ABSTRACT
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). However, a few rat disease genes were unintentionally overlooked; in addition, since this review was published, numerous rat genes were inactivated by targeted mutations, revealing their potential role in diseases. It thus seems appropriate to update these data, which is the aim of this paper.
Subject(s)
Disease Models, Animal , Phenotype , Animals , Humans , RatsABSTRACT
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. The availability of these resources has stimulated numerous studies aimed at discovering causal disease genes by positional identification. Numerous rat genes have now been identified that underlie monogenic or complex diseases and remarkably, these results have been translated to the human in a significant proportion of cases, leading to the identification of novel human disease susceptibility genes, helping in studying the mechanisms underlying the pathological abnormalities and also suggesting new therapeutic approaches. In addition, reverse genetic tools have been developed. Several genome-editing methods were introduced to generate targeted mutations in genes the function of which could be clarified in this manner [generally these are knockout mutations]. Furthermore, even when the human gene causing a disease had been identified without resorting to a rat model, mutated rat strains (in particular KO strains) were created to analyze the gene function and the disease pathogenesis. Today, over 350 rat genes have been identified as underlying diseases or playing a key role in critical biological processes that are altered in diseases, thereby providing a rich resource of disease models. This article is an update of the progress made in this research and provides the reader with an inventory of these disease genes, a significant number of which have similar effects in rat and humans.
Subject(s)
Disease Models, Animal , Disease/genetics , Phenotype , Rats , Animals , Chromosome Mapping , Genomics , HumansABSTRACT
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. Here we show that this process is largely dependent on the Rhesus factor Rhcg. Mice lacking Rhcg have abnormal urinary acidification due to impaired ammonium excretion on acid loading-a feature of distal renal tubular acidosis. In vitro microperfused collecting ducts of Rhcg(-/-) acid-loaded mice show reduced apical permeability to NH(3) and impaired transepithelial NH(3) transport. Furthermore, Rhcg is localized in epididymal epithelial cells and is required for normal fertility and epididymal fluid pH. We anticipate a critical role for Rhcg in ammonium handling and pH homeostasis both in the kidney and the male reproductive tract.
Subject(s)
Cation Transport Proteins/metabolism , Fertility/physiology , Kidney/physiology , Membrane Glycoproteins/metabolism , Quaternary Ammonium Compounds/urine , Acidosis/physiopathology , Acids/metabolism , Animals , Biological Transport , Body Fluids , Cation Transport Proteins/deficiency , Cation Transport Proteins/genetics , Epithelial Cells/metabolism , Gene Deletion , Genitalia, Male/cytology , Genitalia, Male/metabolism , Homeostasis , Hydrogen-Ion Concentration , Kidney Tubules, Collecting/physiology , Kidney Tubules, Distal/physiology , Male , Membrane Glycoproteins/deficiency , Membrane Glycoproteins/genetics , Mice , Permeability , Stress, Physiological , Weight LossABSTRACT
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. To identify chromosomal regions potentially involved in the initiation and progression of mammary cancer, in the present work we subjected a subset of experimental mammary tumors to cytogenetic and molecular genetic analysis. METHODS: Mammary tumors were induced with DMBA (7,12-dimethylbenz[a]anthrazene) in female rats from the susceptible SPRD-Cu3 strain and from crosses and backcrosses between this strain and the resistant WKY strain. We first produced a general overview of chromosomal aberrations in the tumors using conventional kartyotyping (G-banding) and Comparative Genome Hybridization (CGH) analyses. Particular chromosomal changes were then analyzed in more details using an in-house developed BAC (bacterial artificial chromosome) CGH-array platform. RESULTS: Tumors appeared to be diploid by conventional karyotyping, however several sub-microscopic chromosome gains or losses in the tumor material were identified by BAC CGH-array analysis. An oncogenetic tree analysis based on the BAC CGH-array data suggested gain of rat chromosome (RNO) band 12q11, loss of RNO5q32 or RNO6q21 as the earliest events in the development of these mammary tumors. CONCLUSIONS: Some of the identified changes appear to be more specific for DMBA-induced mammary tumors and some are similar to those previously reported in ACI rat model for estradiol-induced mammary tumors. The later group of changes is more interesting, since they may represent anomalies that involve genes with a critical role in mammary tumor development. Genetic changes identified in this work are at very small scales and thus may provide a more feasible basis for the identification of the target gene(s). Identification of the genes underlying these chromosome changes can provide new insights to the mechanisms of mammary carcinogenesis.
Subject(s)
Chromosome Aberrations , Comparative Genomic Hybridization , Diploidy , Mammary Neoplasms, Experimental/genetics , 9,10-Dimethyl-1,2-benzanthracene/adverse effects , Animals , Cell Transformation, Neoplastic/genetics , Chromosome Banding , Chromosomes, Artificial, Bacterial , Chromosomes, Mammalian , Female , Mammary Neoplasms, Experimental/chemically induced , Rats , Rats, Inbred WKYABSTRACT
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. We previously identified a zinc finger protein gene ZBTB20. To determine its physiological functions in vivo, we have generated hepatocyte-specific ZBTB20 knockout mice by the Cre/loxP approach and demonstrated here that ZBTB20 ablation in liver led to dramatic derepression of the AFP gene in entire liver throughout adult life, although the hepatocytes were normally under nonproliferating status. Furthermore, we found that ZBTB20 was a transcriptional repressor capable of specifically inhibiting AFP promoter-driven transcriptional activity. Liver chromatin immunoprecipitation and mobility shift assays showed that ZBTB20 bound to AFP promoter directly. ZBTB20 was developmentally activated in liver after birth and inversely correlated with its AFP gene expression, suggesting that activated ZBTB20 expression in liver mediated AFP gene repression. Our data point to ZBTB20 as a key regulator governing AFP gene transcription and postulate a new model for the postnatal gene repression of AFP in liver.
Subject(s)
Gene Expression Regulation/genetics , Liver/metabolism , Transcription Factors/metabolism , alpha-Fetoproteins/metabolism , Animals , Blotting, Southern , Blotting, Western , Cell Proliferation , Chromatin Immunoprecipitation , Electrophoretic Mobility Shift Assay , Hepatocytes , Immunohistochemistry , Mice , Mice, Knockout , Transcription Factors/geneticsABSTRACT
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. Lack of Nampt expression strongly affects development of both T and B lymphocytes. Analysis of hemizygous cells and in vitro cell lines expressing distinct levels of Nampt illustrates the critical role of this protein in regulating intracellular NAD levels. Consequently, a clear relationship was found between intracellular Nampt levels and cell death in response to the genotoxic agent MNNG (N-methyl-N'-nitro-N-nitrosoguanidine), confirming that this enzyme represents a key regulator of cell sensitivity to NAD-consuming stress secondary to poly(ADP-ribose) polymerases overactivation. By using mutant forms of this protein and a well-characterized pharmacological inhibitor (FK866), we unequivocally demonstrate that the ability of the Nampt to regulate cell viability during genotoxic stress requires its enzymatic activity. Collectively, these data demonstrate that Nampt participates in cellular resistance to genotoxic/oxidative stress, and it may confer to cells of the immune system the ability to survive during stressful situations such as inflammation.
Subject(s)
Cell Differentiation/immunology , Cytokines/physiology , Immunity, Cellular , Lymphocytes/enzymology , Lymphocytes/immunology , Nicotinamide Phosphoribosyltransferase/physiology , Animals , Cell Death/genetics , Cell Death/immunology , Cell Differentiation/drug effects , Cell Differentiation/genetics , Cell Line , Cell Survival/genetics , Cell Survival/immunology , Cytokines/biosynthesis , Cytokines/deficiency , Cytokines/genetics , Gene Deletion , Humans , Immunity, Cellular/drug effects , Immunity, Cellular/genetics , Inflammation Mediators/metabolism , Inflammation Mediators/physiology , Lymphocytes/drug effects , Methylnitronitrosoguanidine/toxicity , Mice , Mice, Inbred C57BL , Mutagenesis, Site-Directed , NIH 3T3 Cells , Nicotinamide Phosphoribosyltransferase/biosynthesis , Nicotinamide Phosphoribosyltransferase/deficiency , Nicotinamide Phosphoribosyltransferase/genetics , Oxidative Stress/drug effects , Oxidative Stress/genetics , Oxidative Stress/immunology , Signal Transduction/drug effects , Signal Transduction/genetics , Signal Transduction/immunologyABSTRACT
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. Here we show that the brain and behavior of female Afp(-/-) mice were masculinized and defeminized. However, when estrogen production was blocked by embryonic treatment with the aromatase inhibitor 1,4,6-androstatriene-3,17-dione, the feminine phenotype of these mice was rescued. These results clearly demonstrate that prenatal estrogens masculinize and defeminize the brain and that AFP protects the female brain from these effects of estrogens.
Subject(s)
Brain/embryology , Estrogens/metabolism , Sex Differentiation/physiology , alpha-Fetoproteins/metabolism , Animals , Aromatase Inhibitors/pharmacology , Brain/drug effects , Female , Immunohistochemistry , Mice , Mice, Mutant Strains , Sex Differentiation/drug effects , Tyrosine 3-Monooxygenase/biosynthesis , Vasopressins/biosynthesis , alpha-Fetoproteins/drug effectsABSTRACT
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.g., NMU and DMBA)-induced rat mammary models are valuable tools for genetic studies of breast cancer. In NMU-induced rat mammary tumors, activating mutations in Hras codon 12 have frequently been reported and are supposed to contribute to the mammary carcinogenic process. Involvement of Ras mutations in DMBA-induced tumors is less clear. In the present study we investigated the mutation status of the three Ras genes, Hras, Kras, and Nras, in DMBA-induced rat mammary tumors. We examined codons 12, 13, and 61 of all three genes for mutations in 71 tumors using direct sequencing method that in experimental conditions is sensitive enough to detect single nucleotide mutations even when present in only 25% of the test sample. No activating Ras gene mutation was found. Thus, in contrast to NMU-induced rat mammary tumor, tumorigenesis in DMBA-induced rat mammary tumors seems to be independent on activating mutations in the Ras genes. Our finding suggests that the genetic pathways selected in mammary tumor development are influenced by and perhaps dependent on the identity of the inducing agent, again emphasizing the importance of tumor etiology on the genetic changes in the tumor cells.
Subject(s)
9,10-Dimethyl-1,2-benzanthracene/toxicity , Carcinogens/toxicity , Genes, ras , Mammary Neoplasms, Experimental/genetics , Mutation , Animals , Codon , Female , Mammary Neoplasms, Experimental/chemically induced , RatsABSTRACT
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. However, pituitary gene expression could be normalized and fertility could be rescued by blocking prenatal estrogen synthesis using an aromatase inhibitor. These results show that AFP protects the developing female brain from the adverse effects of prenatal estrogen exposure and clarify a long-running debate on the role of this fetal protein in brain sexual differentiation.
Subject(s)
Fertility/genetics , Fetal Development/genetics , Gene Expression Regulation, Developmental , Pituitary Hormone-Releasing Hormones/metabolism , alpha-Fetoproteins/metabolism , Androstatrienes/pharmacology , Animals , Aromatase Inhibitors/pharmacology , Brain/embryology , Estrogens/metabolism , Female , Gonadotropin-Releasing Hormone/genetics , Hypothalamus/physiology , Infertility, Female/drug therapy , Infertility, Female/genetics , Mice , Mice, Knockout , Pituitary Gland/physiology , Pregnancy , Protein Precursors/genetics , alpha-Fetoproteins/geneticsABSTRACT
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. Afp(-/-) mice lack the protective actions of AFP against estrogens circulating during embryonic development, leading to infertility probably due to a hypothalamic dysfunction. Therefore, we first determined whether Afp(-/-) females are capable of showing a steroid-induced preovulatory LH surge by FOS/GnRH1 immunohistochemistry and RIA of plasma LH levels. Because the KISS1/GPR54 system is a key upstream regulator of the GnRH1 system as well as being sexually dimorphic, we also analyzed whether Kisspeptin-10 neurons were activated in Afp(-/-) mice after treatment with estradiol and progesterone. We found that the GnRH1 and Kisspeptin-10 neuronal systems are defeminized in Afp(-/-) females because they did not show either steroid-induced LH surges or significant FOS/GnRH1 double labeling. Furthermore, Kisspeptin-10 immunoreactivity and neural activation, measured by the number of double-labeled FOS/Kisspeptin-10 cells, were lower in Afp(-/-) females, suggesting a down-regulation of GnRH1 function. Thus, the sex difference in the ability to show preovulatory LH surges depends on the prenatal actions of estrogens in the male hypothalamus and, thus, is lost in Afp(-/-) females because they lack AFP to protect them against the defeminizing effects of estrogens during prenatal development.
Subject(s)
Estrogens/pharmacology , Feminization/blood , Gonadotropin-Releasing Hormone/metabolism , Luteinizing Hormone/blood , Ovulation/blood , Prenatal Exposure Delayed Effects/blood , Proteins/metabolism , alpha-Fetoproteins/genetics , Animals , Down-Regulation , Female , Kisspeptins , Male , Mice , Mice, Knockout , Neurons/metabolism , Oncogene Proteins v-fos/metabolism , Pregnancy , Sex CharacteristicsABSTRACT
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. The R1142C mutation specifically identified in Goto-Kakizaki (GK) and spontaneously hypertensive rat strains disrupts a potential class II ligand for Src homology (SH)-3 domain and slightly impairs insulin signaling in cell culture. In humans, a deletion identified in the SHIP2 3' untranslated region (UTR) of type 2 diabetic subjects includes a motif implicated in the control of protein synthesis. In cell culture, the deletion results in reporter messenger RNA and protein overexpression. Finally, genotyping of a cohort of type 2 diabetic and control subjects showed a significant association between the deletion and type 2 diabetes. Altogether, our results show that mutations in the SHIP2 gene contribute to the genetic susceptibility to type 2 diabetes in rats and humans.
Subject(s)
Chromosome Mapping , Diabetes Mellitus, Type 2/genetics , Phosphoric Monoester Hydrolases/genetics , 3' Untranslated Regions/genetics , Animals , Base Sequence , CHO Cells , Cell Line , Cohort Studies , Cricetinae , Diabetes Mellitus, Type 2/enzymology , Gene Amplification , Genes, Reporter , Genotype , Humans , In Situ Hybridization, Fluorescence , Kidney/embryology , Kidney/enzymology , Luciferases/genetics , Mice , Molecular Sequence Data , Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases , Phosphoric Monoester Hydrolases/metabolism , Rats , Recombinant Proteins/metabolism , Reference Values , Sequence Deletion , Transfection , src Homology Domains/geneticsABSTRACT
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). The unliganded T3R stimulating activity effect is thus associated with protein deacetylation, contrary to the usual situation. In combination with previous results, our observations suggest that T3-mediated down regulation of the Afp promoter is due to T3-induced protein acetylation leading to loss of a nucleosomal structure (required for promoter activity) and chromatin opening.
Subject(s)
DNA-Binding Proteins , Nuclear Proteins , Promoter Regions, Genetic , Receptors, Thyroid Hormone/metabolism , Thyroid Hormones/physiology , alpha-Fetoproteins/genetics , alpha-Fetoproteins/metabolism , Base Sequence , Cells, Cultured , Down-Regulation , Electrophoretic Mobility Shift Assay , Gene Expression Regulation , Hepatocyte Nuclear Factor 1 , Hepatocyte Nuclear Factor 1-alpha , Hepatocyte Nuclear Factor 1-beta , Histone Deacetylase Inhibitors , Histone Deacetylases/metabolism , Humans , Luciferases/metabolism , Molecular Sequence Data , Mutation , Polymerase Chain Reaction , Thyroid Hormones/metabolism , Transcription Factors/genetics , Transcription Factors/metabolism , Transcription, GeneticABSTRACT
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. Some were obtained spontaneously, while others were generated either by mutagenesis of tumor suppressor genes or by transgenesis of activated oncogenes (transgenesis can be performed efficiently in the rat). In addition, among the hundreds of inbred rat strains that have been isolated, some are highly susceptible or resistant to certain types of cancer, and these divergent phenotypes were shown to be polygenic. Numerous quantitative trait loci (QTLs) controlling cancer susceptibility/resistance have been defined in linkage analyses, and several of these QTLs were physically demonstrated in congenic strains. These studies led, in particular, to rapid translation to the human, with the identification of loci controlling susceptibility to a form of multiple endocrine neoplasia (monogenic trait) and to breast cancer (polygenic disease). The biology of cancer resistance has also been analyzed, and in some (but not all) cases, it was linked to regression of preneoplasic lesions. Rat tumors have been the subject of various types of analyses, and these studies led to important conclusions, including that tumors can be classified on the basis of the identity of the inducing agent, thereby suggesting that analyses of human tumors may be valuable in determining retrospectively the role of specific carcinogens in the formation of human cancers, and of human breast cancer in particular.
Subject(s)
Neoplasms, Experimental/genetics , Neoplasms/genetics , Rats/genetics , Animals , Genetic Predisposition to Disease , Genetic Techniques , Humans , Quantitative Trait LociABSTRACT
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. The WKY allele at this QTL (Mcsta1) reduces the growth rate of the fastest growing tumors by 26%. We also previously showed that two SPRD-Cu3-WKY congenic strains containing a WKY chromosome segment derived either from Chr 5 or from Chr 18 exhibit a reduction in tumor multiplicity (QTLs Msctm1 and Mcstm2, respectively) (with no reduction in tumor growth rate in the Chr 18 congenic). In this study we generated a double congenic strain, which contains the two WKY differential segments from Chr 5 and 18, to determine how these two segments interact with one another. Interestingly, two types of epistatic interactions were found: no additive effect was seen with respect to tumor multiplicity, while a reduction in tumor growth rate was observed. It thus appears that WKY alleles located on Chr 5 and Chr 8 interact epistatically in a contrasting manner to modulate tumor multiplicity (in a nonadditive manner) and growth rate (in a synergic manner). Tumor growth rate is thus influenced by two QTLs, on Chr 10 (Mcsta1) and on Chr 18 (Mcsta2), the action of the latter being dependent on the presence of the Chr5 QTL (Mcstm1). The expression level of positional and functional candidate genes was also analyzed. On Chr 5, Pla2g2a is subject to a syntenic control while expression of the Tp53 (Chr 10) and Pmai1/Noxa (Chr 18) genes appears to be controlled by several mammary cancer resistance QTLs.
Subject(s)
Epistasis, Genetic/physiology , Mammary Neoplasms, Animal/genetics , Quantitative Trait Loci , Animals , Animals, Congenic , Base Sequence , Chromosome Mapping , Female , Gene Expression , Genes, p53/physiology , Genetic Predisposition to Disease , Group II Phospholipases A2/genetics , Male , Molecular Sequence Data , Proto-Oncogene Proteins c-bcl-2/genetics , Rats , Rats, Inbred Strains , Rats, Inbred WKY , Sequence Homology, Nucleic AcidABSTRACT
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. To gain insight into the biological function of the SP6 protein, we knocked out the gene by eliminating the full coding region. The resulting Sp6 null mice are nude, lack functional teeth, and present limb and lung malformations. We also showed that the identified abnormalities are associated with apoptotic misregulations. In conclusion, this work indicates that Sp6 plays a critical role in the development of several epithelium-containing organs or appendages, possibly by regulating apoptosis.
Subject(s)
Congenital Abnormalities , Kruppel-Like Transcription Factors/metabolism , Morphogenesis/genetics , Alopecia/genetics , Animals , Apoptosis/physiology , Epidermis/abnormalities , Extremities/growth & development , Extremities/pathology , Gene Expression Regulation, Developmental , Kruppel-Like Transcription Factors/genetics , Limb Deformities, Congenital , Mice , Mice, Knockout , Morphogenesis/physiology , Polydactyly/genetics , Pulmonary Alveoli/cytology , Pulmonary Alveoli/pathology , Syndactyly/genetics , Tooth/growth & development , Tooth/physiology , Tooth AbnormalitiesABSTRACT
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. In the context of significant progress in rat genomic resources over the past decade, we outline achievements in rat gene discovery to date, show how these findings have been translated to human disease, and document an increasing pace of discovery of new disease genes, pathways and mechanisms. Finally, we present a set of principles that justify continuing and strengthening genetic studies in the rat model, and further development of genomic infrastructure for rat research.
Subject(s)
Disease Models, Animal , Genetic Diseases, Inborn/genetics , Genome , Genomics/trends , Rats/genetics , Animals , Animals, Genetically Modified , Chromosome Mapping , Gene Targeting , HumansABSTRACT
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. The function of several susceptibility genes indicates that one critical biological pathway is the DNA damage response. However, other pathways certainly play a significant role in breast cancer susceptibility. Rodent models of breast cancer are useful models in two respects. They can help identify new mammary susceptibility genes by taking advantage of the very divergent susceptibilities exhibited by different mouse or rat strains and carrying out relevant genetic analyses. They also provide investigators with experimental systems that can help decipher the mechanism(s) of resistance to mammary cancer. Recent genetic and biological results obtained with mouse and especially with rat strains indicate that (1) numerous quantitative trait loci control mammary cancer susceptibility or resistance, with distinct loci acting in different strains, and (2) distinct resistance mechanisms operate in different rat resistant strains, precocious mammary differentiation being one of these mechanisms.
Subject(s)
Breast Neoplasms/genetics , DNA Damage , Genetic Predisposition to Disease/genetics , Mammary Neoplasms, Animal/genetics , Animals , Disease Models, Animal , Female , Germ-Line Mutation , Humans , Mice , Neoplasm Proteins/genetics , RatsABSTRACT
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. AFP sequestrates estrogens and by so doing protects the female developing brain from deleterious (defeminizing/masculinizing) effects of these hormones.
ABSTRACT
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. WKY females are characterized by precocious mammary tissue differentiation, including active expression of the beta-casein gene in young virgin females. This trait might be critical in resistance to mammary carcinogenesis of WKY rats. To test this hypothesis, we took advantage of 2 congenic strains that contain a limited chromosome segment of WKY origin, derived either from chromosome 5 or from chromosome 18, introgressed in the susceptible genetic background (SPRD-Cu3). Each of these congenic strains has been shown to be partially resistant to chemically induced mammary carcinogenesis (reduction in tumour multiplicity with respect to the susceptible SPRD-Cu3 rats). We show here that these 2 congenic strains also exhibit precocious mammary differentiation, though to a lower extent than the WKY females. The conclusion of this study is thus 2-fold: (i) eradication of preneoplastic lesions is not a general phenomenon in mammary cancer resistance; (ii) the same segment of rat chromosomes 5 or 18 that controls mammary cancer resistance also contains a quantitative trait locus imposing precocious mammary differentiation. These 2 traits are thus associated, supporting the hypothesis that there might be a cause-effect relationship between precocious mammary differentiation and cancer resistance.
Subject(s)
Cell Differentiation , Mammary Glands, Animal/pathology , Mammary Neoplasms, Experimental/genetics , Quantitative Trait Loci , Animals , Caseins/genetics , Chromosome Mapping , Chromosomes, Mammalian , Female , Genetic Predisposition to Disease , Mammary Neoplasms, Experimental/pathology , Precancerous Conditions/chemically induced , Rats , Rats, Inbred WKY , Rats, Mutant Strains , Rats, Sprague-Dawley , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
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. The chromosome 5 QTL (Mcstm1) accounts for 7 tumors per animal (versus a total of 11 tumors per SPRD-Cu3 rat). The chromosome 18 QTL (Mcstm2) accounts for 3 tumors per animal and is the first chemically-induced mammary cancer susceptibility locus assigned to this chromosome. In addition, the Mcstm1 region was shown to also controls tumor latency. These loci thus play a major role in chemically-induced mammary tumor development. QTLs controlling chemically-induced or estrogen-induced mammary tumor development have independently been identified on chromosomes 5 and 18, using susceptible strains others than SPRD-Cu3. Therefore the haplotype structure of the relevant chromosome regions was analyzed in the different strains. Some chromosome regions were found to be highly mosaic (haplotype blocks < 1 Mb), while one region showed an apparently conserved haplotype block of 7.5 Mb. This analysis points to limited regions that could harbor the causative genes and also indicates that at least Mcstm2 is a novel QTL.