Hematopoietic defects in the Ts1Cje mouse model of Down syndrome

Down syndrome (DS) persons are born with various hematopoietic abnormalities, ranging from relatively benign, such as neutrophilia and macrocytosis, to a more severe transient myeloproliferative disorder (TMD). In most cases, these abnormalities resolve in the first few months to years of life. However, sometimes the TMD represents a premalignant disease that develops into acute megakaryocytic leukemia (AMKL), usually in association with acquired GATA1 mutations. To gain insight into the mechanisms responsible for these abnormalities, we analyzed the hematopoietic development of the Ts1Cje mouse model of DS. Our analyses identified defects in mature blood cells, including macrocytosis and anemia, as well as abnormalities in fetal liver and bone marrow stem and progenitor cell function. Despite these defects, the Ts1Cje mice do not develop disease resembling either TMD or AMKL, and this was not altered by a loss of function allele of Gata1. Thus, loss of Gata1 and partial trisomy of chromosome 21 orthologs, when combined, do not appear to be sufficient to induce TMD or AMKL-like phenotypes in mice.

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Trisomy of Erg is required for myeloproliferation in a mouse model of Down syndrome

Blood ◽

10.1182/blood-2009-09-242107 ◽

2010 ◽

Vol 115 (19) ◽

pp. 3966-3969 ◽

Cited By ~ 45

Author(s):

Ashley P. Ng ◽

Craig D. Hyland ◽

Donald Metcalf ◽

Catherine L. Carmichael ◽

Stephen J. Loughran ◽

...

Keyword(s):

Down Syndrome ◽

Mouse Model ◽

Trisomy 21 ◽

Progenitor Cell ◽

Gene Dosage ◽

Myeloproliferative Disorder ◽

Chromosome 21 ◽

Loss Of Function ◽

Hematologic Disorders ◽

Acute Megakaryocytic Leukemia

Abstract Down syndrome is characterized by multiple phenotypic manifestations associated with trisomy of chromosome 21. The transient myeloproliferative disorder and acute megakaryocytic leukemia associated with Down syndrome are uniquely associated with mutations in the transcription factor GATA1; however, the identity of trisomic genes on chromosome 21 that predispose to these hematologic disorders remains unknown. Using a loss-of-function allele, we show that specific reduction to functional disomy of the Erg gene corrects the pathologic and hematologic features of myeloproliferation in the Ts(1716)65Dn mouse model of Down syndrome, including megakaryocytosis and progenitor cell expansion. Our data provide genetic evidence establishing the need for Erg trisomy for myeloproliferation in Ts(1716)65Dn mice and imply that increased ERG gene dosage may be a key consequence of trisomy 21 that can predispose to malignant hematologic disorders in Down syndrome.

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Hematopoiesis in the Ts65Dn Mouse Model of Down Syndrome (DS) Recapitulates Many Features of Human DS.

Blood ◽

10.1182/blood.v104.11.1122.1122 ◽

2004 ◽

Vol 104 (11) ◽

pp. 1122-1122

Author(s):

Gina Mundschau ◽

Sarah Jilani ◽

Michelle Le Beau ◽

John Crispino

Keyword(s):

Down Syndrome ◽

Mouse Model ◽

Trisomy 21 ◽

Fetal Liver ◽

Hemoglobin Concentration ◽

Chromosome 16 ◽

Ts65dn Mouse ◽

Cd34 Cells ◽

Complete Blood Counts ◽

Acute Megakaryocytic Leukemia

Abstract Down syndrome-associated acute megakaryocytic leukemia (DS-AMKL) is a complex malignancy that evolves in hematopoietic progenitors with trisomy 21 that acquire a somatic mutation in the blood transcription factor GATA1. The mechanistic relationship between these two genetic factors that leads to leukemia is poorly understood. In order to study the interplay between trisomy 21 and GATA1 mutations, we are developing a mouse model of this malignancy. The Ts65Dn mouse, which contains a segmental trisomy for mouse chromosome 16, homologous to human 21, has been reported to display several of the cognitive and craniofacial phenotypes seen in humans with DS, but the hematopoietic system has not been assessed as a model for blood development in humans with DS. We have evaluated adult hematopoiesis in the Ts65Dn strain by comparing monthly complete blood counts (CBC) of peripheral blood from 14 trisomic and 20 disomic littermates. Similar to humans with DS, Ts65Dn trisomic mice display persistent erythrocyte macrocytosis, with values at the high end of the normal range. Trisomic mice also harbor decreased numbers of red blood cells, mildly elevated platelet counts, a higher percentage of monocytes and a lower hemoglobin concentration. Interestingly infants with DS frequently display thrombocytosis. In addition, we have characterized fetal liver hematopoiesis in the Ts65Dn strain by FACS analysis of hematopoietic precursors and by performing colony assays. In general, we did not detect any significant differences in erythroid, myeloid, or megakaryocytic colony formation between trisomic or disomic fetuses. Likewise flow cytometry for CD34, TER119, and CD41 demonstrated overall similar numbers of cells in these compartments for Ts65Dn mice and disomic littermates. However, one of seven trisomic embryos displayed a significant increase in the proportion of CD34+ cells with concomitant decrease in both Ter119+ and CD41+ populations. In addition, cells from this fetal liver gave rise to seven-fold and three-fold increases in BFU-E and CFU-Mk colonies respectively, with no change in the CFU-GM. Although the sample size is small, these findings suggest that a subset of Ts65Dn trisomic fetuses exhibit aberrant hematopoiesis. Taken together, our study indicates that the Ts65Dn trisomic mouse may be an excellent model to study human DS hematopoiesis.

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Ts65Dn, a Mouse Model of Down Syndrome, Exhibits Increased GABAB-Induced Potassium Current

Journal of Neurophysiology ◽

10.1152/jn.00626.2006 ◽

2007 ◽

Vol 97 (1) ◽

pp. 892-900 ◽

Cited By ~ 74

Author(s):

Tyler K. Best ◽

Richard J. Siarey ◽

Zygmunt Galdzicki

Keyword(s):

Down Syndrome ◽

Mouse Model ◽

Hippocampal Neurons ◽

Single Channel ◽

Extra Chromosome ◽

Functional Expression ◽

Chromosome 21 ◽

Fluctuation Analysis ◽

Response Curves ◽

Girk Channel

Down syndrome (DS) is the most common nonheritable cause of mental retardation. DS is the result of the presence of an extra chromosome 21 and its phenotype may be a consequence of overexpressed genes from that chromosome. One such gene is Kcnj6/Girk2, which encodes the G-protein-coupled inward rectifying potassium channel subunit 2 (GIRK2). We have recently shown that the DS mouse model, Ts65Dn, overexpresses GIRK2 throughout the brain and in particular the hippocampus. Here we report that this overexpression leads to a significant increase (∼2-fold) in GABAB-mediated GIRK current in primary cultured hippocampal neurons. The dose response curves for peak and steady-state GIRK current density is significantly shifted left toward lower concentrations of baclofen in Ts65Dn neurons compared with diploid controls, consistent with increased functional expression of GIRK channels. Stationary fluctuation analysis of baclofen-induced GIRK current from Ts65Dn neurons indicated no significant change in single-channel conductance compared with diploid. However, significant increases in GIRK channel density was found in Ts65Dn neurons. In normalized baclofen-induced GIRK current and GIRK current kinetics no difference was found between diploid and Ts65Dn neurons, which suggests unimpaired mechanisms of interaction between GIRK channel and GABAB receptor. These results indicate that increased expression of GIRK2 containing channels have functional consequences that likely affect the balance between excitatory and inhibitory neuronal transmission.

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Partial trisomy 21 map: Ten cases further supporting the highly restricted Down syndrome critical region (HR‐DSCR) on human chromosome 21

Molecular Genetics & Genomic Medicine ◽

10.1002/mgg3.797 ◽

2019 ◽

Vol 7 (8) ◽

Cited By ~ 3

Author(s):

Maria Chiara Pelleri ◽

Elena Cicchini ◽

Michael B. Petersen ◽

Lisbeth Tranebjærg ◽

Teresa Mattina ◽

...

Keyword(s):

Down Syndrome ◽

Human Chromosome ◽

Critical Region ◽

Trisomy 21 ◽

Partial Trisomy ◽

Chromosome 21 ◽

Human Chromosome 21

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A Myeloproliferative Disorder in the Tc1 Mouse Model of Down Syndrome

Blood ◽

10.1182/blood.v112.11.2790.2790 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2790-2790

Author(s):

Kate A. Alford ◽

Lesley Vanes ◽

Zhe Li ◽

Stuart H. Orkin ◽

Elizabeth M. C. Fisher ◽

...

Keyword(s):

Down Syndrome ◽

Mouse Model ◽

Extramedullary Hematopoiesis ◽

Myeloproliferative Disorder ◽

Chromosome 21 ◽

Gene Encoding ◽

Megakaryoblastic Leukemia ◽

Cell Counts ◽

Hematopoietic Disorders

Abstract Down syndrome (DS) children have a one in ten chance of being diagnosed with leukemia within the first ten years of life. Acute megakaryoblastic leukemia (AMKL) is a subtype of acute myeloid leukemia (AML) that accounts for nearly 50% of these leukemias. AMKL is associated with a self-regressing neoplasia found almost exclusively in DS newborns called Transient Myeloproliferative Disorder (TMD). In all cases of TMD and DS-AMKL, leukemic blast cells show mutations in the gene encoding the hematopoietic transcription factor GATA1, resulting in production of a truncated form of the protein called GATA1s. Mutations in GATA1 are not seen in non-DS-AMKL or other DS leukemias and it is clear both trisomy of human chromosome 21 (HSA21) and a mutation in GATA1 are required for the development of both TMD and AMKL. However, it is unknown which genes on HSA21 need to be trisomic in order to predispose an individual with DS to AMKL. Our group has generated mice (termed the Tc1 mice) that contain an almost complete, freely segregating copy of HSA21. These mice display phenotypic features of DS. We have examined adult hematopoiesis in these mice. Blood samples taken from a cohort of Tc1 mice were examined from 4 weeks until 60 weeks of age. Complete blood cell counts show that whilst the mice do not develop leukemia they displayed persistent macrocytosis and had reduced erythrocyte numbers. Crossing the Tc1 mice with mice that express GATA1s protein did not perturb or exacerbate this phenotype. Over the age of 15 months more than 50% of Tc1 mice examined were found to have developed splenomegaly. These mice displayed megakaryocyte hyperplasia and had increased numbers of cells of the erythroid lineage. In vitro colony forming assays demonstrated an increase in the frequency of megakaryocytic and granulocyte-macrophage progenitors in the spleen, consistent with extramedullary hematopoiesis. In the bone marrow, no abnormalities were seen in the lineage-, c-Kit+, Sca1+ (LSK) compartment, however there was a significant increase in the percentage of common myeloid progenitors (CMP) and a corresponding decrease in megakaryocyte-erythrocyte progenitors (MEP). This suggests a possible block in development from CMP to MEP. These data demonstrate defects in hematopoietic development in a proportion of adult Tc1 mice. However, preliminary data suggest that these mice do not develop a neonatal myeloproliferative disorder that is comparable with human TMD. It may be that the phenotype seen in the adult Tc1 mice is due to defects in hematopoietic progenitors that are different to those responsible for development of TMD and DS-AMKL. This mouse model may therefore provide a useful tool to examine the role of HSA21 genes in adult hematopoietic disorders.

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Partial trisomy of chromosome 21 without the Down syndrome phenotype

Prenatal Diagnosis ◽

10.1002/pd.4796 ◽

2016 ◽

Vol 36 (5) ◽

pp. 492-495 ◽

Cited By ~ 7

Author(s):

Mei-Tsz Su ◽

Long-Ching Kuan ◽

Yen-Yin Chou ◽

Shang-Yi Tan ◽

Tsung-Cheng Kuo ◽

...

Keyword(s):

Down Syndrome ◽

Partial Trisomy ◽

Chromosome 21 ◽

Down Syndrome Phenotype

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Gene Expression Profiling in a Mouse Model Identifies Fetal Liver- and Placenta-Derived Potential Biomarkers for Down Syndrome Screening

PLoS ONE ◽

10.1371/journal.pone.0018866 ◽

2011 ◽

Vol 6 (4) ◽

pp. e18866 ◽

Cited By ~ 16

Author(s):

Jeroen L. A. Pennings ◽

Wendy Rodenburg ◽

Sandra Imholz ◽

Maria P. H. Koster ◽

Conny T. M. van Oostrom ◽

...

Keyword(s):

Gene Expression ◽

Down Syndrome ◽

Mouse Model ◽

Gene Expression Profiling ◽

Expression Profiling ◽

Fetal Liver ◽

Potential Biomarkers ◽

Down Syndrome Screening

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Neurodevelopmental wiring deficits in the Ts65Dn mouse model of Down syndrome

10.1101/784314 ◽

2019 ◽

Author(s):

Shruti Jain ◽

Christina A. Watts ◽

Wilson C.J. Chung ◽

Kristy Welshhans

Keyword(s):

Down Syndrome ◽

Corpus Callosum ◽

Mouse Model ◽

Hippocampal Neurons ◽

Anterior Commissure ◽

Axon Growth ◽

Chromosome 21 ◽

Ts65dn Mouse ◽

Hippocampal Commissure ◽

Interhemispheric Connectivity

AbstractDown syndrome is the most common genetic cause of intellectual disability and occurs due to the trisomy of human chromosome 21. Adolescent and adult brains from humans with Down syndrome exhibit various neurological phenotypes including a reduction in the size of the corpus callosum, hippocampal commissure and anterior commissure. However, it is unclear when and how these interhemispheric connectivity defects arise. Using the Ts65Dn mouse model of Down syndrome, we examined interhemispheric connectivity in postnatal day 0 (P0) Ts65Dn mouse brains. We find that there is no change in the volume of the corpus callosum or anterior commissure in P0 Ts65Dn mice. However, the volume of the hippocampal commissure is significantly reduced in P0 Ts65Dn mice, and this may contribute to the impaired learning and memory phenotype of this disorder. Interhemispheric connectivity defects that arise during development may be due to disrupted axon growth. In line with this, we find that developing hippocampal neurons display reduced axon length in vitro, as compared to neurons from their euploid littermates. This study is the first to report the presence of defective interhemispheric connectivity at the time of birth in Ts65Dn mice, providing evidence that early therapeutic intervention may be an effective time window for the treatment of Down syndrome.

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Disfagia fase oral dan faring pada anak sindrom Down

Oto Rhino Laryngologica Indonesiana ◽

10.32637/orli.v48i1.261 ◽

2018 ◽

Vol 48 (1) ◽

pp. 102

Author(s):

Susyana Tamin ◽

Elvie Zulka ◽

Iman Pradana Maryadi ◽

Rahmanofa Yunizaf

Keyword(s):

Down Syndrome ◽

Pediatric Patients ◽

Partial Trisomy ◽

Neck Surgery ◽

Chromosome 21 ◽

Google Scholar ◽

Endoscopic Evaluation ◽

Children With Down Syndrome ◽

Feeding Difficulty ◽

Surgery Department

Latar Belakang: Sindrom Down merupakan kelainan kromosom autosomal yang terjadi akibat trisomi seluruh atau sebagian dari kromosom 21, yang terjadi kurang lebih 1 dari 700 kelahiran hidup. Berbagai studi mendapatkan bahwa gangguan makan (feeding difficulty) dan disfagia merupakan masalah yang umum terjadi dan terkadang persisten pada anak sindrom Down. Tujuan: Memaparkan karakteristik kelainan disfagia fase oral dan fase faring yang dapat timbul pada anak dengan sindrom Down menggunakan instrument pemeriksaan Fiberoptic Endoscopic Evaluation of Swallowing (FEES). Laporan kasus: Dilaporkan 8 pasien anak dengan sindrom Down yang didapatkan dari rekam medis pasien sejak Oktober 2016 hingga September 2017, yang dilakukan pemeriksaan FEES di Poli Endoskopi Bronkoesofagologi Departemen Telinga Hidung Tenggorok-Bedah Kepala Leher (THT-KL) Rumah Sakit Dr. Cipto Mangunkusumo. Metode: Pencarian literatur secara terstruktur dilakukan dengan menggunakan Pubmed, ClinicalKey, Cochrane, dan Google scholar, sesuai dengan pertanyaan klinis berupa bagaimana karakteristik disfagia pada pasien anak dengan sindrom Down melalui pemeriksaan FEES. Pemilihan artikel dilakukan berdasarkan kriteria inklusi dan eksklusi. Hasil didapatkan 1 artikel yang relevan. Hasil: Artikel yang didapat merupakan suatu studi retrospektif yang melaporkan gambaran deskriptif karakteristik disfagia pada anak dengan sindrom Down. Kesimpulan: Kelainan anatomis pada sindrom Down berperan pada terjadinya gangguan makan dan disfagia. ABSTRACTBackground: Down syndrome is an autosomal chromosomal disorder caused by entire or partial trisomy of chromosome 21, which occurs in approximately 1 out of 700 live births. Several studies had found that feeding difficulty and swallowing disorder (dysphagia) are common and persistent problems in children with Down syndrome. Purpose: to describe characteristics of abnormalities that can occur in children with Down syndrome using the Fiberoptic Endoscopic Evaluation of Swallowing (FEES) examination. Case report: 8 Pediatric patients with Down syndrome, obtained from medical record of FEES examination in Endoscopic Bronchoesophagology Clinic of Otorhinolaryngology-Head and Neck Surgery Department (ENT-HNS) Cipto Mangunkusumo Hospital, from October 2016 up to September 2017. Method: A structured literature search was performed using Pubmed, ClinicalKey, Cochrane, and Google scholar, according to clinical question of how the characteristics of dysphagia in pediatric patients with Down syndrome through FEES examination? The selection of articles is based on inclusion and exclusion criteria which resulted in 1 relevant paper. Results: The article obtained was a retrospective study reporting descriptive characteristics of dysphagia in children with Down syndrome. Conclusion: Anatomical abnormalities in children with Down syndrome play a role in eating disorders and dysphagia. Keywords:

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