Partial deletion of Pten in the hypothalamus leads to growth defects that cannot be rescued by exogenous growth hormone.
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+Ptenfl/fl mice, which exhibit PTEN deletion in insulin-transcribing neurons of the hypothalamus in addition to pancreatic beta-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+Ptenfl/fl mice. Our results showed no significant difference in their growth between the RIPcre+Ptenfl/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.
Choi
Diana
D
Institute of Medical Science, Ontario Cancer Institute, 610 University Avenue, Room 8-113, Toronto, Ontario, Canada M5G 2M9.
Nguyen
Kinh-Tung T
KT
Wang
Linyuan
L
Schroer
Stephanie A
SA
Suzuki
Akira
A
Mak
Tak W
TW
Woo
Minna
M
D000818:Animals; D049628:Body Size / Q000235:genetics; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D006130:Growth Disorders / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D013006:Growth Hormone / Q000627:therapeutic use*; D007031:Hypothalamus / Q000378:metabolism*; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000097:blood / Q000235:genetics / Q000378:metabolism; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood / Q000235:genetics / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D017211:Treatment Failure
D007328:Insulin; D018970:Insulin-Like Growth Factor Binding Protein 1; D018972:Insulin-Like Growth Factor Binding Protein 3; D012333:RNA, Messenger; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse