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.
|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|
|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|
|Heuzé, Yann; Singh, Nandini; Basilico, Claudio et al. (2014) Morphological comparison of the craniofacial phenotypes of mouse models expressing the Apert FGFR2 S252W mutation in neural crest- or mesoderm-derived tissues. Bone 63:101-9|
|Singh, Nandini (2014) Ontogenetic study of allometric variation in Homo and Pan mandibles. Anat Rec (Hoboken) 297:261-72|
|Das, Ishita; Park, Joo-Min; Shin, Jung H et al. (2013) Hedgehog agonist therapy corrects structural and cognitive deficits in a Down syndrome mouse model. Sci Transl Med 5:201ra120|
|Gutierrez-Castellanos, Nicolas; Winkelman, Beerend H J; Tolosa-Rodriguez, Leonardo et al. (2013) Size does not always matter: Ts65Dn Down syndrome mice show cerebellum-dependent motor learning deficits that cannot be rescued by postnatal SAG treatment. J Neurosci 33:15408-13|
|Haydar, Tarik F; Reeves, Roger H (2012) Trisomy 21 and early brain development. Trends Neurosci 35:81-91|
|Currier, Duane G; Polk, Renita C; Reeves, Roger H (2012) A Sonic hedgehog (Shh) response deficit in trisomic cells may be a common denominator for multiple features of Down syndrome. Prog Brain Res 197:223-36|
|Starbuck, John; Reeves, Roger H; Richtsmeier, Joan (2011) Morphological integration of soft-tissue facial morphology in Down Syndrome and siblings. Am J Phys Anthropol 146:560-8|
|Yang, Annan; Reeves, Roger H (2011) Increased survival following tumorigenesis in Ts65Dn mice that model Down syndrome. Cancer Res 71:3573-81|
Showing the most recent 10 out of 40 publications