Placental-specific insulin-like growth factor 2 ( Igf2 ) regulates the diffusional exchange characteristics of the mouse placenta

Abstract

Restricted fetal growth is associated with postnatal mortality and morbidity and may be directly related to alterations in the capacity of the placenta to supply nutrients. We proposed previously that imprinted genes can regulate nutrient supply by the placenta. Here, we tested the hypothesis that the insulin-like growth factor 2 gene (Igf2) transcribed from the placental-specific promoter (P0) regulates the development of the diffusional permeability properties of the mouse placenta. Using mice in which placental-specific Igf2 had been deleted (P0), we measured the transfer in vivo of three inert hydrophilic solutes of increasing size ( 14 C-mannitol, 51 CrEDTA, and 14 C-inulin). At embryonic day 19, placental and fetal weights in P0 conceptuses were reduced to 66% and 76%, respectively, of wild type. In P0 mutants, the permeability⅐surface area product for the tracers at this stage of development was 68% of that of controls; this effect was independent of tracer size. Stereological analysis of histological sections revealed the surface area of the exchange barrier in the labyrinth of the mouse placenta to be reduced and thickness increased in P0 fetuses compared to wild type. As a result, the average theoretical diffusing capacity in P0 knockout placentas was dramatically reduced to 40% of that of wild-type placentas. These data show that placental Igf2 regulates the development of the diffusional exchange characteristics of the mouse placenta. This provides a mechanism for the role of imprinted genes in controlling placental nutrient supply and fetal growth. Altered placental Igf2 could be a cause of idiopathic intrauterine growth restriction in the human.

Hypoxia Regulates the Expression of PHLDA2 in Primary Term Human Trophoblasts

“…Unlike p57 Kip2 or PHLDA2, IGF-II plays an important role in trophoblast proliferation, invasion and migration [48e50], as well as in cell overgrowth conditions such as BeckwitheWiedemann Syndrome or Wilm's tumor [12,51,52]. Consistent with these findings, IGF-II stimulates the development of the diffusional permeability capacity of murine placenta [53]. We found that hypoxia exerts a divergent influence on the expression of PHLDA2, p57…”

The placenta: a multifaceted, transient organ

“…In addition, one of the major benefits of transportermediated exchange is that under adverse conditions the rate can be modulated by altering the number of proteins inserted into the plasma membrane [26]. Thus, if the surface area for exchange is reduced experimentally in mice, or the mother is subjected to undernutrition, placental expression of certain amino acid transporters is increased, enhancing the flux [27,28]. Full details of the signalling pathways involved are not available at present, although experimental data implicate placental Igf2 [29].…”

Placental-specific Igf2 knockout mice exhibit hypocalcemia and adaptive changes in placental calcium transport

“…Although a reduced net flux might result from a number of factors, such as poor maternal nutrition, and therefore reduced maternal plasma concentration of specific solutes, the major cause of FGR in the developed world is placental insufficiency (7). It is now clear that all of the factors that determine the capacity of the placenta to transfer nutrients, including blood flow, exchange of barrier structure, and the activity of specific nutrient transporters, may be abnormal in FGR (8)(9)(10)(11)(12)(13)(14)(15)(16). Recent data suggest (reviewed in ref.…”