Unlike the majority of genes expressed in mammals, imprinted genes are expressed from only one parental allele- which allele depends on the particular gene. Thus the Insulin like growth factor 2 (Igf2) is expressed almost exclusively from the paternal allele, whereas p57Kip2, a CDK inhibitor is expressed from the maternal allele. This form of gene regulation is, among vertebrates, unique to mammals. Why it exists is still unclear. Much evidence has suggested that imprinted genes are involved in regulating cell proliferation and viability. Androgenetic embryos, in which the entire genome is paternal in origin, exhibit overgrowth of the extraembryonic membranes and in increase in fetal size at mid gestation. Parthenogenetic embryos, where the entire genome is maternal in origin show retarded embryonic growth. To facilitate an understanding of imprinting and to identify novel imprinted genes, we established fibroblast lines which are either exclusively androgenetic or parthenogenetic in origin. The lines show diametrically opposite patterns of growth with the androgenetic cells having a shorter cell cycle time, reaching a higher saturation density and forming tumors, whereas the parthenotes senesced and died. Using mouse lines deficient for imprinted genes such as Igf2, one of its receptors, the Igf2r, and p57Kip2 revealed that Igf2 was a major determinant regulating proliferation and viability of these cells.? In addition to these growth studies, we have used these lines to identify novel imprinted genes. Using a suppressive subtractive screen we identified the nuclear receptor cofactor repressor/activator Zac1 and epsilon sarcoglycan as being imprinted genes expressed from the paternal allele, as well as an Est that is strongly expressed in the brain, and is transcribed from the maternal allele. Current studies are centered on determining the function of these genes in development and growth regulation.? We are developing mouse models for a human congenital disease associated with a defect in imprinting called Prader-Willi syndrome. In this condition, newborns are hypotonic, have breathing difficulties and often fail to thrive. Those that survive develop an eating disorder and frequently become obese. The disease is associated with loss of part of the paternal chromosome 15. A homologous region is found on mouse chromosome 7. We recently described the derivation of mice lacking the paternal allele of a gene Necdin located in the Prader-Willi region. Such mice die shortly after birth due to respiratory problems and have mimicked one aspect of Prader-Willi syndrome. Their respiratory physiology is being studied in greater detail to determine the function of Necdin. We are also analyzing the function of another rclosely linked gene to Necdin, Magel2, that is also expressed from the paternal allele in certain key appetite and circadian regulatory areas in the brain.? Overall, a molecular analysis of imprinting will provide insights into the epigenetic control of gene expression, an aspect that is of increasing relevance to understanding the regulation of certain tumor suppressor genes in cancer formation.

Agency
National Institute of Health (NIH)
Institute
Division of Basic Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC010349-06
Application #
7291747
Study Section
(CDBL)
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2005
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
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