Sex and death in the mouse: genetically delayed reproduction and senescence

Genome ◽  
1997 ◽  
Vol 40 (2) ◽  
pp. 229-235 ◽  
Author(s):  
F. G. Biddle ◽  
S. A. Eden ◽  
J. S. Rossler ◽  
B. A. Eales
Keyword(s):  
Genetic Model ◽  
Late Onset ◽  
Laboratory Mouse ◽  
Laboratory Strain ◽  
Antagonistic Pleiotropy ◽  
Mus Musculus Domesticus ◽  
Delayed Reproduction ◽  
Aging Studies ◽  
Aging Curve ◽  
Postponed Aging

A mammalian model of genetically postponed aging would be an important tool to test not only different mechanisms of aging but also the predictive value of various biomarkers of the aging process. Under conventional conditions, the historical strains of the laboratory mouse produce their first litter between 9 and 13 weeks of age and have a median time of death in their 2nd year. Our POSCH-2 strain, which was derived from wild-caught Mus musculus domesticus, produces its first litter in the current breeding generations at approximately 47 weeks of age and continues to breed throughout its 2nd and into its 3rd year of life. The aging curve of POSCH-2 has not yet been determined for economic reasons. Late onset of breeding is a characteristic of both females and males, but sexual maturity is more reliably assessed in females. The later breeding phenotype of POSCH-2 is genetically recessive to early breeding of the C57BL/6J historical laboratory strain and, since POSCH-2 females can be induced to ovulate at 8 weeks of age (but pregnancy does not result), the signal rather than the ovarian receptor to ovulate may be delayed. The genetically delayed reproduction and potentially longer life of the POSCH-2 strain appears to be a new trait in the mouse. The strain may be a useful mammalian model for aging studies and for the evaluation of antagonistic pleiotropy as a genetic model for the evolution of aging.Key words: delayed reproduction, senescence, aging, genetics, mouse.

scholarly journals α-Secretase nonsense mutation (ADAM10 Tyr167*) in familial Alzheimer’s disease

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Pablo Agüero ◽  
María José Sainz ◽  
María-Salud García-Ayllón ◽  
Javier Sáez-Valero ◽  
Raquel Téllez ◽  
...  
Keyword(s):  
Nonsense Mutation ◽  
Genetic Model ◽  
Late Onset ◽  
Future Research ◽  
Clinical Genetic ◽  
Csf Analysis ◽  
Amyloidogenic Processing ◽  
Age Related ◽  
Spanish Cohort

Abstract Background The disintegrin metalloproteinase 10 (ADAM10) is the main α-secretase acting in the non-amyloidogenic processing of APP. Some ADAM10 gene variants have been associated with higher susceptibility to develop late-onset AD, though clear clinical-genetic correlates remain elusive. Methods Clinical-genetic and biomarker study of a first family with early- and late-onset AD associated with a nonsense ADAM10 mutation (p.Tyr167*). CSF analysis included AD core biomarkers, as well as Western blot of ADAM10 species and sAPPα and sAPPβ peptides. We evaluate variant’s pathogenicity, pattern of segregation, and further screened for the p.Tyr167* mutation in 197 familial AD cases from the same cohort, 200 controls from the same background, and 274 AD cases from an independent Spanish cohort. Results The mutation was absent from public databases and segregated with the disease. CSF Aβ42, total tau, and phosphorylated tau of affected siblings were consistent with AD. The predicted haploinsufficiency effect of the nonsense mutation was supported by (a) ADAM10 isoforms in CSF decreased around 50% and (b) 70% reduction of CSF sAPPα peptide, both compared to controls, while sAPPβ levels remained unchanged. Interestingly, sporadic AD cases had a similar decrease in CSF ADAM10 levels to that of mutants, though their sAPPα and sAPPβ levels resembled those of controls. Therefore, a decreased sAPPα/sAPPβ ratio was an exclusive feature of mutant ADAM10 siblings. The p.Tyr167* mutation was not found in any of the other AD cases or controls screened. Conclusions This family illustrates the role of ADAM10 in the amyloidogenic process and the clinical development of the disease. Similarities between clinical and biomarker findings suggest that this family could represent a genetic model for sporadic late-onset AD due to age-related downregulation of α-secretase. This report encourages future research on ADAM10 enhancers.

scholarly journals Unraveling the Gordian knot: genetics and the troubled road to effective therapeutics for Alzheimer’s disease

Genetics ◽  
2021 ◽  
Author(s):  
Linda L Restifo
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Enzyme Inhibitors ◽  
Genetic Model ◽  
Late Onset ◽  
Model Organisms ◽  
Major Protein ◽  
Late 20Th Century ◽  
Protein Components

Abstract In the late 20th century, identification of the major protein components of amyloid plaques and neurofibrillary tangles provided a window into the molecular pathology of Alzheimer’s disease, ushering in an era of optimism that targeted therapeutics would soon follow. The amyloid-cascade hypothesis took hold very early, supported by discoveries that dominant mutations in APP, PSEN1, and PSEN2 cause the very rare, early-onset, familial forms of the disease. However, in the past decade a stunning series of failed Phase-3 clinical trials, testing anti-amyloid antibodies or processing-enzyme inhibitors, prompts the question, What went wrong? The FDA’s recent controversial approval of aducanumab, despite widespread concerns about efficacy and safety, only amplifies the question. The assumption that common, late-onset Alzheimer's is a milder form of the familial disease was not adequately questioned. The differential timing of discoveries, including blood-brain-barrier-penetrant tracers for imaging of plaques and tangles, made it easy to focus on amyloid. Furthermore, the neuropathology community initially implemented Alzheimer's diagnostic criteria based on plaques only. The discovery that MAPT mutations cause frontotemporal dementia with tauopathy made it even easier to overlook the tangles in Alzheimer's. Many important findings were simply ignored. The accepted mouse models did not predict the human clinical trials data. Given this lack of pharmacological validity, input from geneticists in collaboration with neuroscientists is needed to establish criteria for valid models of Alzheimer's disease. More generally, scientists using genetic model organisms as whole-animal bioassays can contribute to building the pathogenesis network map of Alzheimer’s disease.

scholarly journals Knockout Mice Lacking Steroidogenic Factor 1 Are a Novel Genetic Model of Hypothalamic Obesity

Endocrinology ◽  
2002 ◽  
Vol 143 (2) ◽  
pp. 607-614 ◽  
Author(s):  
Gregor Majdic ◽  
Morag Young ◽  
Elise Gomez-Sanchez ◽  
Paul Anderson ◽  
Lidia S. Szczepaniak ◽  
...  
Keyword(s):  
Genetic Model ◽  
Late Onset ◽  
Ventromedial Hypothalamus ◽  
Hypothalamic Nucleus ◽  
Weight Regulation ◽  
Wild Type ◽  
Hypothalamic Obesity ◽  
Steroidogenic Factor 1 ◽  
Ventromedial Hypothalamic Nucleus

Abstract Knockout (KO) mice lacking steroidogenic factor 1 (SF-1) exhibit a phenotype that includes adrenal and gonadal agenesis, impaired gonadotropin expression, and abnormalities of the ventromedial hypothalamic nucleus (VMH). Studies in rodents with lesions of the ventromedial hypothalamus have implicated the VMH in body weight regulation, suggesting that SF-1 KO mice may provide a genetic model of obesity. To prevent death, SF-1 KO mice were rescued with corticosteroid injections, followed by syngeneic adrenal transplants from wild-type (WT) littermates. Corticosterone and ACTH levels in WT and SF-1 KO mice were indistinguishable, documenting restoration of hypothalamic-pituitary-adrenal function. Although weights at earlier ages did not differ significantly from WT littermates, SF-1 KO mice were significantly heavier by 8 wk of age and eventually weighed almost twice as much as WT controls. Obesity in SF-1 KO mice predominantly resulted from decreased activity rather than increased food intake. Leptin was increased markedly, insulin was modestly elevated, and glucose was indistinguishable from WT mice. Although sex steroids in rodents affect weight, ovariectomy did not abolish the weight difference between WT and SF-1 KO mice. These SF-1 KO mice are a genetic model of late-onset obesity that may help elucidate the role of the VMH in weight regulation.

scholarly journals A genetic model for human polyglutamine-repeat disease in Drosophila melanogaster

1999 ◽  
Vol 354 (1386) ◽  
pp. 1057-1060 ◽  
Author(s):  
Nancy M. Bonini
Keyword(s):  
Drosophila Melanogaster ◽  
Genetic Model ◽  
Late Onset ◽  
Spinocerebellar Ataxia Type ◽  
Gene Encoding ◽  
Spinocerebellar Ataxia Type 3 ◽  
Neural Degeneration ◽  
Polyglutamine Repeat ◽  
Disease Protein ◽  
Type 3

To apply genetics to the problem of human polyglutamine–repeat disease, we recreated polyglutamine–repeat disease in Drosophila melanogaster . To do this, we expressed forms of the human gene encoding spinocerebellar ataxia type 3, also called Machado–Joseph disease (SCA–3/MJD). This gene is responsible for the most common form of human ataxia worldwide. Expression of a normal form of the MJD protein with 27 polyglutamines (MJDtr–Q27) had no phenotype. However, expression of a form of the protein with an expanded run of 78 glutamines (MJDtr–Q78) caused late onset progressive degeneration. In addition, the MJDtr–Q78 formed abnormal protein aggregates, or nuclear inclusions (NIs), whereas the control protein was cytoplasmic. These data indicate that the mechanisms of human polyglutamine–repeat disease are conserved to Drosophila . We are currently using this model to address potential mechanisms by which the mutant disease protein causes neural degeneration, as well as to define genes that can prevent polyglutamine–induced degeneration. By applying the power of Drosophila genetics to the problem of human polyglutamine–induced neural degeneration, we hope to identify ways to prevent and treat these diseases in humans.

Most classical Mus musculus domesticus laboratory mouse strains carry a Mus musculus musculus Y chromosome

Nature ◽  
1985 ◽  
Vol 315 (6014) ◽  
pp. 70-72 ◽  
Author(s):  
C. E. Bishop ◽  
P. Boursot ◽  
B. Baron ◽  
F. Bonhomme ◽  
D. Hatat
Keyword(s):  
Y Chromosome ◽  
Mus Musculus ◽  
Laboratory Mouse ◽  
Mouse Strains ◽  
Mus Musculus Domesticus ◽  
Mus Musculus Musculus

Haldane's rule and heterogametic female and male sterility in the mouse

Genome ◽  
1994 ◽  
Vol 37 (2) ◽  
pp. 198-202 ◽  
Author(s):  
Fred G. Biddle ◽  
Brenda A. Eales ◽  
Wendy L. Dean
Keyword(s):  
Interspecific Cross ◽  
Laboratory Mouse ◽  
Laboratory Strain ◽  
Interspecific Crosses ◽  
Marker Genes ◽  
Laboratory Mice ◽  
Separate Species ◽  
Haldane’S Rule ◽  
Chromosome Marker ◽  
Haldane's Rule

Failed genetic experiments or experiments designed for other purposes sometimes reveal novel genetic information. The interspecific cross between laboratory strain mice of the Mus musculus musculus/domesticus complex and the separate species M. spretus is known to produce fertile F1 females and sterile F1 males. Infertility of the interspecific F1 XY male is said to be an example of what has become known as Haldane's rule: "When in the F1 offspring of two different animal races one sex is absent, rare, or sterile, that sex is the heterozygous [heterogametic] sex." We attempted to use fertile single-X (or XO) female laboratory mice of the M. m. musculus/domesticus complex mated to M. spretus males to construct females with specific X chromosomes to study segregation distortion of X chromosome marker genes that we reported previously in crosses with the two species. We assumed that the interspecific F1 XO female would be fertile like the interspecific F1 XX female but, instead, we found that it is infertile. Haldane's rule is not specific to sex, but demonstration of this has required study of separate species pairs with heterogametic males or with heterogametic females. The fertile XO laboratory mouse is female, but it is also heterogametic, producing both X and nullo-X eggs. Infertility of both the interspecific and heterogametic F1 XO female and F1 XY male in the same cross between laboratory mice and M. spretus suggests that heterogamety is at the cause of the infertility. The most parsimonious interpretation is that there is an interaction between the single X and heterozygous or heterospecific autosomes that may affect the same fundamental step in both female and male meiosis in the interspecific F1 hybrid. This hypothesis is now testable in the mouse.Key words: interspecific crosses, mouse, Haldane's rule.

Mouse genetic model for left-right hand usage: Context, direction, norms of reaction, and memory

Genome ◽  
1999 ◽  
Vol 42 (6) ◽  
pp. 1150-1166 ◽  
Author(s):  
Fred G Biddle ◽  
Brenda A Eales
Keyword(s):  
Genetic Model ◽  
Quantitative Difference ◽  
Laboratory Mouse ◽  
Qualitative Difference ◽  
Test Chamber ◽  
Inbred Strains ◽  
The Difference ◽  
Left Right Asymmetry ◽  
Conditioned Behaviour ◽  
The Right

Asymmetry of paw usage in the laboratory mouse is an experimental model for left-right asymmetry of hand usage. Given a set number of reaches into a centrally placed food tube (an unbiased or U-world test), individual mice exhibit a number of left and right paw reaches that is reliably expressed on retesting. Whereas different inbred strains appear to have equal numbers of individual mice with a left- or a right-preferred paw after a U-world test, there are significant differences among strains in the degree or strength of lateralization of the preferred paw. We report here a systematic series of tests of paw usage with naive mice and retests of the individuals in test chambers with the food tube biased to the left or to the right, contrasting the highly lateralized C57BL/6J and the very weakly lateralized (or ambilateral) CDS/Lay inbred strains and their (B6 × CDS) F1 generation. The results caused a shift in the paradigm of paw usage. There is an unexpected qualitative difference in paw usage between C57BL/6J and CDS/Lay. C57BL/6J is random in its left-right paw usage, but it is conditioned by the left or right direction of the initial biased-world test and by usage. CDS/Lay is constitutively equal-pawed, responds very little to direction of the test chamber, and is not conditioned by it. The probability of left-paw versus right-paw usage depends on both the genotype and the context of the test. The (B6 × CDS) F1 generation suggests that constitutive equal-paw usage of CDS/Lay is dominant to experience-conditioned paw usage of C57BL/6J. There is also an apparent quantitative difference between the very weakly lateralized (ambilateral) preferred paw usage in CDS/Lay and the highly lateralized preferred paw usage in C57BL/6J. The difference in degree of lateralization of preferred paw usage between the constitutively equal-pawed CDS/Lay strain and (B6 × CDS) F1 generation must originate from allelic differences at other gene loci between the CDS/Lay and C57BL/6J parental strains. The SWV and NOD/Lt strains were also assessed in asymmetrical tests because they were known to be weakly lateralized and similar to each other in a U-world test and to be significantly different from both C57BL/6J and CDS/Lay. SWV is experience-conditioned and weakly lateralized; NOD/Lt is constitutively equal-pawed and weakly lateralized. Further analysis will determine the genetic cause of the qualitative difference between constitutive equal-paw and experience-conditioned paw usage and the genetic cause of the quantitative differences in degree of lateralization of the preferred paw within each type of paw usage.Key words: mouse, left-right handedness, behavioural genetics, phenotypic reaction norms, constitutive behaviour, experience-conditioned behaviour, memory.

scholarly journals Evolutionary Theories of Aging and Longevity

2002 ◽  
Vol 2 ◽  
pp. 339-356 ◽  
Author(s):  
Leonid A. Gavrilov ◽  
Natalia S. Gavrilova
Keyword(s):  
Mutation Accumulation ◽  
Antagonistic Pleiotropy ◽  
August Weismann ◽  
Evolutionary Theories ◽  
Theories Of Aging ◽  
Programmed Death ◽  
Aging Studies ◽  
Theory Of Aging ◽  
Wide Readership ◽  
Experimental Findings

The purpose of this article is to provide students and researchers entering the field of aging studies with an introduction to the evolutionary theories of aging, as well as to orient them in the abundant modern scientific literature on evolutionary gerontology. The following three major evolutionary theories of aging are discussed: 1) the theory of programmed death suggested by August Weismann, 2) the mutation accumulation theory of aging suggested by Peter Medawar, and 3) the antagonistic pleiotropy theory of aging suggested by George Williams. We also discuss a special case of the antagonistic pleiotropy theory, the disposable soma theory developed by Tom Kirkwood and Robin Holliday. The theories are compared with each other as well as with recent experimental findings. At present the most viable evolutionary theories are the mutation accumulation theory and the antagonistic pleiotropy theory; these theories are not mutually exclusive, and they both may become a part of a future unifying theory of aging.Evolutionary theories of aging are useful because they open new oppor-tunities for further research by suggesting testable predictions, but they have also been harmful in the past when they were used to impose limitations on aging studies. At this time, the evolutionary theories of aging are not ultimate completed theories, but rather a set of ideas that themselves require further elaboration and validation. This theoretical review article is written for a wide readership.

Directional dominance and a developmental model for the expression of the Tda testis-determining autosomal trait of the mouse

Genome ◽  
1996 ◽  
Vol 39 (3) ◽  
pp. 520-527 ◽  
Author(s):  
Brenda A. Eales ◽  
Mirna Nahas ◽  
Fred G. Biddle
Keyword(s):  
Y Chromosome ◽  
Laboratory Mouse ◽  
Strain Differences ◽  
Gonadal Development ◽  
Developmental Model ◽  
Mus Musculus Domesticus ◽  
Native Strain ◽  
Testis Development ◽  
Threshold Trait ◽  
Normally Distributed

The POSCH-2 Y chromosome from the poschiavinus variety of Mus musculus domesticus causes incomplete testis development in the recessive autosomal background of the C57BL/6J laboratory mouse strain. Testis development is normal with the POSCH-2 Y in its native strain background as well as in some strains of the laboratory mouse such as DBA/2J. The phenotype or expression of XY gonadal hermaphroditism in a C57BL/6J strain, which was constructed to be consomic for the POSCH-2 Y, is a threshold trait in which liability is normally distributed and thresholds in the development of the testis define the probability of observing XY embryos with different combinations of ovaries, ovotestes, and testes. The difference in this testis-determining autosomal or Tda trait between the C57BL/6J and DBA/2J strain pair has been demonstrated to be multigenic. We conducted a survey among different strains of the laboratory mouse by test mating females with C57BL/6J.Y-POS males that are consomic for the POSCH-2 Y We identified five groups of strains with significantly different response of XY gonadal hermaphroditism in their XY-POS F1 test embryos. In test embryos, four groups of strains produced gonadal hermaphroditism with different distributions of the types of gonad that appear to have the same variance or shape of a normally distributed liability, but the means of the distributions are at different locations on a scale of gonadal development. The fifth group of strains produced only testes in the test embryos. Several additional matings produced results suggesting that a model of dominance, in the direction of more complete testis development, could interpret the strain differences. The differences in response to the POSCH-2 Y chromosome among the five groups of strains may represent the phenotypes of the genetic recombinants in the Tda trait that were suggested previously by a segregation analysis between C57BL/6J and DBA/2J. The strains may also provide the tools to further dissect the allelic differences and locus determinants of the Tda trait. Key words : mouse, Y chromosome, autosomal testis-determining genes, developmental model of XY gonadal hermaphroditism, primary sex determination.

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