However, although these mouse models confirm that the liver is a major contributor to circulating IGF1, a lack of function of liver IGF1 in normal postnatal growth is difficult to establish because of compensatory mechanisms. The view, that liver-derived circulating IGF1 is not required in postnatal body growth was recently advocated by reports documenting normal growth in transgenic mice in which IGF1 production was specifically disrupted in the liver ( Sjogren et al., 1999 Yakar et al., 1999). However, in addition to the systemic activity of liver-derived IGF1, GH may have direct effects on target tissues either without IGF1 mediation, or by controlling local IGF1 synthesis at the level of several organs ( D’Ercole et al., 1984 Lindahl et al., 1987). In line with this hypothesis, GH stimulates the liver production of circulating IGF1 ( Mathews et al., 1986 Roberts et al., 1986) and injection of IGF1 into GH-deficient animals restores body growth ( Guler et al., 1988). Igf1 or IGF1 receptor disrupted mice also have impaired embryonic and postnatal growth, demonstrating that IGFs are involved in this physiological function ( Baker et al., 1993 Liu and LeRoith, 1999).Īccording to the somatomedin hypothesis, liver-derived IGF1 is the main mediator of GH functions ( Liu and LeRoith, 1999 Mathews et al., 1986). Pit1, Prop1 and Ghrhr) impair postnatal growth and lead to dwarfism ( Andersen et al., 1995 Camper et al., 1990 Chandrashekar et al., 1999 Li et al., 1990 Lin et al., 1993 Sornson et al., 1996 Zhou et al., 1997). Mutations in the GH receptor gene or in genes regulating GH cell lineage, or GH synthesis/secretion (i.e. For example, disruption of the T3Rα thyroid hormone receptor ( Thra – Mouse Genome Informatics) results in hypothyroidism and dwarfism ( Fraichard et al., 1997). To unravel the functions of these endocrine signals in growth regulation, mouse genetic approaches have recently been developed. Three main endocrine systems play key roles in postnatal growth: thyroid hormones ( Gauthier et al., 1999 Hsu and Brent, 1998) the GH-IGF1 system ( Lupu et al., 2001) and insulin ( Brogiolo et al., 2001 Tamemoto et al., 1994). Because Hoxa5 and homeogenes of the same paralog group are normally expressed in the liver, the present results raise the possibility that homeoproteins, in addition to their established role during early development, regulate systemic physiological functions. In conclusion, we propose that the impaired growth observed in this transgenic line relates to a liver phenotype best explained by a direct interaction between Hoxa5 and liver-specific Forkhead box transcription factors, in particular FKHR but also Foxa2/HNF3β. This context-dependent physiological interaction probably corresponds to the existence of a direct interaction between Hoxa5 and FKHR and FoxA2/HNF3β, as demonstrated by pull-down experiments achieved either in vitro or after cellular co-expression. In HuF cells, Hoxa5 cooperates with FKHR to dramatically enhance IGFBP1 promoter activity. In HepG2 cells, Hoxa5 has little effect by itself but inhibits the FKHR-dependent activation of the IGFBP1 promoter. We have used several cell lines to investigate a possible physiological interaction of Hoxa5 with the main regulator of IGFBP1 promoter activity, the Forkhead box transcription factor FKHR.
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We show that the Hoxa5 transgene is expressed in the liver of these mice, leading to an overexpression of total (endogenous plus transgene) Hoxa5 mRNA in this tissue. These mice present a liver phenotype illustrated by a 12-fold increase in liver insulin-like growth factor binding protein 1 (IGFBP1) mRNA and a 50% decrease in liver insulin-like growth factor 1 (IGF1) mRNA correlated with a 50% decrease in circulating IGF1. Transgenic mice expressing the homeobox gene Hoxa5 under the control of Hoxb2 regulatory elements present a growth arrest during weeks two and three of postnatal development, resulting in proportionate dwarfism.
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