Insulin-like growth factor (IGF) binding protein-4 is both a positive and negative regulator of IGF activity in vivo.
IGFs are required for normal prenatal and postnatal growth. Although actions of IGFs can be modulated by a family of IGF-binding proteins (IGFBPs) in vitro, these studies have identified a complicated pattern of stimulatory and inhibitory IGFBP effects, so that understanding relevant aspects of IGFBP action in vivo has been limited. Here we have produced a null mutation of one specific IGFBP, IGFBP-4, which is coexpressed with IGF-II early in development. Surprisingly, mutation of IGFBP-4, believed from in vitro studies to be exclusively inhibitory, leads to a prenatal growth deficit that is apparent from the time that the IGF-II growth deficit first arises, which strongly suggests that IGFBP-4 is required for optimal IGF-II-promoted growth during fetal development. Mice encoding a mutant IGFBP-4 protease (pregnancy-associated plasma protein-A), which facilitates IGF-II release from an inactive IGF-II/IGFBP-4 complex in vitro, are even smaller than IGFBP-4 mutant mice. However, the more modest IGFBP-4 growth deficit is completely restored in double IGFBP-4/pregnancy-associated plasma protein-A-deficient mice. Taken together these results indicate not only that IGFBP-4 functions as a local reservoir to optimize IGF-II actions needed for normal embryogenesis, but also establish that IGFBP-4 proteolysis is required to activate most, if not all, IGF-II mediated growth-promoting activity.
Ning
Yun
Y
Department of Neuroscience and Cell Biology, University of Medicine and Dentistry of New Jersey, Piscataway, New Jersey 08854, USA.
Schuller
Alwin G P
AG
Conover
Cheryl A
CA
Pintar
John E
JE
D000818:Animals; D015153:Blotting, Western; D005260:Female; D018507:Gene Expression Regulation, Developmental; D017403:In Situ Hybridization; D018974:Insulin-Like Growth Factor Binding Protein 4 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D008954:Models, Biological; D013002:Somatomedins / Q000378:metabolism*
D018974:Insulin-Like Growth Factor Binding Protein 4; D013002:Somatomedins; D007335:Insulin-Like Growth Factor II