Insulin-like Growth Factor 2 (IGF2) is a peptide hormone structurally similar to insulin. This molecule regulates growth, primarily influencing the earliest stages of life. IGF2 is a primary driver of the rapid cell division and tissue expansion that defines prenatal development. Its function is crucial for establishing an organism’s final size, leading to specialized genetic control mechanisms.
What is IGF2 and How is it Made?
IGF2 is a 67-amino-acid protein synthesized from a larger precursor molecule and processed into its mature, active form. While various tissues produce it, the liver and the placenta are major sites of production. As a mitogen, IGF2 promotes cell proliferation, migration, differentiation, and survival by acting on target cells.
The hormone exerts its effects primarily by binding to the Insulin-like Growth Factor 1 Receptor (IGF-1R), initiating a signaling cascade that stimulates growth. It also binds to the short isoform of the insulin receptor (IR-A), linking it to cell growth pathways. The Insulin-like Growth Factor 2 Receptor (IGF-2R) plays a different role. This receptor binds IGF2 with high affinity but lacks an internal signaling domain, functioning instead as a clearance mechanism to remove excess IGF2 from circulation by targeting it for lysosomal degradation.
The Unique Genetics of IGF2 (Genomic Imprinting)
The IGF2 gene is located on human chromosome 11, subject to a specialized form of gene regulation called genomic imprinting. Unlike most genes, which are expressed from both inherited copies, the IGF2 gene is typically expressed solely from the copy inherited from the father. The maternal copy is actively silenced, ensuring a precise dosage of the growth factor.
This parent-specific gene expression is controlled by an Imprinting Control Region (ICR), a stretch of DNA located near the IGF2 gene. The silencing mechanism involves a process called DNA methylation, where small chemical tags, or methyl groups, are added to the DNA sequence. On the paternal chromosome, the ICR is methylated, which allows the IGF2 gene to be active and produce the growth factor.
Conversely, the maternal ICR remains unmethylated, which allows a protein called CTCF to bind to this region. The binding of CTCF creates a physical barrier, acting as an insulator that blocks the IGF2 gene from accessing necessary enhancer elements, thereby silencing the maternal copy. This reciprocal regulation ensures that only the paternal allele drives the expression of IGF2.
The evolutionary rationale for this unique regulation is explained by the “parental conflict hypothesis.” This theory suggests that paternal genes promote aggressive fetal growth to maximize the offspring’s demand for maternal resources. Maternal genes, however, limit the drain on the mother’s resources to ensure her survival and ability to have future offspring. The imprinted expression of IGF2 (active paternal copy, silent maternal copy) reflects this evolutionary conflict over resource allocation during pregnancy.
Primary Role in Human Development
The primary function of IGF2 occurs during gestation, where it acts as the predominant growth factor controlling overall fetal size and developmental rate. Its levels are typically three to ten times higher than those of IGF-1 in the fetal circulation during late gestation. The molecule provides a constitutive drive for intrauterine growth that is less dependent on immediate nutrient supply than IGF-1.
IGF2’s influence is particularly important in the development of the placenta, the organ responsible for nutrient and waste exchange between the mother and fetus. High levels of the growth factor stimulate placental growth and function, which directly impacts the efficiency of nutrient transfer to the developing fetus. Insufficient IGF2 expression in the placenta leads to reduced placental weight and function, which can restrict fetal growth.
The molecule promotes the proliferation and differentiation of cells across various fetal tissues, ensuring that organs and body structures reach the appropriate size. By controlling fetal growth and placental capacity, IGF2 sets the foundation for prenatal survival and health. Its expression is significantly downregulated in most tissues shortly after birth, indicating its specialized role in the prenatal environment.
IGF2 Dysfunction and Associated Health Conditions
Disruption of the genetic imprinting mechanism controlling IGF2 expression is directly linked to two contrasting congenital growth disorders. The balance of having a single active copy of the gene can be upset, leading to effects on development. These disorders provide clear evidence of the gene’s control over human growth.
Over-expression of IGF2, often resulting from a failure to silence the maternal allele (Loss of Imprinting or LOI), causes both parental copies to be active, leading to an excessive dosage of the growth factor. This over-expression is a major cause of Beckwith-Wiedemann Syndrome (BWS), an overgrowth disorder characterized by a large body size, an enlarged tongue, and an increased risk of specific childhood cancers, such as Wilms tumor.
In contrast, reduced IGF2 expression causes the opposite effect, resulting in growth restriction disorders like Silver-Russell Syndrome (SRS). In many cases of SRS, the reduced expression is caused by an epigenetic error where the paternal IGF2 allele is inappropriately silenced, effectively mimicking the maternal methylation pattern. The subsequent lack of the growth factor leads to severe intrauterine and postnatal growth retardation.
Beyond congenital disorders, the dysregulation of IGF2 expression is a recurrent finding in various adult cancers, where it acts as a proto-oncogene. Loss of imprinting is one of the most common molecular changes observed in tumors, including colorectal, breast, and lung cancers. The resulting overproduction of IGF2 drives uncontrolled cell proliferation and survival, enabling the aggressive growth characteristic of malignant cells.