Papers by Elizabeth Fisher
The American Journal of Human Genetics, 2008
Down syndrome (DS) is the most common cause of mental retardation. Many neural phenotypes are sha... more Down syndrome (DS) is the most common cause of mental retardation. Many neural phenotypes are shared between DS individuals and DS mouse models; however, the common underlying molecular pathogenetic mechanisms remain unclear. Using a transchromosomic model of DS, we show that a 30%-60% reduced expression of Nrsf/Rest (a key regulator of pluripotency and neuronal differentiation) is an alteration that persists in trisomy 21 from undifferentiated embryonic stem (ES) cells to adult brain and is reproducible across several DS models. Using partially trisomic ES cells, we map this effect to a three-gene segment of HSA21, containing DYRK1A. We independently identify the same locus as the most significant eQTL controlling REST expression in the human genome. We show that specifically silencing the third copy of DYRK1A rescues Rest levels, and we demonstrate altered Rest expression in response to inhibition of DYRK1A expression or kinase activity, and in a transgenic Dyrk1A mouse. We reveal that undifferentiated trisomy 21 ES cells show DYRK1A-dosesensitive reductions in levels of some pluripotency regulators, causing premature expression of transcription factors driving early endodermal and mesodermal differentiation, partially overlapping recently reported downstream effects of Rest þ/À. They produce embryoid bodies with elevated levels of the primitive endoderm progenitor marker Gata4 and a strongly reduced neuroectodermal progenitor compartment. Our results suggest that DYRK1A-mediated deregulation of REST is a very early pathological consequence of trisomy 21 with potential to disturb the development of all embryonic lineages, warranting closer research into its contribution to DS pathology and new rationales for therapeutic approaches.
Introduction:The Tc1 model is an aneuploid mouse line that stably transmits a human chromosome 21... more Introduction:The Tc1 model is an aneuploid mouse line that stably transmits a human chromosome 21 (Hsa21). Trisomy of this chromosome is the genetic cause of Down syndrome. The Tc1 model has previously been shown to exhibit many of the features found in human Down syndrome, including deficits in synaptic plasticity, congenital heart defects and reduced cerebellar neuron density[1]. Here we undertake the first volumetric study of the Tc1 mouse brain, in order to observe regions affected by the additional chromosome and determine the correspondence to the human condition. Human Down syndrome individuals exhibit marked neurological deficits, the most pronounced being reduction in total brain volume, and a further reduction in the size of the cerebellum as a proportion of total brain volume, here we show that some features are replicated in the Tc1 model, and others not. Methodology: Image acquisition: 14 Tc1 mice and 14 wild-type (WT) littermate controls, age 18-21 weeks, were perfuse-...
Down syndrome (DS) is caused by trisomy of chromosome 21 (Hsa21) and presents a complex phenotype... more Down syndrome (DS) is caused by trisomy of chromosome 21 (Hsa21) and presents a complex phenotype that arises from
abnormal dosage of genes on this chromosome. However, the individual dosage-sensitive genes underlying each
phenotype remain largely unknown. To help dissect genotype – phenotype correlations in this complex syndrome, the first
fully transchromosomic mouse model, the Tc1 mouse, which carries a copy of human chromosome 21 was produced in
2005. The Tc1 strain is trisomic for the majority of genes that cause phenotypes associated with DS, and this freely available
mouse strain has become used widely to study DS, the effects of gene dosage abnormalities, and the effect on the basic
biology of cells when a mouse carries a freely segregating human chromosome. Tc1 mice were created by a process that
included irradiation microcell-mediated chromosome transfer of Hsa21 into recipient mouse embryonic stem cells. Here, the
combination of next generation sequencing, array-CGH and fluorescence in situ hybridization technologies has enabled us
to identify unsuspected rearrangements of Hsa21 in this mouse model; revealing one deletion, six duplications and more
than 25 de novo structural rearrangements. Our study is not only essential for informing functional studies of the Tc1 mouse
but also (1) presents for the first time a detailed sequence analysis of the effects of gamma radiation on an entire human
chromosome, which gives some mechanistic insight into the effects of radiation damage on DNA, and (2) overcomes
specific technical difficulties of assaying a human chromosome on a mouse background where highly conserved sequences
may confound the analysis. Sequence data generated in this study is deposited in the ENA database, Study Accession
number: ERP000439.
Down syndrome (DS) is caused by trisomy of chromosome 21 (Hsa21) and is associated with a number ... more Down syndrome (DS) is caused by trisomy of chromosome 21 (Hsa21) and is associated with a number of deleterious phenotypes, including learning disability, heart defects, early-onset Alzheimer’s disease and childhood leukaemia. Individuals with DS are affected by these phenotypes to a variable extent; understanding the cause of this variation is a key challenge. Here, we review recent research progress in DS, both in patients and relevant animal models. In particular, we highlight exciting advances in therapy to improve cognitive function in people with DS and the significant developments in understanding the gene content of Hsa21. Moreover, we discuss future research directions in light of new technologies. In particular, the useof chromosome engineering to generate new trisomic mouse models and large-scale studies of genotype–phenotype relationships in patients are likely to significantly contribute to the future understanding of DS.
Down syndrome (DS) results from trisomy of human chromosome 21 (Hsa21) and is associated with an ... more Down syndrome (DS) results from trisomy of human chromosome 21 (Hsa21) and is associated with an increased risk of Alzheimer’sdisease (AD). Here, using the unique transchromosomic Tc1 mouse model of DS we investigate the influence of trisomy of Hsa21 on the protein tau, which is hyperphosphorylated in Alzheimer’s disease. We show that in old, but not young, Tc1 mice increased phosphorylation of tau occurs at a site suggested to be targeted by the Hsa21 encoded kinase, dual-specificity tyrosine-(Y)-phosphorylation regulated kinase
1A (DYRK1A). We show that DYRK1A is upregulated in young and old Tc1 mice, but that young trisomic mice may be protected from
accumulating aberrantly phosphorylated tau. We observe that the key tau kinase, glycogen synthase kinase3- (GSK-3) is aberrantly
phosphorylated at an inhibitory site in the aged Tc1 brain which may reduce total glycogen synthase kinase3- activity. It is possible that a similar mechanism may also occur in people with DS.
: Similar axial slices through the same brain imaged after 1 week (left) and 5 weeks (right). SNR... more : Similar axial slices through the same brain imaged after 1 week (left) and 5 weeks (right). SNR is visibly improved in the 5 week image, especially in the regions of the cortex and basal ganglia. Figure 1: (Top) Graph showing timecourse of T 1 reduction in a central basal ganglia region of interest and the cortex. (Bottom) Example T 1 maps from an individual over 5 weeks; (*) map from an individual in our 28-brain study population.
F1000 - Post-publication peer review of the biomedical literature, 2000
F1000 - Post-publication peer review of the biomedical literature, 2000
F1000 - Post-publication peer review of the biomedical literature, 2000
F1000 - Post-publication peer review of the biomedical literature, 2000
F1000 - Post-publication peer review of the biomedical literature, 2000
Hum Genet, 1996
To understand the architecture of the human genome, we need a complete definition of all the repe... more To understand the architecture of the human genome, we need a complete definition of all the repeat sequence families, as these make up the majority of human DNA. We have isolated a small DNA fragment from human chromosome 21 and have used sequence analysis of this fragment to uncover a new low copy repeat element of approximately 300 bp that we term the Mermaid repeat. This repeat is related to, but is different from, the MER12 repeat and is interspersed in the genome. Mermaid family members that we have studied are between 81%-87% identical to our preliminary consensus sequence. Therefore, we have added a new member to the large collection of human repetitive elements. In addition, we have mapped a Mermaid repeat to a telomeric position on the long arm of human chromosome 21, at 21q22.3.
Genomics 24 615 617, 1994
Amer J Hum Genet, 1994
Sperm typing was used to measure recombination fractions among pseudoautosomal markers and the be... more Sperm typing was used to measure recombination fractions among pseudoautosomal markers and the beginning of the X/Y-specific sequences located at the pseudoautosomal boundary. These experiments included primer-extension preamplification and PCR followed by allele typing using gel electrophoresis. A newly developed data-analysis program allowed the construction of the first multipointlinkage sperm-typing map, using results obtained on seven loci from three individuals. The large sample size not only confirmed the increased recombination activity of the pseudoautosomal region but allowed an estimate of interference of recombination to be made. The coefficient of coincidence was calculated to be .26 over a physical distance of only -1,800 kb. The observation of a few sperm presumably resulting from double recombination argues that more than one crossover event can occur in this region during male meiosis.
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Papers by Elizabeth Fisher
abnormal dosage of genes on this chromosome. However, the individual dosage-sensitive genes underlying each
phenotype remain largely unknown. To help dissect genotype – phenotype correlations in this complex syndrome, the first
fully transchromosomic mouse model, the Tc1 mouse, which carries a copy of human chromosome 21 was produced in
2005. The Tc1 strain is trisomic for the majority of genes that cause phenotypes associated with DS, and this freely available
mouse strain has become used widely to study DS, the effects of gene dosage abnormalities, and the effect on the basic
biology of cells when a mouse carries a freely segregating human chromosome. Tc1 mice were created by a process that
included irradiation microcell-mediated chromosome transfer of Hsa21 into recipient mouse embryonic stem cells. Here, the
combination of next generation sequencing, array-CGH and fluorescence in situ hybridization technologies has enabled us
to identify unsuspected rearrangements of Hsa21 in this mouse model; revealing one deletion, six duplications and more
than 25 de novo structural rearrangements. Our study is not only essential for informing functional studies of the Tc1 mouse
but also (1) presents for the first time a detailed sequence analysis of the effects of gamma radiation on an entire human
chromosome, which gives some mechanistic insight into the effects of radiation damage on DNA, and (2) overcomes
specific technical difficulties of assaying a human chromosome on a mouse background where highly conserved sequences
may confound the analysis. Sequence data generated in this study is deposited in the ENA database, Study Accession
number: ERP000439.
1A (DYRK1A). We show that DYRK1A is upregulated in young and old Tc1 mice, but that young trisomic mice may be protected from
accumulating aberrantly phosphorylated tau. We observe that the key tau kinase, glycogen synthase kinase3- (GSK-3) is aberrantly
phosphorylated at an inhibitory site in the aged Tc1 brain which may reduce total glycogen synthase kinase3- activity. It is possible that a similar mechanism may also occur in people with DS.
abnormal dosage of genes on this chromosome. However, the individual dosage-sensitive genes underlying each
phenotype remain largely unknown. To help dissect genotype – phenotype correlations in this complex syndrome, the first
fully transchromosomic mouse model, the Tc1 mouse, which carries a copy of human chromosome 21 was produced in
2005. The Tc1 strain is trisomic for the majority of genes that cause phenotypes associated with DS, and this freely available
mouse strain has become used widely to study DS, the effects of gene dosage abnormalities, and the effect on the basic
biology of cells when a mouse carries a freely segregating human chromosome. Tc1 mice were created by a process that
included irradiation microcell-mediated chromosome transfer of Hsa21 into recipient mouse embryonic stem cells. Here, the
combination of next generation sequencing, array-CGH and fluorescence in situ hybridization technologies has enabled us
to identify unsuspected rearrangements of Hsa21 in this mouse model; revealing one deletion, six duplications and more
than 25 de novo structural rearrangements. Our study is not only essential for informing functional studies of the Tc1 mouse
but also (1) presents for the first time a detailed sequence analysis of the effects of gamma radiation on an entire human
chromosome, which gives some mechanistic insight into the effects of radiation damage on DNA, and (2) overcomes
specific technical difficulties of assaying a human chromosome on a mouse background where highly conserved sequences
may confound the analysis. Sequence data generated in this study is deposited in the ENA database, Study Accession
number: ERP000439.
1A (DYRK1A). We show that DYRK1A is upregulated in young and old Tc1 mice, but that young trisomic mice may be protected from
accumulating aberrantly phosphorylated tau. We observe that the key tau kinase, glycogen synthase kinase3- (GSK-3) is aberrantly
phosphorylated at an inhibitory site in the aged Tc1 brain which may reduce total glycogen synthase kinase3- activity. It is possible that a similar mechanism may also occur in people with DS.