Trisomy 21 (Down syndrome, DS), is among the most complicated genetic situations compatible with substantial survival. The clinical presentation of DS represents the interaction of many triplicated genes throughout development. Understanding what individual genes do is a necessary component of approaches to therapy for features of Down syndrome, but it is not sufficient. The earlier periods of this award focused on creating and characterizing animal models in which to study DS, supporting assessment of all tissues at all stages of life. In the last award period we used these models and principles to make three significant advances. First, we determined that trisomic mice recapitulate (and predict) structural problems observed in the very small DS cerebellum, defined the timing, cell type, process and growth factor (SHH) responsible for this hypocellularity and then cured it in mice. Second, we provided the first experimental evidence that DS is a neurocristopathy by showing that the craniofacial hypoplasia in DS and in mouse models originates with problems in delamination, migration and proliferation of neural crest cells (NCC) in the first pharyngeal arch. Third, we provided biological evidence to answer a 50 year old statistical argument that people with DS get substantially (90%) less cancer than do euploid individuals and identified a single gene, Ets2, dosage for which is inversely correlated with intestinal tumor number in a model of colon cancer. Because NCC and SHH each affect many (overlapping) aspects of development, we will test the hypothesis that they represent """"""""common denominators"""""""" of DS phenotypes. We will use a pharmacological approach to """"""""cure"""""""" the NCC deficit leading to craniofacial hypoplasia. We have begun a survey of the entire Hsa21 gene set to determine gene dosage effects on early development in zebrafish. We will further characterize gene expression with regard to nuclear compartmentalization, a newly appreciated epigenetic regulatory mechanism. We will define more precisely the mechanism of Ets2 tumor repression, and screen for drugs that might act on this pathway as a prophylactic for cancer in everyone, regardless of ploidy.

Public Health Relevance

Determining how Down syndrome is caused is essential to treat it, so we will use several methods to understand gene effects. We will use information from the last award to ameliorate the characteristic facial appearance in DS mice. People with DS get less cancer and may have fewer strokes and heart attacks, we will determine why that is and apply that information to prevention of these serious health problems in all.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD038384-14
Application #
8606480
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Oster-Granite, Mary Lou
Project Start
2000-03-01
Project End
2016-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
14
Fiscal Year
2014
Total Cost
$562,449
Indirect Cost
$195,126
Name
Johns Hopkins University
Department
Physiology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Singh, Nandini; Dutka, Tara; Reeves, Roger H et al. (2016) Chronic up-regulation of sonic hedgehog has little effect on postnatal craniofacial morphology of euploid and trisomic mice. Dev Dyn 245:114-22
Li, Huiqing; Edie, Sarah; Klinedinst, Donna et al. (2016) Penetrance of Congenital Heart Disease in a Mouse Model of Down Syndrome Depends on a Trisomic Potentiator of a Disomic Modifier. Genetics 203:763-70
Yang, Annan; Currier, Duane; Poitras, Jennifer L et al. (2016) Increased Skin Tumor Incidence and Keratinocyte Hyper-Proliferation in a Mouse Model of Down Syndrome. PLoS One 11:e0146570
Baab, Karen L; Brown, Peter; Falk, Dean et al. (2016) A Critical Evaluation of the Down Syndrome Diagnosis for LB1, Type Specimen of Homo floresiensis. PLoS One 11:e0155731
Potier, Marie-Claude; Reeves, Roger H (2016) Editorial: Intellectual Disabilities in Down Syndrome from Birth and Throughout Life: Assessment and Treatment. Front Behav Neurosci 10:120
Dutka, Tara; Hallberg, Dorothy; Reeves, Roger H (2015) Chronic up-regulation of the SHH pathway normalizes some developmental effects of trisomy in Ts65Dn mice. Mech Dev 135:68-80
Fernandez, Fabian; Reeves, Roger H (2015) Assessing cognitive improvement in people with Down syndrome: important considerations for drug-efficacy trials. Handb Exp Pharmacol 228:335-80
Polk, Renita C; Gergics, Peter; Steimle, Jeffrey D et al. (2015) The pattern of congenital heart defects arising from reduced Tbx5 expression is altered in a Down syndrome mouse model. BMC Dev Biol 15:30
Singh, Nandini; Dutka, Tara; Devenney, Benjamin M et al. (2015) Acute upregulation of hedgehog signaling in mice causes differential effects on cranial morphology. Dis Model Mech 8:271-9
Starbuck, John M; Dutka, Tara; Ratliff, Tabetha S et al. (2014) Overlapping trisomies for human chromosome 21 orthologs produce similar effects on skull and brain morphology of Dp(16)1Yey and Ts65Dn mice. Am J Med Genet A 164A:1981-90

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