IGF2: Development, Genetic and Epigenetic Abnormalities

Abstract

In the 30 years since the first report of parental imprinting in insulin-like growth factor 2 (Igf2) knockout mouse models, we have learnt much about the structure of this protein, its role and regulation. Indeed, many animal and human studies involving innovative techniques have shed light on the complex regulation of IGF2 expression. The physiological roles of IGF-II have also been documented, revealing pleiotropic tissue-specific and developmental-stage-dependent action. Furthermore, in recent years, animal studies have highlighted important interspecies differences in IGF-II function, gene expression and regulation. The identification of human disorders due to impaired IGF2 gene expression has also helped to elucidate the major role of IGF-II in growth and in tumor proliferation. The Silver-Russell and Beckwith-Wiedemann syndromes are the most representative imprinted disorders, as they constitute both phenotypic and molecular mirrors of IGF2-linked abnormalities. The characterization of patients with either epigenetic or genetic defects altering IGF2 expression has confirmed the central role of IGF-II in human growth regulation, particularly before birth, and its effects on broader body functions, such as metabolism or tumor susceptibility. Given the long-term health impact of these rare disorders, it is important to understand the consequences of IGF2 defects in these patients.

Keywords: Beckwith–Wiedemann syndrome; IGF2; Silver–Russell syndrome; growth; parental imprinting.

Figure 1

Schematic representation of the modes of action of IGF-II. In the bloodstream, IGF-II is mostly bound in a ternary complex with the acid-labile subunit (ALS) and IGF-binding proteins (IGFBP)-3 and -5. Once released from this complex by PAPP-A2 proteolysis, IGF-II can bind either the type A insulin receptor (INSR-A) or IGF receptor type 1 or 2 (IGF-1R and IGF-2R), inducing cell proliferation or IGF-II clearance.

Figure 2

The human IGF2/H19 11p15.5 locus. (A) The IGF2 and H19 genes are separated by about 80 kb. IGF2 is paternally expressed (blue arrow), whereas H19 is maternally expressed (red arrow). The four DMR (green boxes) and enhancers (yellow ellipses) are represented. (B) H19/IGF2:IG-DMR (ICR1) in detail: OCT4/SOX2 (blue stars) and CTCF (green circles) binding sites on the maternal allele (red), and methylation sites (black lollipops), ZFP57 binding sites (orange stars) and the undefined ZNF445 binding site consensus sequence (purple dash) on the paternal allele (blue) are shown.

Figure 3

(A) Schematic representation of the structure of the IGF2 gene in humans. The IGF2 gene consists of 10 exons and is driven by five different promotors. The exons of the IGF2 gene are boxed. The black boxes indicate non-coding exons. The colored boxes indicate the coding exons. The turned arrows show the promotors (P) and indicate the transcription start sites. The blue lines indicate the differentially methylated regions (DMR) in the IGF2 gene. (B) Transcripts of the human IGF2 gene. IGF2 has six alternative transcripts, depending on promotors and splice sites used. (C) Human IGF-II proteins. IGF-II has two precursor proteins. Only exons 5, 8, 9 and 10 encode IGF-II proteins. Exon 5 is not included in the composition of the second precursor protein, which therefore has a smaller signal peptide. SP: signal peptide; AA: amino acids.

Figure 4

Adapted from Rovina et al. [60]. Three-dimensional representation of the IGF2-H19 locus on the paternal (left) and maternal (right) chromosomes. The ICR1 of the paternal allele is methylated (black lollipops), with enhancers A and B (yellow ellipses) close to the IGF2 promoter; this conformation allows IGF2 expression and H19 repression. The CTCF of the maternal allele can bind the unmethylated ICR1 (green circles), regulating the interaction with DMR1 (green box) and the matrix attachment region (MAR)3 (brown box); the A and B (yellow ellipses) enhancers are close to the H19 promoter. This conformation allows H19 expression and IGF2 repression.

Figure 5

Diagram summarizing the physiological roles of IGF-II described in humans and mouse models.