Role of imprinted genes in fetal growth

A number of genes affect fetal and early postnatal growth and these fall into different categories (Efstratiadis 1998). We only consider genes as growth controlling (Table 1) if they have a direct effect on fetal size or organ size. We exclude, for example, genes that result in aberrant functioning of the heart leading to poor circulation, which may cause reduced growth. However, in a following section we also consider genes with an indirect effect on growth due to their action in development or function of the placenta, which in turn has an effect on nutrient transfer. More difficult are genes that act in placental differentiation and development before the placenta even begins to function in nutrient transfer. Mutations in these are lethal to the fetus, but more subtle changes might well interfere with nutrient function of the placenta at later stages. The current assessment may therefore require revision in the future.

There is only one major system of interacting growth factors and receptors in the fetus — the insulin (INS) and insulin-like growth factor (IGF) system (Table 1 and Fig. 1). Ignoring various binding proteins that modulate IGF actions in tissues and

TABLE 1 Major growth control genes in the mouse

Gene members (chromosome)

Effect

Phenotype ( loss of function )

The growth hormone pathway

Ghrh (2), Ghrhr (6), Gh (11), Growth-promoting Propi (11), Ghr (15), Pit1 (16)

The insulin (INS) andinsulin-like growth factor (IGF) pathways

Igf2r (l7)

Growth-promoting

Growth-promoting Growth promoting

Growth-promoting

Growth-inhibiting

Growth promoting

Growth promoting Growth-inhibiting

Postnatal growth retardation

Fetal and postnatal growth retardation Fetal growth retardation

Fetal growth retardation; perinatal death

Fetal growth retardation; neonatal lethality

Fetal overgrowth; perinatal death

Fetal growth retardation;

death by p5 Fetal growth retardation

Fetal overgrowth (Paternal Disomy)

Imprinted genes are shown in bold; p15, postnatal day 15; p5, postnatal day 5. (Adapted from Efstratiadis 1998.)

the circulation, the system consists of three ligands (INS, IGF1, IGF2) and four receptors (INSR, IGF1R, IGF2R, receptor X), one of which is a 'scavenging' receptor (IGF2R) and one of which has only been identified genetically so far (receptor X) (Efstratiadis 1998). IGF1 acts mainly on the IGF1R; INS acts mainly on the INSR; IGF2 acts on IGF1R, INSR, IGF2R and receptor X (Fig. 1). IGF1 acts exclusively in the fetus (and postnatally), but the IGF2 system acts both in the fetus and in the placenta. Intriguingly, of these seven components, three are imprinted (Igf2, Ins, Igf2r) and it is thus mainly the IGF2 system that has imprinted components.

On the other hand, of the 45 or so imprinted genes that have been identified so far, seven have been shown by genetic analysis to have an effect on fetal growth as judged by altered birth weights of pups (Table 2).

We propose that additional imprinted genes that affect fetal growth will either turn out to be interacting components of the IGF system (Grb10 is a strong candidate, for example), or will turn out to be genes that act in the placenta and affect nutrient transfer (perhaps Mash2 or placental Igf2, see below).

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