Infants with Prader-Willi syndrome (PWS) often suffer failure to thrive that gives way to obesity and excessive eating (hyperphagia) during early childhood. The syndrome is due to the absence of several genes on chromosome 15. Animal models can be used to investigate the etiology of the syndrome and to test potential therapies. Several mutations affecting individual genes involved in Prader-Willi syndrome have been engineered into the mouse in order develop a mouse model. These mutations have resulted in mice that have the traits of obesity or hyperphagia, but to date no animal model has shown both traits. Surprisingly, other PWS models that show neonatal failure to thrive lack both traits of hyperphagia and obesity. In our first year of funding, we created a mouse mutation that should allow PWS genes to be shut off at various times or in select tissues. We anticipate that delayed appearance of the mutation will lead to bypass the neonatal failure to thrive in the newborn mice. In the second year, we propose to test the effects of delayed triggering the mutation. We will determine the best time at which to trigger the mutation, and then determine if this delay leads to a model that exhibits hyperphagia and obesity. To optimize the usefulness of this model, we will also begin to transfer this conditional mutation onto the strain of mouse most widely used in obesity studies.
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.
James Resnick, Ph.D.
University of Florida