ROLES OF THE IMPRINTED GENE IGF2 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 em bryonic stem cells frequently die at the perinatal stage and exhibit a range of defects, the most noticeable being a pronounced overgrowth o f 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 n ormal cells, Here, we show that chimeras made with androgenetic embryo nic stem cells, homozygous for an Igf2 null mutation, do not develop r ib 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 an d perinatal death, are still prevalent, indicating that the abnormal e xpression of one or more imprinted genes, other than lgf2, is also cap able of inducing most of the defects of androgenetic chimeras. Many of these genes may reside on distal chromosome 7, as we also show that p erinatal chimeras made with embryonic stem cells possessing paternal d uplication of distal chromosome 7 exhibit a range of defects similar t o those of androgenetic chimeras, The relevance of these findings for the human imprinting-related disorder, Beckwith-Wiedemann syndrome, is discussed.