Laron syndrome [growth hormone (GH) insensitivity syndrome] is a hereditary dwarfism resulting from defects in the GH receptor (GHR) gene. GHR deficiency has not been reported in mammals other than humans. Many aspects of GHR dysfunction remain unknown because of ethical and practical limitations in studying humans. To create a mammalian model for this disease, we generated mice bearing a disrupted GHR͞binding protein (GHR͞BP) gene through a homologous gene targeting approach. Homozygous GHR͞BP knockout mice showed severe postnatal growth retardation, proportionate dwarfism, absence of the GHR and GH binding protein, greatly decreased serum insulin-like growth factor I and elevated serum GH concentrations. These characteristics represent the phenotype typical of individuals with Laron syndrome. Animals heterozygous for the GHR͞BP defect show only minimal growth impairment but have an intermediate biochemical phenotype, with decreased GHR and GH binding protein expression and slightly diminished insulin-like growth factor I levels. These findings indicate that the GHR͞BP-deficient mouse (Laron mouse) is a suitable model for human Laron syndrome that will prove useful for the elucidation of many aspects of GHR͞BP function that cannot be obtained in humans.

Members of the cytokine/growth hormone (GH)/prolactin receptor superfamily transduce signals by association and activation of JAK tyrosine kinases. For GH receptor (GHR), both JAK2 and the GHR undergo tyrosine phosphorylation upon GH stimulation. Also, GH has recently been shown to activate the transcription factor STAT5 by tyrosine phosphorylation. In the present study, we demonstrate that GH induces rapid tyrosine phosphorylation of different isoforms of STAT5 in mouse L cells stably transfected with a cDNA encoding porcine GHR (pGHR). In this cell system, STAT5 directly interacts with the GHR in a GH-dependent manner. Additionally, GH-induced tyrosine phosphorylation of STAT5 and the interaction of STAT5 with GHR can be observed in mouse 3T3-F442A cells which express endogenous mouse GHR. Interestingly, when cDNAs encoding the two mouse STAT5 homologs (STAT5A and STAT5B) were individually transfected into mouse L cells expressing pGHR, only STAT5A demonstrated the ability to interact with the pGHR and subsequently underwent GH-dependent tyrosine phosphorylation. STAT5B did not. Therefore, the GH-dependent interaction of a particular STAT5 with tyrosine-phosphorylated GHR may play an important role in GH-mediated signal transduction. The GH receptor (GHR)1 is a member of the cytokine/GH/ prolactin receptor superfamily whose members share homology in the extracellular ligand binding domain (1-5). Members of the superfamily also share a proline-rich motif (Box-1) in the cytoplasmic domain (6, 7). GH binding to GHR has been shown to induce tyrosine phosphorylation and activation of JAK2 tyrosine kinase and tyrosine phosphorylation of GHR itself (8 -13). GH also induces tyrosine phosphorylation of a number of cellular proteins which are known as signal transducers and activators of transcription (STATs), including STAT1, STAT3, and STAT5 (14 -17). These findings suggest that activation of JAK-STAT pathways in response to GH plays an important role in the GH signaling system which leads to GH-induced biological responses.STAT5 was originally purified and cloned from mammary epithelial cells in sheep and identified as a signal transducer that confers the specific biological responses of prolactin (18 -20). It can bind to the promoter sequence of the ␤-casein gene and regulate its expression in response to prolactin. Amino acid sequence analyses revealed that STAT5 shares amino acid sequences with other members in the STAT family and contains a SH2 and a SH3 domain (19). Two mouse STAT5 homologs have been identified (STAT5A and STAT5B) (21). The two proteins share 96% identity at the amino acid level. Recently, ligand binding to a number of the receptors of the cytokine receptor superfamily have been shown to stimulate the tyrosine phosphorylation of STAT5. These include receptors for interleukin (IL)-2, IL-3, IL-5, IL-6, erythropoietin (EPO), leukemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF), oncostatin M (OSM), granulocyte-macrophage colony-stimulating factor, prolactin, and GH (21-27). Moreover,...