific genetic aberrations in tumor cells. Rat and human mammary glands have high similarity in physiology and show comparable hormone responsiveness. Thus, spontaneous and carcinogen (e.

Progress and prospects in rat genetics: a community view.

The rat is an important system for modeling human disease. Four years ago, the rich 150-year history of rat research was transformed by the sequencing of the rat genome, ushering in an era of exceptional opportunity for identifying genes and pathways underlying disease phenotypes. Genome-wide association studies in human populations have recently provided a direct approach for finding robust genetic associations in common diseases, but identifying the precise genes and their mechanisms of action remains problematic.

The development of several organs and appendages is impaired in mice lacking Sp6.

SP6 belongs to the SP/KLF family of transcription factors, characterized by a DNA-binding domain composed of three zinc fingers of the C(2)H(2) type. The Sp6 gene generates two different transcripts, termed Sp6 and epiprofin, which differ in the first exon and encode the same SP6 protein. These transcripts are mainly expressed in the skin, the teeth, and the limb buds of embryos and also in the adult lungs.

Absence of gonadotropin-releasing hormone 1 and Kiss1 activation in alpha-fetoprotein knockout mice: prenatal estrogens defeminize the potential to show preovulatory luteinizing hormone surges.

Sex differences in gonadal function are driven by either cyclical (females) or tonic (males) hypothalamic GnRH1 release and, subsequently, gonadotrophin (LH and FSH) secretion from the pituitary. This sex difference seems to depend on the perinatal actions of gonadal hormones on the hypothalamus. We used alpha-fetoprotein (AFP) knockout mice (Afp(-/-)) to study the mechanisms by which estrogens affect the sexual differentiation of the GnRH1 system.

Mammary cancer susceptibility: human genes and rodent models.

Breast cancer is a complex disease, showing a strong genetic component. Several human susceptibility genes have been identified, especially in the last few months. Most of these genes are low-penetrance genes and it is clear that numerous other susceptibility genes remain to be identified.

Mammary cancer resistance and precocious mammary differentiation in the WKY rat: identification of 2 quantitative trait loci.

The COP and WKY rat strains are resistant to mammary cancer. It has shown previously that upon chemical carcinogen treatment, COP females exhibit mammary preneoplastic lesions which disappear within a few weeks. We show here that in similar conditions, WKY females do not exhibit any visible preneoplastic lesions.

Isolation of two regions on rat chromosomes 5 and 18 affecting mammary cancer susceptibility.

We previously mapped several quantitative trait loci (QTLs) controlling DMBA-induced mammary tumor development in female rats derived from a SPRD-Cu3 (susceptible strain) x WKY (resistant strain) cross. Two of these QTLs were assigned to chromosomes 5 and 18. In the present study, we generated and characterized congenic strains in which a segment of WKY chromosomes 5 or 18 was introduced in the SPRD-Cu3 genetic background, thereby physically demonstrating that each of these two chromosomes controls mammary tumor multiplicity.

Alpha-fetoprotein: from a diagnostic biomarker to a key role in female fertility.

Alpha-fetoprotein (AFP) is a well-known diagnostic biomarker used in medicine to detect fetal developmental anomalies such as neural tube defects or Down's syndrome, or to follow up the development of tumors such as hepatocellular carcinomas. However, and despite the fact that the protein was discovered almost half a century ago, little was known about its physiological function. The study of Afp knock-out mice uncovered a surprising function of AFP: it is essential for female fertility and for expression of normal female behaviors, and this action is mediated through its estrogen binding capacity.

Genetic identification of distinct loci controlling mammary tumor multiplicity, latency, and aggressiveness in the rat.

The rat is considered an excellent model for studying human breast cancer. Therefore, understanding the genetic basis of susceptibility to mammary cancer in this species is of great interest. Previous studies based on crosses involving the susceptible strain WF (crossed with the resistant strains COP or WKY) and focusing on tumor multiplicity as the susceptibility phenotype led to the identification of several loci that control chemically induced mammary cancer.

Alpha-fetoprotein controls female fertility and prenatal development of the gonadotropin-releasing hormone pathway through an antiestrogenic action.

It has been shown previously that female mice homozygous for an alpha-fetoprotein (AFP) null allele are sterile as a result of anovulation, probably due to a defect in the hypothalamic-pituitary axis. Here we show that these female mice exhibit specific anomalies in the expression of numerous genes in the pituitary, including genes involved in the gonadotropin-releasing hormone pathway, which are underexpressed. In the hypothalamus, the gonadotropin-releasing hormone gene, Gnrh1, was also found to be down-regulated.

Alpha-fetoprotein protects the developing female mouse brain from masculinization and defeminization by estrogens.

Two clearly opposing views exist on the function of alpha-fetoprotein (AFP), a fetal plasma protein that binds estrogens with high affinity, in the sexual differentiation of the rodent brain. AFP has been proposed to either prevent the entry of estrogens or to actively transport estrogens into the developing female brain. The availability of Afp mutant mice (Afp(-/-)) now finally allows us to resolve this longstanding controversy concerning the role of AFP in brain sexual differentiation, and thus to determine whether prenatal estrogens contribute to the development of the female brain.

Quantitative trait loci for hypercalciuria in a rat model of kidney stone disease.

Hypercalciuria is the most common risk factor for kidney stones and has a recognized familial component. The genetic hypercalciuric stone-forming (GHS) rat is an animal model that closely resembles human idiopathic hypercalciuria, with excessive intestinal calcium absorption, increased bone resorption, and impaired renal calcium reabsorption; overexpression of the vitamin D receptor (VDR) in target tissues; and calcium nephrolithiasis. For identifying genetic loci that contribute to hypercalciuria in the GHS rat, an F2 generation of 156 rats bred from GHS female rats and normocalciuric WKY male rats was studied.

Cloning of a rat gene encoding the histo-blood group B enzyme: rats have more than one Abo gene.

A genomic DNA fragment corresponding to exon 7 of the human ABO gene was amplified from rats of several inbred and outbred strains. Five different sequences were obtained, four of them corresponding to A-type sequences and one to a B-type sequence based on the amino acids equivalent to residues at positions 266 and 268 of the human enzymes. In rats from inbred strains, a single A-type sequence and the unique B-type sequence were found, whereas some animals of outbred strains presented two or three A-type sequences along with the B-type sequence.

Alpha-fetoprotein, the major fetal serum protein, is not essential for embryonic development but is required for female fertility.

The alpha-fetoprotein gene (Afp) is a member of a multigenic family that comprises the related genes encoding albumin, alpha-albumin, and vitamin D binding protein. The biological role of this major embryonic serum protein is unknown although numerous speculations have been made. We have used gene targeting to show that AFP is not required for embryonic development.

Cloning of a rat gene encoding the histo-blood group A enzyme. Tissue expression of the gene and of the A and B antigens.

The complete coding sequence of a BDIX rat gene homologous to the human ABO gene was determined. Identification of the exon-intron boundaries, obtained by comparison of the coding sequence with rat genomic sequences from data banks, revealed that the rat gene structure is identical to that of the human ABO gene. It localizes to rat chromosome 3 (q11-q12), a region homologous to human 9q34.

The gene INPPL1, encoding the lipid phosphatase SHIP2, is a candidate for type 2 diabetes in rat and man.

Genetic susceptibility to type 2 diabetes involves many genes, most of which are still unknown. The lipid phosphatase SHIP2 is a potent negative regulator of insulin signaling and sensitivity in vivo and is thus a good candidate gene. Here we report the presence of SHIP2 gene mutations associated with type 2 diabetes in rats and humans.

Stimulation of the alpha-fetoprotein promoter by unliganded thyroid hormone receptor in association with protein deacetylation.

alpha-Fetoprotein (AFP) is a serum protein expressed during fetal life, the expression of which is shut off after birth. The activity of the mouse Afp gene promoter region comprised between -80 and -38 bp is regulated by the thyroid hormone receptor (T3R): negatively in the presence of T3 and positively in the absence of T3. The stimulating effect of unliganded T3R is, unexpectedly, antagonized by cofactors that have histone-acetyl-transferase activity, or by sodium butyrate, which inhibits histone acetylases (HDACs).