Selective Alterations in Organ Sizes in Mice with a Targeted Disruption of the Insulin-Like Growth Factor Binding Protein-2 Gene

Abstract

Insulin-like growth factor binding protein 2 (IGFBP-2) is one member of the family of IGF binding proteins believed to have both endocrine functions elicited by modulating serum IGF half-life and transport as well as autocrine/paracrine functions that result from blocking or enhancing the availability of IGFs to bind cell surface receptors. To clarify the in vivo role of IGFBP-2, we have used gene targeting to introduce a null IGFBP-2 allele into the mouse genome. Animals homozygous for the altered allele are viable and fertile, contain no IGFBP-2 mRNA, and have no detectable IGFBP-2 in the adult circulation. Heterozygous and homozygous animals showed no significant differences in prenatal or postnatal body growth. Analyses of organ weights in adult males, however, revealed that spleen weight was reduced and liver weight was increased in the absence of IGFBP-2. In addition, ligand blot analyses of sera from adult IGFBP-2 null males showed that IGFBP-1, IGFBP-3, and IGFBP-4 levels were increased relative to wild-type mice. These results demonstrate that up-regulation of multiple IGFBPs accompanies the absence of IGFBP-2 and that IGFBP-2 has a critical role, either directly or indirectly, in modulating spleen and liver size.

Insulin-like Growth Factor-binding Protein-3 Plays an Important Role in Regulating Pharyngeal Skeleton and Inner Ear Formation and Differentiation

“…Previous studies have shown that most rodent fetal tissues/cell types produce multiple IGFBPs (8 -15). In comparison, there is little overlap in the expression domains of different IGFBPs during zebrafish embryogenesis (5,33,37) (this study). Second, disruption to the expression of one component of the IGF system often influences the expression of other IGF family members in the mouse model (33,52).…”

“…In comparison, there is little overlap in the expression domains of different IGFBPs during zebrafish embryogenesis (5,33,37) (this study). Second, disruption to the expression of one component of the IGF system often influences the expression of other IGF family members in the mouse model (33,52). For instance, it was reported that serum levels of IGFBP-1, -3, and -4 were increased in IGFBP-2 knock-out mice (33).…”

“…Second, altered expression of other IGFBPs may compensate for the loss of IGFBP-3. In support of this view, serum levels of IGFBP-1, -3, and -4 were increased in IGFBP-2 knock-out mice (33). Finally, there exists the possibility of maternal compensation in gene knock-out progeny, via placental circulation.…”

“…Second, disruption to the expression of one component of the IGF system often influences the expression of other IGF family members in the mouse model (33,52). For instance, it was reported that serum levels of IGFBP-1, -3, and -4 were increased in IGFBP-2 knock-out mice (33). The compensatory adjustments in the expression of other IGFBPs may have minimized deleterious effects of the loss of one IGFBP gene.…”

“…Likewise, there was no detectable difference in the mRNA expression pattern of nkx2.5, a cardiac marker, or fli-1, a vascular marker (50), indicating that knockdown of IGFBP-3 did not affect these tissues. Disruptions in the expression of one IGFBP gene in the mouse model has previously been shown to influence the expression of other IGFBP gene family members (33). We therefore carried out in situ hybridization analysis for IGFBP-2 mRNA, a related gene in the IGFBP gene family.…”