Control of Fetal Growth by Genomic Imprinting

Wolf Reik
Laboratory of Developmental Genetics and Imprinting; The Babraham Institute

Imprinted genes have important roles in normal development and disease, particularly in the control of fetal growth, placental development, and behaviour after birth. We are particularly interested in the local and regional regulation of one of the more prominent imprinting clusters on chromosome 11p15.5 in human and chromosome distal 7 in mouse. In mouse we have completely cloned and characterized the cluster which contains at least 8 imprinted genes with dramatic effects on fetal growth and cell proliferation. In the human the cluster is associated with the fetal overgrowth and cancer syndrome, Beckwith-Wiedemann syndrome. In this syndrome, the otherwise imprinted insulin like growth factor 2 gene (IGF2) is frequently biallelically expressed. We have demonstrated that transgenic expression of Igf2 leads to many of the symptoms of BWS. The control of IGF2 imprinting and expression is therefore crucial. We have made new mutations, one by Cre loxP mediated knockout and one by radiation mutagenesis, that affects Igf2 imprinting and expression. The radiation induced mutation results in methylation of H19, a neighboring imprinted gene which is involved in the control of Igf2 imprinting. The Cre loxP knockout deletes a placental specific control region and results in a specific form of intrauterine growth retardation.