An improved mouse model of Prader-Willi syndrome

Mammals have two copies of most genes, one copy having been inherited from each parent. While most genes are expressed equally from both parental copies, some genes are expressed from only one parent's copy. Genes involved in Prader-Willi syndrome are normally expressed exclusively from the chromosome inherited from the father, and PWS patients have mutations in their paternally inherited genes. Most PWS patients have large deletions that remove many genes, but some patients have much smaller deletions that leave most PWS genes intact but prevent their expression. These small deletions define a short DNA sequence that controls the expression of all PWS genes. We previously developed an animal model of PWS by creating a similar deletion in the mouse genome. Like PWS infants, pups inheriting this paternal deletion are small, weak, and feed poorly. We used this mouse to investigate how PWS genes are regulated. The results suggest that the controlling element is necessary throughout embryonic development. We now propose to make an improved mouse model to investigate the functions of this element. This model will allow the control element to be deleted later in embryogenesis, thereby establishing when it is required for PWS genes to be expressed. Unlike PWS patients, our current mouse model does not exhibit obesity or constant hunger as adults. This disparity may be due to a severe failure to thrive exhibited by the newborn pups that protects them from becoming obese adults.
To create an improved animal model of adult PWS traits, we would also delete the controlling element very late in embryonic development. This should result in pups that bypass the early failure to thrive, but display adult traits such as obesity and hunger. This would provide a robust animal model in which to investigate the physiology underlying PWS and to test potential treatments.

Research Outcomes:

Temporal and developmental requirements for the Prader-Willi imprinting center. DuBose AJ, Smith EY, Johnstone KA, Resnick JL.  Proc Natl Acad Sci U S A. 109(9):3446-50, 2012.

A new deletion refines the boundaries of the murine Prader-Willi syndrome imprinting center. Dubose AJ, Smith EY, Yang TP, Johnstone KA, Resnick JL. Human Molecular Genetics. 2011 Sep 1;20(17):3461-6.