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Partial Deletion of Pten in the Hypothalamus Leads to Growth Defects that Cannot be Rescued by Exogenous Growth Hormone

Institute of Medical Science (D.C., K.-T.T.N., M.W.) and Department of Medical Biophysics (L.W., S.A.S., T.W.M., M.W.), Ontario Cancer Institute, and The Advanced Medical Discovery Institute (T.W.M.), University of Toronto, Toronto, Ontario, Canada M5G 2M9; Department of Molecular Biology (A.S.), Akita University, School of Medicine, Akita 10-8543, Japan; and Department of Medicine and Keenan Research Centre in the Li Ka Shing Knowledge Institute (M.W.), St. Michael’s Hospital, Toronto, Ontario, Canada M5B 1W8

Address all correspondence and requests for reprints to: Minna Woo, Ontario Cancer Institute, 610 University Avenue, Room 8-113, Toronto, Ontario, Canada M5G 2M9. E-mail: mwoo{at}uhnres.utoronto.ca.

The GH/IGF-I axis plays a critical role in mammalian body growth. GH is secreted by the anterior pituitary, and its actions are primarily mediated by IGF-I that is secreted by the liver and other tissues. Local and circulating IGF-I action is largely mediated by the phosphoinositide 3-kinase signaling pathway, and phosphatase with tensin homology (PTEN) is a potent negative regulator of this pathway. Here we show that RIPcre⁺Pten^fl/fl mice, which exhibit PTEN deletion in insulin-transcribing neurons of the hypothalamus in addition to pancreatic β-cells, result in a small-body phenotype that is associated with an unexpected increase in serum IGF-I levels. We tested whether exogenous GH can override the growth defect in RIPcre⁺Pten^fl/fl mice. Our results showed no significant difference in their growth between the RIPcre⁺Pten^fl/fl mice injected with GH or vehicle. Together, PTEN in the hypothalamic insulin-transcribing neurons plays an essential role in body size determination, and systemic GH cannot overcome the growth defect in these mice.