Roles of the imprinted gene lgf2 and paternal duplication of distal chromosome 7 in the perinatal abnormalities of androgenetic mouse chimeras

Mouse chimeras made with androgenetic (two paternal genomes) ova or embryonic stem cells frequently die at the perinatal stage and exhibit a range of defects, the most noticeable being a pronounced overgrowth of rib cartilage. Excess concentrations of IGFII, a potent mitogen, has been suggested to play a major role in these defects, as androgenetic cells possess two active paternal copies of the imprinted Igf2 gene, rather than one inactive maternal and one active paternal copy as in normal cells. Here, we show that chimeras made with androgenetic embryonic stem cells, homozygous for an Igf2 null mutation, do not develop rib cartilage hyperplasia, demonstrating the dependence of this defect on Igf2 activity produced by androgenetic cells. In contrast, in these same chimeras, many other defects, including whole body overgrowth and perinatal death, are still prevalent, indicating that the abnormal expression of one or more imprinted genes, other than Igf2, is also capable of inducing most of the defects of androgenetic chimeras. Many of these genes may reside on distal chromosome 7, as we also show that perinatal chimeras made with embryonic stem cells possessing paternal duplication of distal chromosome 7 exhibit a range of defects similar to those of androgenetic chimeras. The relevance of these findings for the human imprinting-related disorder, Beckwith-Wiedemann syndrome, is discussed.