REQUIREMENT OF STAT5B FOR SEXUAL DIMORPHISM OF BODY GROWTH-RATES AND LIVER GENE-EXPRESSION

The signal transducer and activator of transcription, STAT5b, has been implicated in signal transduction pathways for a number of cytokines and growth factors, including growth hormone (GH). Pulsatile but not c ontinuous GH exposure activates liver STAT5b by tyrosine phosphorylati on, leading to dimerization, nuclear translocation, and transcriptiona l activation of the STAT, which is proposed to play a key role in regu lating the sexual dimorphism of liver gene expression induced by pulsa tile plasma GH. We have evaluated the importance of STAT5b for the phy siological effects of GH pulses using a mouse gene knockout model. STA T5b gene disruption fed to a major loss of multiple, sexually differen tiated responses associated with the sexually dimorphic pattern of pit uitary GH secretion. Male-characteristic body growth rates and male-sp ecific liver gene expression were decreased to wild-type female levels in STAT5b(-/-) males, while female-predominant liver gene products we re increased to a level intermediate between wild-type male and female levels. Although these responses are similar to those observed in GH- deficient Little mice, STAT5b(-/-) mice are not GH-deficient, suggesti ng that they may be GH pulse-resistant. Indeed, the dwarfism, elevated plasma GH, low plasma insulin-like. growth factor I, and development of obesity seen in STAT5b(-/-) mice are all characteristics of Laron-t ype dwarfism, a human GH-resistance disease generally associated with a defective GH receptor. The requirement of STAT5b to maintain sexual dimorphism of body growth rates and liver gene expression suggests tha t STAT5b may be the major, if not the sole, STAT protein that mediates the sexually dimorphic effects of GH pulses in liver and perhaps othe r target tissues. STAT5b thus has unique physiological functions for w hich, surprisingly, the highly homologous STAT5a is unable to substitu te.