Molecular characterization of the translocation breakpoints in the Down syndrome mouse model Ts65Dn.Mamm

The Jackson Laboratory, Genetic Resource Science, ME, 04609, USA.
Mammalian Genome (Impact Factor: 3.07). 09/2011; 22(11-12):685-91. DOI: 10.1007/s00335-011-9357-z
Source: PubMed


Ts65Dn is a mouse model of Down syndrome: a syndrome that results from chromosome (Chr) 21 trisomy and is associated with congenital defects, cognitive impairment, and ultimately Alzheimer's disease. Ts65Dn mice have segmental trisomy for distal mouse Chr 16, a region sharing conserved synteny with human Chr 21. As a result, this strain harbors three copies of over half of the human Chr 21 orthologs. The trisomic segment of Chr 16 is present as a translocation chromosome (Mmu17(16)), with breakpoints that have not been defined previously. To molecularly characterize the Chrs 16 and 17 breakpoints on the translocation chromosome in Ts65Dn mice, we used a selective enrichment and high-throughput paired-end sequencing approach. Analysis of paired-end reads flanking the Chr 16, Chr 17 junction on Mmu17(16) and de novo assembly of the reads directly spanning the junction provided the precise locations of the Chrs 16 and 17 breakpoints at 84,351,351 and 9,426,822 bp, respectively. These data provide the basis for low-cost, highly efficient genotyping of Ts65Dn mice. More importantly, these data provide, for the first time, complete characterization of gene dosage in Ts65Dn mice.

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Available from: Anne Czechanski, Mar 23, 2015
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    • "mice were genotyped by PCR (Fotaki et al., 2002; Guedj et al., 2012) and Ts65Dn mice by PCR (Reinholdt et al., 2011) or by quantitative PCR ( All the experimental procedures were carried out in accordance with the European Union guidelines (Directive 2010/63/EU) and the followed protocols were approved by the ethics committee of the Parc Científic de Barcelona (PCB). "
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    ABSTRACT: Alterations in cerebral cortex connectivity lead to intellectual disability and in Down syndrome, this is associated with a deficit in cortical neurons that arises during prenatal development. However, the pathogenic mechanisms that cause this deficit have not yet been defined. Here we show that the human DYRK1A kinase on chromosome 21 tightly regulates the nuclear levels of Cyclin D1 in embryonic cortical stem (radial glia) cells, and that a modest increase in DYRK1A protein in transgenic embryos lengthens the G1 phase in these progenitors. These alterations promote asymmetric proliferative divisions at the expense of neurogenic divisions, producing a deficit in cortical projection neurons that persists in postnatal stages. Moreover, radial glial progenitors in the Ts65Dn mouse model of Down syndrome have less Cyclin D1, and Dyrk1a is the triplicated gene that causes both early cortical neurogenic defects and decreased nuclear Cyclin D1 levels in this model. These data provide insights into the mechanisms that couple cell cycle regulation and neuron production in cortical neural stem cells, emphasizing that the deleterious effect of DYRK1A triplication in the formation of the cerebral cortex begins at the onset of neurogenesis, which is relevant to the search for early therapeutic interventions in Down syndrome.
    02/2015; 2(2):120-134. DOI:10.1016/j.ebiom.2015.01.010
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    • "In particular, they noted that APP transgenic mice show consistent sleep disturbances in multiple studies (Colas et al. 2004). However, recent findings in Tc1 mice that the final coding exon of APP is rearranged with no human APP protein detectable would argue that loci other than APP contribute to the sleep phenotypes in Down syndrome mutant models (Reinholdt et al. 2011). Although not fully investigated in Tc1 mice, data from human studies and from other mouse models would suggest that rest/activity and rhythm disturbances may arise as a consequence of either generalized synaptic deficits or disturbances in particular brain circuitries. "
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    ABSTRACT: Down syndrome is a common disorder associated with intellectual disability in humans. Amongst a variety of severe health problems, patients with Down syndrome exhibit disrupted sleep and abnormal 24 h rest/activity patterns. The transchromosomic mouse model of Down syndrome, Tc1, is a trans-species mouse model for Down syndrome, carrying most of human chromosome 21 in addition to the normal complement of mouse chromosomes and expresses many of the phenotypes characteristic of Down syndrome. To date, however, sleep and circadian rhythms have not been characterised in Tc1 mice. Using both circadian wheel running analysis and video-based sleep scoring we show that these mice exhibited fragmented patterns of sleep-like behavior during the light phase of a 12:12 h light:dark cycle with an extended period of continuous wakefulness at the beginning of the dark phase. Moreover, an acute light pulse during night time was less effective in inducing sleep-like behavior in Tc1 animals than in wild-type controls. In wheel-running analysis, free running in constant light or constant darkness revealed no changes in the circadian period of Tc1 animals although they did express subtle behavioural differences including a reduction in total distance travelled on the wheel and differences in the acrophase of activity in light:dark and in constant darkness. Our data confirm that Tc1 mice express sleep-related phenotypes that are comparable to those seen in Down syndrome patients with moderate disruptions in rest/activity patterns and hyperactive episodes while circadian period under constant lighting conditions is essentially unaffected.
    Genes Brain and Behavior 01/2015; 14(2). DOI:10.1111/gbb.12198 · 3.66 Impact Factor
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    • "Ts65Dn has an extra freely segregating marker chromosome that is the product of a reciprocal translocation between mouse chromosomes 16 and 17 (Mmu16 and Mmu17). This marker chromosome results in trisomy for over half of the human Chr 21 orthologs carried on Mmu16 and for the centromeric part of Mmu17, which includes 30-40 genes that are homologous to chromosomes other than Hsa21 (Davisson et al., 1993; Reinholdt et al., 2011). The Ts65Dn mice have abnormalities of the cerebellum, hippocampus and craniofacial skeleton that parallel the human DS "
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    ABSTRACT: Hedgehog (HH) signaling, particularly by sonic hedgehog (SHH), is implicated in several essential activities during morphogenesis, and its misexpression causes a number of developmental disorders in humans. In particular, a reduced mitogenic response of cerebellar granule cell precursors to SHH signaling in a mouse model for Down syndrome (DS), Ts65Dn, is substantially responsible for reduced cerebellar size. A single treatment of newborn trisomic mice with an agonist of the SHH pathway (SAG) normalized cerebellar morphology and restored some cognitive deficits, suggesting a possible therapeutic application of SAG for treating the cognitive impairments of DS. While the beneficial effects on the cerebellum are compelling, inappropriate activation of the HH pathway causes anomalies elsewhere in the head, particularly in the formation and patterning of the craniofacial skeleton. To determine whether an acute treatment of SAG has an effect on craniofacial morphology, we quantitatively analyzed the cranial form of adult euploid and Ts65Dn mice that were injected with either SAG or vehicle at birth. We found significant deformation of adult craniofacial shape in some animals that had received SAG at birth. The most pronounced differences between the treated and untreated mice were in the midline structures of the facial skeleton. The SAG-driven craniofacial dysmorphogenesis was dose-dependent and possibly incompletely penetrant at lower concentrations. Our findings illustrate that activation of HH signaling, even with an acute postnatal stimulation can lead to localized dysmorphology of the skull by generating modular shape changes in the facial skeleton. These observations have important implications for translating HH agonist-based treatments for DS.
    Disease Models and Mechanisms 12/2014; 8(3). DOI:10.1242/dmm.017889 · 4.97 Impact Factor
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