Placental overgrowth in mice lacking the imprinted gene lpl

The IpI (Tssc3) gene lies in an extended imprinted region of distal mouse chromosome 7, which also contains the Igf2 gene. Expression of IpI is highest in placenta and yolk sac, where its mRNA is derived almost entirely from the maternal allele. IpI encodes a small cytoplasmic protein with a pleckstrin-homology (PH) domain. We constructed two lines of mice with germ-line deletions of this gene (IpI(neo) and IpI(IoxP)) and another line deleted for the similar but nonimprinted gene Tih1. All three lines were viable. There was consistent overgrowth of the IpI-null placentas, with expansion of the spongiotrophoblast. These larger placentas did not confer a fetal growth advantage; fetal size was normal in IpI nulls with the IpI(neo) allele and was decreased slightly in nulls with the IpI(IoxP) allele. When bred into an Igf2 mutant background, the IpI deletion partially rescued the placental but not fetal growth deficiency. Neither fetal nor placental growth was affected by deletion of Tih1. These results show a nonredundant function for IpI in restraining placental growth. The data further indicate that IpI can act, at least in part, independently of insulin-like growth factor-2 signaling. Thus, genomic imprinting regulates multiple pathways to control placental size.