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bioRxiv · 10.1101/520536

Fetus-derived IGF2 matches placental development to fetal demand

Sandovici, I.·Georgopoulou, A.·Hufnagel, A. S.·Schiefer, S. N.·Santos, F.·Hoelle, K.·Lam, B. Y. H.·Yeo, G. S. H.·Burling, K.·Lopez-Tello, J.·Reiterer, M.·Fowden, A. L.·Burton, G. J.·Sferruzzi-Perri, A. N.·Branco, C. M.·Constancia, M.
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Abstract

In all eutherian mammals, growth of the fetus is dependent upon a functional placenta, but whether and how the latter adapts to putative fetal signals is currently unknown. Here we demonstrate, through fetal, endothelial, hematopoietic and trophoblast-specific genetic manipulations in the mouse, that endothelial and fetus-derived IGF2 is required for the continuous expansion of the feto-placental microvasculature in late pregnancy. The effects of IGF2 on placental microvasculature expansion are mediated, in part, through IGF2R and angiopoietin-Tie2/TEK signalling. Additionally, IGF2 exerts IGF2R-ERK1/2-dependent pro-proliferative and angiogenic effects on primary feto-placental endothelial cells ex vivo. Endothelial and fetus-derived IGF2 also plays an important role in trophoblast morphogenesis, acting through Gcm1 and Synb. Thus, our study reveals a direct role for the imprinted Igf2-Igf2r axis on matching placental development to fetal growth and establishes the principle that hormone-like signals from the fetus play important roles in controlling placental microvasculature and trophoblast morphogenesis.

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Sandovici, I., Georgopoulou, A., Hufnagel, A. S., Schiefer, S. N., Santos, F., Hoelle, K., Lam, B. Y. H., Yeo, G. S. H., Burling, K., Lopez-Tello, J., Reiterer, M., Fowden, A. L., Burton, G. J., Sferruzzi-Perri, A. N., Branco, C. M., Constancia, M.. 2019-01-16. Fetus-derived IGF2 matches placental development to fetal demand. https://doi.org/10.1101/520536

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