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Background: The insulin-like growth factor (IGF) system is important for pituitary development and control, with each member of this axis having a specific temporal and spatial expression. Because IGF-binding protein-5 (IGFBP-5) is one of the most highly expressed binding proteins in the anterior pituitary (AP), it might be of special importance in this gland., Objective: The purpose of this study was to examine the temporal relationship between the expression of the IGFs and IGFBP-5 in the AP during postnatal development., Design and Methods: Quantitative reverse transcription polymerase chain reaction was used to study the mRNA levels of these proteins in the AP of male and female rats at 10, 20, 30, 40 and 60 days of age., Results: The highest mRNA levels of IGF-I and II occurred at 10 and 20 days of age with a dramatic decrease at 30 days (p < 0.0001). IGF-I, but not IGF-II, mRNA levels increased again during adulthood (60 days). The pattern of IGFBP-5 mRNA was inversely expressed, with maximum values occurring at 40 days. IGF-I mRNA levels were higher in males at 10 days, but higher in females at 20 days. The expression of IGF-II was higher in males both at 10 and 20 days. IGFBP-5 gene expression was higher in females at 40 days., Conclusion: The dramatic changes in the expression of IGF-I, IGF-II and IGFBP-5 throughout postnatal development suggest that these factors play important roles in the development of this gland and that their actions are highly interrelated., (Copyright 2002 S. Karger AG, Basel)

Unlabelled: Compensatory renal growth in uninephrectomized adult mice is growth hormone dependent., Background: Growth hormone (GH) and insulin-like growth factors (IGFs) have been implicated as pathogenic factors in compensatory renal growth (CRG) following unilateral nephrectomy in rodents. CRG in adult rats has been suggested to be GH dependent and GH independent in immature rats. However, the exact role of GH as a regulating or permissive factor in CRG in adult rodents has not been fully resolved to date., Methods: To elucidate a possible direct, permissive role of GH in CRG, we examined the effect of a newly developed specific GH receptor (GHR) antagonist (G120K-PEG) on kidney IGF-I accumulation and renal/glomerular hypertrophy over seven days after uninephrectomy in adult mice., Results: Placebo-treated uninephrectomized mice were characterized by a transient increase in kidney IGF-I concentration preceding CRG and an increase in glomerular volume. In G120K-PEG-treated uninephrectomized animals, increased kidney IGF-I levels, kidney weight, and glomerular volume were fully abolished. No differences were seen between the two uninephrectomized groups with respect to body weight, food intake, blood glucose, serum GH, IGF-I, or IGFBP-3 levels., Conclusions: The administration of a GHR antagonist in uninephrectomized adult mice has renal effects without affecting circulating levels of GH/IGFs, indicating that the effect of G120K-PEG may be mediated through a direct inhibitory effect on renal IGF-I accumulation through the renal GHR. This study shows, to our knowledge for the first time, that CRG in adult mice is strictly GH dependent.

Insulin-like growth factors (IGF-I and -II) promote cellular mitosis and differentiation and have been implicated in fetal and placental growth. Together with the IGF receptors and IGF binding proteins (IGFBPs) they form a complex network, with tissue specific activity. This review will discuss the data generated to elucidate the functions of the IGF system during mouse development.

During limb development the primary limb bud requires various signals to differentiate. Insulin-like growth factor (IGF)-I and IGF-II serve as ubiquitous cellular growth promoters and are modulated by their binding proteins (IGFBPs), which inhibit or augment IGF bioavailability. This is the first study to give a complete overview of the mRNA expression patterns of Igf-1, Igf-2, type 1 Igf receptor (Igf1r) and six Igf binding proteins (IGFBP-1-6) in embryonic mouse limbs, at various stages of development, by whole mount in situ hybridization (ISH). Our results show that all the members of the Igf system, except Igfbp-1 and -6, have specific spatio-temporal mRNA expression patterns. IGFBP-2 and -5 are found in the apical ectodermal ridge (AER), and IGF-I and IGFBP-4 in the region of the zone of polarizing activity (ZPA). IGF-II and IGF1R are found in regions of pre-cartilage formation. At 13.5 days post coitus (dpc) the IGF system colocalizes with apoptosis areas; IGFBP-2, -4 and -5 are found in the interdigital zone, while IGFBP-3 and IGF-I border this region. Furthermore, IGFBP-3, -4 and -5 are found in the phalangeal joint areas, at an early stage of joint formation. This supports the hypothesis that the IGF system may be involved in chondrogenic differentiation of mesenchyme and the regulation of apoptosis in the developing limb.

The IGF binding proteins (IGFBPs) comprise at least six distinct species which may modulate the action of IGFs. IGFs are important regulators of fetal growth and differentiation. We have studied the mRNA expression of the six IGFBPs during post-implantation embryogenesis (day 11-18) by in situ hybridization techniques. Expression of IGFBP-1 was detected in mouse conceptuses after day 12 of gestation and seemed restricted to the liver. Transcripts for IGFBP-2, -4 and -5 were detected in various tissues and were found in all stages tested. In contrast, expression of IGFBP-3 and -6 could be detected only weakly in late gestational embryos. Comparison of the expression pattern of IGFBP-2, -4 and -5, which were found widely distributed in mouse conceptuses, revealed that IGFBP-2 was expressed mainly in the ectodermal layer and also in the mesoderm derived part of the tongue (day 13.5). Transcripts for IGFBP-4 however, only were detected in the mesoderm derived tissues, whereas expression of IGFBP-5 was restricted to the ectodermal layer. A similar distribution pattern was observed in the lung. In general, expression of IGFBP-2 and -5 was detected in the same cells, whereas IGFBP-4 and -5 were expressed mainly in different cell types. In rodents as in the human there is widespread expression of the genes coding IGFs, the IGFBPs and the receptors during pre- and postimplantation embryogenesis. These data support the assumption that the IGFs play an important role during embryogenesis.

To date six IGF binding proteins (IGFBP) have been characterized. Analysis of the amino acid sequence reveals that the IGFBPs are clearly distinct but are sharing regions with strong homology. Specifically the hydrophobic cysteine rich N-terminal region and to a lesser extend the C-terminal part are preserved. The alignment of the cysteine molecules is strongly conserved across the 6 IGFBPs. The middle one-third region, where no cysteines are present (except for IGFBP-4) is most divergent. IGFBP-3 and -4 are glycosylated, whereas IGFBP-1 and -2 contain an Arg-Gly-Asp sequence near the carboxyl terminus. Determination of the number of free-SH groups of IGFBP-1 and -3 has revealed that most likely all cysteine residues are involved in disulfide bond formation. All members of the IGFBP family bind IGF-I and IGF-II with about equal affinity. Studies involving deletion mutation and site-directed mutagenesis of IGFBP-1 and -3 have suggested that the three-dimensional structure of the protein plays an important role in IGF binding. However at present it is unclear whether the IGFBPs share one or more specific IGF binding domain. The predominant function of the IGFBPs is to allocate IGF in the various body fluid compartments and tissues and to modulate IGF binding to receptors. For this purpose there exists a very sophisticated control of the routing of circulating IGF both from and to the cell. There is mounting evidence that the structure of the IGFBP proteins plays a key role in the regulation of IGF bioavailability, by modulating its molecular size, capillary membrane permeability, target tissue specificity, cell membrane adherence and IGF affinity.

Human genomic clones encompassing the tissue specific expressed gene IBP-1, an insulin-like growth factor binding protein were isolated and characterized. The gene is organized in four exons and spans 5.9 kb. S1 nuclease analysis determined a single transcription start site. The first exon and 5' flanking region are highly GC rich and located in a CpG island. The CpG island enclose the CAAT box, the TATA box, the transcription start site and a potential SP1 transcription factor binding site. The presumptive promoter region is characteristic for genes expressed in a tissue specific fashion. All signals required for cleavage/polyadenylation are located within exon IV, predicting a mRNA of 1.5 kb which is consistent with the size seen on RNA blots.

The purpose of this study was to examine the relation between attributional cognitions, coping behavior, and self-esteem of inpatients with severe spinal cord injuries. Thirty inpatients from rehabilitation centers were interviewed. Their coping behavior was assessed by a physician, a nurse, and a psychologist. The results showed sometimes different tendencies for the recently vs. long-disabled patients with respect to the direction of the relation between attributional cognitions and rehabilitation outcome (coping behavior and self-esteem). Especially noteworthy is the evident adaptiveness in the group of the long-disabled inpatients with regard to being concerned with the causes of the accident and being concerned with the avoidability of the accident that led to the injury, while in the recently disabled group these cognitions are related to nonadaptiveness. To be concerned with the question, "Why did this have to occur to me?" was strongly related for the long-disabled inpatients with poor coping behavior, while this was not the case for the recently disabled.

The breakpoint regions of both translocation products of the (9;22) Philadelphia translocation of CML patient 83-H84 and their normal chromosome 9 and 22 counterparts have been cloned and analysed. Southern blotting with bcr probes and DNA sequencing revealed that the breaks on chromosome 22 occurred 3' of bcr exon b3 and that the 88 nucleotides between the breakpoints in the chromosome 22 bcr region were deleted. Besides this small deletion of chromosome 22 sequences a large deletion of chromosome 9 sequences (greater than 70 kb) was observed. The chromosome 9 sequences remaining on the 9q+ chromosome (9q+ breakpoint) are located at least 100 kb upstream of the v-abl homologous c-abl exons whereas the translocated chromosome 9 sequences (22q-breakpoint) could be mapped 30 kb upstream of these c-abl sequences. The breakpoints were situated in Alu-repetitive sequences either on chromosome 22 or on chromosome 9, strengthening the hypothesis that Alu-repetitive sequences can be hot spots for recombination.