Promoter-specific insulin-like growth factor 2 gene imprinting in human fetal liver and hepatoblastoma

ABSTRACT Matemal diabetes is associated in humans and rats with an increased risk for fetal growth abnormalities and malformations. Therefore, the effect of maternal diabetes on expression of genes that regulate fetal growth and differentiation is of considerable interest. Developmental growth is regulated in part by the expression and availability of insulin-like growth factors (IGFs). Postnatal expression of a subset of the IGFs and IGF binding proteins (IGFBPs) has been demonstrated to be regulated in response to diabetes and other metabolic conditions. We used in situ hybridization to analyze the effect of maternal diabetes, induced by streptozotocin (STZ) prior to mating, upon prenatal rat IGF and IGFBP mRNA expression. At gestational day (GD) 14, the most striking effect of maternal diabetes on fetal IGF/IGFBP gene expression was a marked increase in the abundance of IGFBP-1 mRNA within the liver primordia of fetuses isolated from diabetic dams compared to age-matched controls. This upregulation cannot be entirely due to the approximately one-half-day delay in fetal development (based on limb bud staging) associated with maternal diabetes, as there was no gross difference in the level of IGFBP-1 mRNA between GD13 and GD14 control fetal livers. In contrast, the fetal mRNA expression patterns of IGF-I, IGF-II and IGFBP-2, -3, -4, -5 and -6 were not grossly altered by maternal diabetes. These data are consistent with the hypothesis that IGFBP-1 produced within the fetal liver and secreted into fetal circulation may play a role in regulating rat fetal growth.

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Expression levels of the insulin-like growth factor-II gene (IGF2) in the human liver: developmental relationships of the four promoters

Journal of Endocrinology ◽

10.1677/joe.0.1490117 ◽

1996 ◽

Vol 149 (1) ◽

pp. 117-124 ◽

Cited By ~ 41

Author(s):

X Li ◽

H Cui ◽

B Sandstedt ◽

H Nordlinder ◽

E Larsson ◽

...

Keyword(s):

Growth Factor ◽

Human Liver ◽

Fetal Liver ◽

Adult Life ◽

Absolute Amount ◽

Insulin Like Growth Factor ◽

Rnase Protection ◽

Highly Active ◽

Age Related ◽

Factor Ii

Abstract We have studied the insulin-like growth factor-II gene (IGF2) promoter usage in normal human liver from fetal to late adult life by quantifying the specific transcripts by RNase protection assays using exon-specific probes. While the fetal liver uses only three promoters (P2, P3, P4) for the transcription of IGF2, all four promoters can be used from the age of 2 months after birth. The levels of the individual promoter transcripts vary substantially during development and the P3 promoter, which is a highly active fetal promoter, was not used by all the investigated adult patients but was detected in 30% of the adult group as a whole. The PI promoter, which has previously been considered as the only one responsible for IGF2 transcription in the postnatal/adult liver, displayed a trend of increasing relative and absolute activity throughout life, but in some adult cases it was found to be less active than the P4 promoter. The P4 promoter displayed an age-related trend of decreasing activity from a very high fetal level, but individual exceptions were apparent. The P2 promoter transcript, peaking at the age of 2 months, showed a relatively even absolute amount from 18 months onwards. Thus, while P2 and P3 were both found to reach their highest activity after birth, the P4 promoter displayed its highest transcription at the fetal stage. The total IGF2 transcription, primarily from P2, P3 and P4, was found to peak shortly after birth. After this age, the P3 promoter transcript declined most rapidly and a low or zero amount was detected in adulthood. From the age of 18 months to old adulthood the total IGF2 mRNA, derived primarily from P1, P2 and P4, displayed a relatively even amount (approximately one tenth) of that seen at the peak at 2 months. This data may be important in relation to translatability of the various IGF2 transcripts. Journal of Endocrinology (1996) 149, 117–124

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Regulation of insulin-like growth factor binding protein 4 by a specific insulin-like growth factor binding protein 4 proteinase in normal human osteoblast-like cells: Implications in bone cell physiology

Journal of Bone and Mineral Research ◽

10.1002/jbmr.5650090115 ◽

2009 ◽

Vol 9 (1) ◽

pp. 111-117 ◽

Cited By ~ 62

Author(s):

Susan K. Durham ◽

Michael C. Kiefer ◽

Lawrence B. Riggs ◽

Cheryl A. Conover

Keyword(s):

Growth Factor ◽

Binding Protein ◽

Bone Cell ◽

Cell Physiology ◽

Insulin Like Growth Factor ◽

Human Osteoblast ◽

Factor Binding ◽

Normal Human ◽

Normal Human Osteoblast ◽

Specific Insulin

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Intravenous infusion of insulin-like growth factor I in fetal sheep reduces hepatic IGF-I and IGF-II mRNAs

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1996.271.6.r1632 ◽

1996 ◽

Vol 271 (6) ◽

pp. R1632-R1637 ◽

Cited By ~ 3

Author(s):

K. L. Kind ◽

J. A. Owens ◽

F. Lok ◽

J. S. Robinson ◽

K. J. Quinn ◽

...

Keyword(s):

Gene Expression ◽

Skeletal Muscle ◽

Growth Factor ◽

Intravenous Infusion ◽

Feedback Inhibition ◽

Fetal Liver ◽

Plasma Concentrations ◽

Insulin Like Growth Factor ◽

Fetal Sheep ◽

Igf I

Liver contains the highest concentrations of insulin-like growth factor (IGF) I mRNA in adult rats and sheep and is a major source of circulating IGF-I. In rats, inhibition of hepatic IGF-I production by exogenous IGF-I has been reported. In fetal sheep, skeletal muscle and liver are major sites of IGF-I synthesis and potential sources of circulating IGF-I. To determine whether feedback inhibition of IGF gene expression in fetal liver or muscle by IGF-I occurs, IGF-I and IGF-II mRNAs were measured in these tissues after intravenous infusion of recombinant human IGF-I into fetal sheep. Infusion of IGF-I (26 +/- 4 micrograms.h-1.kg-1; n = 6) or saline (n = 6) commenced on day 120 of pregnancy (term = 150 days) and continued for 10 days. Plasma concentrations of IGF-I were threefold higher in infused fetuses at 130 days of gestation (P < 0.0003), whereas those of IGF-II were unchanged. IGF-I infusion reduced the relative abundance of IGF-I mRNA (P < 0.0002) and IGF-II mRNA (P < 0.01) in fetal liver by approximately 50% but did not alter IGF-I or IGF-II mRNA in skeletal muscle. These results indicate that IGF-I inhibits the expression of both IGF-I and IGF-II genes in fetal liver and that IGF gene expression in fetal liver and muscle is differentially regulated by IGF-I.

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Loss of the pregnancy-induced rise in cortisol concentrations in the ewe impairs the fetal insulin-like growth factor axis

Reproduction Fertility and Development ◽

10.1071/rd10317 ◽

2011 ◽

Vol 23 (5) ◽

pp. 665 ◽

Cited By ~ 3

Author(s):

Ellen C. Jensen ◽

Laura Bennet ◽

Charles Wood ◽

Mark Vickers ◽

Bernhard Breier ◽

...

Keyword(s):

Growth Factor ◽

Fetal Growth ◽

Fetal Liver ◽

Plasma Concentrations ◽

Late Gestation ◽

Control Group ◽

Mrna Levels ◽

Insulin Like Growth Factor ◽

Igf I ◽

Low Cortisol

Maternal cortisol levels increase during pregnancy. Although this change is important for optimal fetal growth, the mechanisms of the changes in growth remain unclear. The hypothesis examined was that alterations in maternal plasma cortisol concentrations are associated with changes in the fetal insulin-like growth factor (IGF) axis. Pregnant ewes in late gestation (115 ± 0.4 days) were studied: six control animals, five ewes given 1 mg kg–1 day–1 cortisol (high cortisol) and five adrenalectomised ewes given 0.5–0.6 mg kg–1 day–1 cortisol (low cortisol). Blood samples were taken throughout the experiment and at necropsy (130 ± 0.2 days) and fetal liver was frozen for mRNA analysis. Fetal IGF-I and insulin plasma concentrations were lower and insulin-like growth factor-binding protein-1 (IGFBP-1) concentrations were higher in the low cortisol group compared with those in the control group (P < 0.05). Fetal liver IGF-II and IGFBP-3 mRNA were decreased in low cortisol animals compared with controls (P < 0.05). There were no significant changes in these parameters in the high cortisol group, and there were no changes in fetal liver IGF-I, growth hormone receptor, IGF-I receptor, IGF-II receptor, IGFBP-1 or IGFBP-2 mRNA levels between the groups. These data suggest that reduced fetal IGF availability contributes to reduced fetal growth when maternal cortisol secretion is impaired, but not during exposure to moderate increases in cortisol.

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