Reversal Learning Performance in the XY∗ Mouse Model of Klinefelter and Turner Syndromes.
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ABSTRACT:
SUBMITTER: Aarde SM
PROVIDER: S-EPMC6742981 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:In both Turner syndrome (TS) and Klinefelter syndrome (KS) copy number aberrations of the X chromosome lead to various developmental symptoms. We report a comparative analysis of TS vs. KS regarding differences at the genomic network level measured in primary samples by analyzing gene expression, DNA methylation, and chromatin conformation. X-chromosome inactivation (XCI) silences transcription from one X chromosome in female mammals, on which most genes are inactive, and some genes escape from XCI. In TS, almost all differentially expressed escape genes are down-regulated but most differentially expressed inactive genes are up-regulated. In KS, differentially expressed escape genes are up-regulated while the majority of inactive genes appear unchanged. Interestingly, 94 differentially expressed genes (DEGs) overlapped between TS and female and KS and male comparisons; and these almost uniformly display expression changes into opposite directions. DEGs on the X chromosome and the autosomes are coexpressed in both syndromes, indicating that there are molecular ripple effects of the changes in X chromosome dosage. Six potential candidate genes (RPS4X, SEPT6, NKRF, CX0rf57, NAA10, and FLNA) for KS are identified on Xq, as well as candidate central genes on Xp for TS. Only promoters of inactive genes are differentially methylated in both syndromes while escape gene promoters remain unchanged. The intrachromosomal contact map of the X chromosome in TS exhibits the structure of an active X chromosome. The discovery of shared DEGs indicates the existence of common molecular mechanisms for gene regulation in TS and KS that transmit the gene dosage changes to the transcriptome.
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Project description:The secreted molecule fibroblast growth factor 9 (FGF9) plays a critical role in testis determination in the mouse. In embryonic gonadal somatic cells it is required for maintenance of SOX9 expression, a key determinant of Sertoli cell fate. Conditional gene targeting studies have identified FGFR2 as the main gonadal receptor for FGF9 during sex determination. However, such studies can be complicated by inefficient and variable deletion of floxed alleles, depending on the choice of Cre deleter strain. Here, we report a novel, constitutive allele of Fgfr2, hobbyhorse (hob), which was identified in an ENU-based forward genetic screen for novel testis-determining loci. Fgr2hob is caused by a C to T mutation in the invariant exon 7, resulting in a polypeptide with a mis-sense mutation at position 263 (Pro263Ser) in the third extracellular immunoglobulin-like domain of FGFR2. Mutant homozygous embryos show severe limb and lung defects and, when on the sensitised C57BL/6J (B6) genetic background, undergo complete XY gonadal sex reversal associated with failure to maintain expression of Sox9. Genetic crosses employing a null mutant of Fgfr2 suggest that Fgr2hob is a hypomorphic allele, affecting both the FGFR2b and FGFR2c splice isoforms of the receptor. We exploited the consistent phenotype of this constitutive mutant by analysing MAPK signalling at the sex-determining stage of gonad development, but no significant abnormalities in mutant embryos were detected.
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Project description:Tuberous sclerosis is a single-gene disorder caused by heterozygous mutations in the TSC1 (9q34) or TSC2 (16p13.3) gene and is frequently associated with mental retardation, autism and epilepsy. Even individuals with tuberous sclerosis and a normal intelligence quotient (approximately 50%) are commonly affected with specific neuropsychological problems, including long-term and working memory deficits. Here we report that mice with a heterozygous, inactivating mutation in the Tsc2 gene (Tsc2(+/-) mice) show deficits in learning and memory. Cognitive deficits in Tsc2(+/-) mice emerged in the absence of neuropathology and seizures, demonstrating that other disease mechanisms are involved. We show that hyperactive hippocampal mammalian target of rapamycin (mTOR) signaling led to abnormal long-term potentiation in the CA1 region of the hippocampus and consequently to deficits in hippocampal-dependent learning. These deficits included impairments in two spatial learning tasks and in contextual discrimination. Notably, we show that a brief treatment with the mTOR inhibitor rapamycin in adult mice rescues not only the synaptic plasticity, but also the behavioral deficits in this animal model of tuberous sclerosis. The results presented here reveal a biological basis for some of the cognitive deficits associated with tuberous sclerosis, and they show that treatment with mTOR antagonists ameliorates cognitive dysfunction in a mouse model of this disorder.
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Project description:XY C57BL/6J (B6) mice harboring a Mus musculus domesticus-type Y chromosome (Y POS ), known as B6.Y POS mice, commonly undergo gonadal sex reversal and develop as phenotypic females. In a minority of cases, B6.Y POS males are identified and a proportion of these are fertile. This phenotypic variability on a congenic B6 background has puzzled geneticists for decades. Recently, a B6.Y POS colony was shown to carry a non-B6-derived region of chromosome 11 that protected against B6.Y POS sex reversal. Here. we show that a B6.Y POS colony bred and archived at the MRC Harwell Institute lacks the chromosome 11 modifier but instead harbors an ∼37 Mb region containing non-B6-derived segments on chromosome 13. This region, which we call Mod13, protects against B6.Y POS sex reversal in a proportion of heterozygous animals through its positive and negative effects on gene expression during primary sex determination. We discuss Mod13's influence on the testis determination process and its possible origin in light of sequence similarities to that region in other mouse genomes. Our data reveal that the B6.Y POS sex reversal phenomenon is genetically complex and the explanation of observed phenotypic variability is likely dependent on the breeding history of any local colony.
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Project description:Background: In both Turner syndrome (TS) and Klinefelter syndrome (KS) copy number aberrations of the X chromosome lead to various developmental symptoms. To date there has not been a comprehensive and directly comparative analysis of TS vs. KS regarding the changes on the molecular level Methods: We analyzed gene expression patterns with RNA-Seq and DNA methylation patterns with the CpGiant assay in lymphocytes, and chromatin conformation with in situ Hi-C in lymphoblastoid cell lines, from TS and KS patients together with their same gender controls. Results: In TS, differentially expressed escape genes were downregulated but differentially expressed inactive genes were upregulated. In KS, differentially expressed escape genes were upregulated while inactive genes appeared unchanged. Interestingly, 81 differentially expressed genes (DEGs) were associated with both TS and KS, and uniformly displayed expression changes into opposite directions. DEGs on the X chromosome and the autosomes were coexpressed in both TS and KS, indicating that there are molecular ripple effects of the changes in X chromosome dosage that extend to autosomes. Four potentially candidate genes (RPS4X, SEPT6, NKRF and CX0rf57) for KS were identified on Xq. Broad hypomethylation of the X chromosome is observed in TS whereas hypermethylation of chromosome X is present in KS. Only promoters of inactive genes were differentially methylated in both TS and KS while escape genes remained unchanged. The intrachromosomal contact map of the X chromosome in TS was partitioned into two superdomains and exhibited the structure of an active X chromosome. Conclusions: Components of the molecular basis of TS and KS were identified on the levels of the transcriptome and the epigenome, with candidate central genes on Xp for TS and on Xq for KS. The discovery of shared DEGs indicates the existence of common molecular mechanisms for gene regulation in TS and KS that are transmitting the gene dosage changes to the transcriptome.
2020-02-28 | GSE126712 | GEO
Project description:Investigation of abnormal sexual development in companion animals can allow for the elimination of inherited disorders from breeding populations while contributing to the understanding of the complex process of mammalian sexual development and differentiation. A 1-year-old mixed-breed cat, presented for neutering, was tentatively diagnosed as a male with bilateral cryptorchidism. During surgery, the surgeon identified gonads in an ovarian position and a complete bicornuate uterus. Both testicular and ovarian architecture in the gonads and Mullerian and Wolffian duct derivatives were identified histologically. The karyotype was that of a normal male (38,XY), and no causative mutation was identified in the feline SRY coding sequence amplified from genomic DNA. All features of the case were compatible with a diagnosis of SRY-positive 38,XY sex reversal, true hermaphrodite phenotype. To the authors' knowledge, this is the first report of this disorder in a domestic cat.
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Project description:It has become increasingly clear that a larger brain can confer cognitive benefits. Yet not all of the numerous aspects of cognition seem to be affected by brain size. Recent evidence suggests that some more basic forms of cognition, for instance colour vision, are not influenced by brain size. We therefore hypothesize that a larger brain is especially beneficial for distinct and gradually more complex aspects of cognition. To test this hypothesis, we assessed the performance of brain size selected female guppies (Poecilia reticulata) in two distinct aspects of cognition that differ in cognitive complexity. In a standard reversal-learning test we first investigated basic learning ability with a colour discrimination test, then reversed the reward contingency to specifically test for cognitive flexibility. We found that large-brained females outperformed small-brained females in the reversed-learning part of the test but not in the colour discrimination part of the test. Large-brained individuals are hence cognitively more flexible, which probably yields fitness benefits, as they may adapt more quickly to social and/or ecological cognitive challenges. Our results also suggest that a larger brain becomes especially advantageous with increasing cognitive complexity. These findings corroborate the significance of brain size for cognitive evolution.
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Project description:Patients with 46,XY gonadal dysgenesis (GD) exhibit genital anomalies, which range from hypospadias to complete male-to-female sex reversal. However, a molecular diagnosis is made in only 30% of cases. Heterozygous mutations in the human FGFR2 gene cause various craniosynostosis syndromes including Crouzon and Pfeiffer, but testicular defects were not reported. Here, we describe a patient whose features we would suggest represent a new FGFR2-related syndrome, craniosynostosis with XY male-to-female sex reversal or CSR. The craniosynostosis patient was chromosomally XY, but presented as a phenotypic female due to complete GD. DNA sequencing identified the FGFR2c heterozygous missense mutation, c.1025G>C (p.Cys342Ser). Substitution of Cys342 by Ser or other amino acids (Arg/Phe/Try/Tyr) has been previously reported in Crouzon and Pfeiffer syndrome. We show that the 'knock-in' Crouzon mouse model Fgfr2c(C342Y/C342Y) carrying a Cys342Tyr substitution displays XY gonadal sex reversal with variable expressivity. We also show that despite FGFR2c-Cys342Tyr being widely considered a gain-of-function mutation, Cys342Tyr substitution in the gonad leads to loss of function, as demonstrated by sex reversal in Fgfr2c(C342Y/-) mice carrying the knock-in allele on a null background. The rarity of our patient suggests the influence of modifier genes which exacerbated the testicular phenotype. Indeed, patient whole exome analysis revealed several potential modifiers expressed in Sertoli cells at the time of testis determination in mice. In summary, this study identifies the first FGFR2 mutation in a 46,XY GD patient. We conclude that, in certain rare genetic contexts, maintaining normal levels of FGFR2 signaling is important for human testis determination.
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