A placental growth factor is silenced in mouse embryos by the zinc finger protein ZFP568

Abstract

Insulin-like growth factor 2 (IGF2) is the major fetal growth hormone in mammals. We identify zinc finger protein 568 (ZFP568), a member of the rapidly evolving Kruppel-associated box-zinc finger protein (KRAB-ZFP) family linked primarily to silencing of endogenous retroelements, as a direct repressor of a placental-specific <i>Igf2</i> transcript (designated <i>Igf2-P0</i>) in mice. Loss of <i>Zfp568</i>, which causes gastrulation failure, or mutation of the ZFP568-binding site at the <i>Igf2-P0</i> promoter causes inappropriate <i>Igf2-P0</i> activation. Deletion of <i>Igf2</i> can completely rescue <i>Zfp568</i> gastrulation phenotypes through late gestation. Our data highlight the exquisite selectivity with which members of the KRAB-ZFP family repress their targets and identify an additional layer of transcriptional control of a key growth factor regulating fetal and placental development.