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.
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.
|Smith-Hicks, Constance L; Cai, Peiling; Savonenko, Alena V et al. (2017) Increased Sparsity of Hippocampal CA1 Neuronal Ensembles in a Mouse Model of Down Syndrome Assayed by Arc Expression. Front Neural Circuits 11:6|
|Xiao, Mei-Fang; Xu, Desheng; Craig, Michael T et al. (2017) NPTX2 and cognitive dysfunction in Alzheimer's Disease. Elife 6:|
|Starbuck, John M; Cole 3rd, Theodore M; Reeves, Roger H et al. (2017) The Influence of trisomy 21 on facial form and variability. Am J Med Genet A 173:2861-2872|
|Xiang, Jianxing; Yang, Su; Xin, Ning et al. (2017) DYRK1A regulates Hap1-Dcaf7/WDR68 binding with implication for delayed growth in Down syndrome. Proc Natl Acad Sci U S A 114:E1224-E1233|
|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|
|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|
|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|
|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|
|Burnicka-Turek, Ozanna; Steimle, Jeffrey D; Huang, Wenhui et al. (2016) Cilia gene mutations cause atrioventricular septal defects by multiple mechanisms. Hum Mol Genet 25:3011-3028|
|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|
Showing the most recent 10 out of 55 publications