Prader-Willi syndrome is a neurobehavioral disorder characterized by infantile hypotonia, short stature, and neonatal failure to thrive followed by obsessive-compulsive behavior, hyperphagia, and obesity. PWS results from loss of expression of several imprinted genes located at 15q11-13 and can arise from maternal 15q disomy, paternal deletion of a group of PWS genes, or paternal microdeletions removing an imprinting center (IC) necessary for paternal gene expression. We previously created a PWS mouse model by targeted deletion of the IC. Pups bearing a paternal IC deletion exhibit a failure to thrive inevitably leading to death in the first postnatal week. In the previous funding period, we found that death of IC deletion pups born to mothers of some strains survive, finally providing an opportunity to investigate the role of PWS genes in adult, as well as fetal and postnatal stages. The etiology of early postnatal death in PWS-IC deletion mice is complex. While failure to thrive is one cause, respiratory problems caused by Necdin deficiency is also an important factor. Additionally, we have found evidence for multi-locus failure to thrive.
In specific aim 1, we will use complementation by BAC transgenes expressing groups of PWS genes to identify loci involved in failure to thrive and to confirm the role of Necdin in early postnatal death in PWS mouse models. Obesity and underlying hyperphagia are salient aspects of PWS.
Specific aim 2 proposes to explore various conditions to develop obesity in surviving adult PWS mice, and investigate the roles of PWS genes in progression to obesity. A number of imprinted genes are known to be involved in fetal growth. We have recently found that IC deletion embryos have decreased fetal growth and that some PWS genes are expressed in the placenta.
In specific aim 3, we will combine existing PWS models and BAC transgene complementation to test the role of subsets of PWS genes in placental development. We anticipate that this research will significantly contribute to understanding the roles of individual genes in complex PWS traits, refine mouse models of the disease, and provide new insights into growth and obesity.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Genetics of Health and Disease Study Section (GHD)
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Oster-Granite, Mary Lou
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University of Florida
Schools of Medicine
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Rodriguez-Jato, Sara; Shan, Jixiu; Khadake, Jyoti et al. (2013) Regulatory elements associated with paternally-expressed genes in the imprinted murine Angelman/Prader-Willi syndrome domain. PLoS One 8:e52390
DuBose, Amanda J; Smith, Emily Y; Johnstone, Karen A et al. (2012) Temporal and developmental requirements for the Prader-Willi imprinting center. Proc Natl Acad Sci U S A 109:3446-50
Smith, Emily Y; Futtner, Christopher R; Chamberlain, Stormy J et al. (2011) Transcription is required to establish maternal imprinting at the Prader-Willi syndrome and Angelman syndrome locus. PLoS Genet 7:e1002422
Dubose, Amanda J; Smith, Emily Y; Yang, Thomas P et al. (2011) A new deletion refines the boundaries of the murine Prader-Willi syndrome imprinting center. Hum Mol Genet 20:3461-6
DuBose, Amanda J; Johnstone, Karen A; Smith, Emily Y et al. (2010) Atp10a, a gene adjacent to the PWS/AS gene cluster, is not imprinted in mouse and is insensitive to the PWS-IC. Neurogenetics 11:145-51
Leung, Karen N; Vallero, Roxanne O; DuBose, Amanda J et al. (2009) Imprinting regulates mammalian snoRNA-encoding chromatin decondensation and neuronal nucleolar size. Hum Mol Genet 18:4227-38
Johnstone, Karen A; DuBose, Amanda J; Futtner, Christopher R et al. (2006) A human imprinting centre demonstrates conserved acquisition but diverged maintenance of imprinting in a mouse model for Angelman syndrome imprinting defects. Hum Mol Genet 15:393-404
Chamberlain, Stormy J; Johnstone, Karen A; DuBose, Amanda J et al. (2004) Evidence for genetic modifiers of postnatal lethality in PWS-IC deletion mice. Hum Mol Genet 13:2971-7