The gene the parents fight over

This reference has told the IGF-1 story several ways — as the accelerator the growth-hormone axis works through, and as the molecule whose half-life the vendor pages get backwards. IGF-1 has a sibling, nearly identical in shape and name: IGF-2. It is, by most measures, the stranger and in some ways the more important of the two — the dominant growth factor before birth, and the more abundant IGF in adult human blood. Yet it is rarely discussed, because it plays by rules that have nothing to do with the growth-hormone axis.

IGF-2 is governed by something far older and odder: a genetic tug-of-war between the two parents, written into the gene itself. It is expressed from only one parent’s copy, buffered by a receptor whose only job is to destroy it, and capable of signaling growth through the insulin receptor. Three unusual facts, and each one is a window into how growth is controlled before the familiar hormones ever take over. Bullish on the science, which here is genuinely strange.

Start with the strangest fact. Almost every gene you carry is expressed from both copies — the one from your mother and the one from your father. IGF2 is not. In most tissues, only the paternally inherited copy is switched on; the copy from the mother is chemically silenced, marked according to which parent it came from. This is genomic imprinting, and IGF-2 is its textbook example.

The proof is clean and comes from mice. Knock out the father’s copy of Igf2 and the pups are born small, because the active copy is gone; knock out the mother’s copy and nothing changes, because it was silent anyway (DeChiara et al., Cell, 1991). Same gene, same mutation, opposite consequences, decided entirely by which parent it was inherited from. That asymmetry is not a quirk. It is a clue to a conflict.

Why would evolution ever silence one parent’s copy of a growth gene? The most compelling answer is that the two parents’ genetic interests do not align over how much a fetus should draw from its mother (Moore & Haig, Trends Genet, 1991). A father’s genes benefit from a larger, more demanding offspring that extracts maximal resources now — he may not be the father of the mother’s next child. The mother’s genes benefit from restraint, rationing any single pregnancy to preserve her for the ones to come. Growth before birth becomes a negotiation between those two interests.

And IGF-2 is where the negotiation is written down. The paternally expressed IGF2 gene is the accelerator — push for growth. Its main clearance receptor, the IGF-2/mannose-6-phosphate receptor, is maternally expressed — the brake that removes IGF-2 from circulation. The father’s allele makes the growth signal; the mother’s allele makes the thing that destroys it. The parental conflict is not a metaphor laid over the biology; it is literally encoded as two oppositely imprinted genes pulling in opposite directions on the same axis.

That clearance receptor is worth dwelling on, because it breaks the usual rule that a receptor exists to pass a message along. IGF-2 has three. Two of them signal growth: the IGF-1 receptor, and — distinctively — the A isoform of the insulin receptor, which gives IGF-2 a route to growth signaling that bypasses IGF-1R entirely. This is why IGF-2 carries an insulin-like punch that IGF-1 does not.

The third, the IGF-2/mannose-6-phosphate receptor, signals nothing. It binds IGF-2 and routes it for degradation — a non-signaling sink that sets how much hormone is available by removing the excess. A receptor that regulates its ligand by destroying it is a genuine rarity, and it is no accident that this is the one the mother’s genome keeps switched on. The brake in the tug-of-war is a molecular trash chute, and the whole system’s balance is the difference between how fast the accelerator makes IGF-2 and how fast the chute clears it.

A system held in tension by opposing imprinted genes fails in both directions, and the failures are instructive. Tip it toward too much IGF-2 — by losing the imprinting that silences the maternal copy, so both copies fire — and you get overgrowth: Beckwith-Wiedemann syndrome, with its oversized babies and raised tumor risk. Tip it the other way, toward too little, and you get the growth restriction of Silver-Russell syndrome. The same dial, read from both ends. Loss of IGF2 imprinting is also common in cancer, where reactivating a silenced growth signal is exactly the wrong thing to do.

The adult clinical face is stranger still. Some tumors secrete an incompletely processed form of IGF-2 — “big IGF-2” — in enough quantity to overwhelm the buffering system and spill onto insulin receptors, dropping blood sugar. The result is non-islet-cell tumor hypoglycemia, recognizable by a low insulin and low IGF-1 alongside a raised IGF-2/IGF-1 ratio (systematic review, 2024). It is the fetal growth factor’s insulin-like power, unleashed in an adult, reading out not as growth but as a crashing glucose.

Set the two insulin-like growth factors side by side and the division of labor is almost poetic. IGF-1 is the postnatal growth factor, obedient to the growth-hormone axis, the one the muscle and anti-aging stories are built on. IGF-2 is the prenatal one, deaf to growth hormone and answerable instead to a parental tug-of-war older than the endocrine system itself — signaling through a borrowed insulin receptor and buffered by a receptor that only destroys. The sibling that grew first turns out to be the one that reveals how strange the control of growth really is.

• IGF-2 is the prenatal growth factor. The dominant IGF before birth and the more abundant one in adult blood — but governed by imprinting, not the GH axis that runs IGF-1.
• It is expressed from only the father's copy. Genomic imprinting silences the maternal allele. Mouse knockouts prove it: lose the paternal copy and growth fails; lose the (silent) maternal copy and nothing happens.
• The imprinting encodes a parental tug-of-war. Paternal genes favor a bigger offspring; maternal genes favor restraint. IGF2 (paternal) is the accelerator; its clearance receptor IGF2R (maternal) is the brake — conflict written as two genes.
• Three receptors — one only destroys. IGF-2 signals growth through IGF-1R and insulin receptor isoform A (bypassing IGF-1R), while the IGF-2/M6P receptor is a non-signaling sink that clears it.
• The balance breaks both ways. Too much (loss of imprinting) → overgrowth (Beckwith-Wiedemann) and cancer; too little → Silver-Russell; tumor-secreted 'big IGF-2' → hypoglycemia. Every disorder is the dial tipping.