Non-imprinted Igf2r expression decreases growth and rescues the Tme mutation in mice

In the mouse the insulin-like growth factor receptor type 2 gene (Igf2r) is imprinted and maternally expressed. Igf2r encodes a trans-membrane recepto r that transports mannose-6-phosphate tagged proteins and insulin-like grow th factor 2 to lysosomes. During development the receptor reduces the amoun t of insulin-like growth factors and thereby decreases embryonic growth. Th e dosage of the gene is tightly regulated by genomic imprinting, leaving on ly the maternal copy of the gene active. Although the function of Igf2r in development is well established, the function of imprinting the gene remain s elusive. Gene targeting experiments in mouse have demonstrated that the m ajority of genes are not sensitive to gene dosage, and mice heterozygous fo r mutations generally lack phenotypic alterations. To investigate whether r eduction of Igf2r gene dosage by genomic imprinting has functional conseque nces for development we generated a non-imprinted allele In the mouse the i nsulin-like growth factor receptor type 2 gene (Igf2r) is imprinted and mat ernally expressed. Igf2r encodes a trans-membrane receptor that transports mannose-6-phosphate tagged proteins and insulin-like growth factor 2 to lys osomes. During development the receptor reduces the amount of insulin-like growth factors and thereby decreases embryonic growth. The dosage of the ge ne is tightly regulated by genomic imprinting, leaving only the maternal co py of the gene active. Although the function of Igf2r in development is wel l established, the function of imprinting the gene remains elusive. Gene ta rgeting experiments in mouse have demonstrated that the majority of genes a re not sensitive to gene dosage, and mice heterozygous for mutations genera lly lack phenotypic alterations. To investigate whether reduction of Igf2r gene dosage by genomic imprinting has functional consequences for developme nt we generated a non-imprinted allele (R2 Delta), We restored biallelic ex pression to Igf2r by deleting a critical element for repression of the pate rnal allele (region 2) in mouse embryonic stem cells. Maternal inheritance of the R2 Delta allele has no phenotype; however, paternal inheritance resu lts in bialleleic expression of Igf2r, which causes a 20% reduction in weig ht late in embryonic development that persists into adulthood. Paternal inh eritance of the R2 Delta allele rescues the lethality of a maternally inher ited Igf2r null allele and a maternally inherited Tme (T-associated materna l effect) mutation. These data show that the biological function of imprint ing Igf2r is to increase birth weight and they also establish Igf2r as the Tme gene.