GENETIC AND FUNCTIONAL-ANALYSIS OF NEURONATIN IN MICE WITH MATERNAL OR PATERNAL DUPLICATION OF DISTAL CHR-2

Functional differences between parental genomes are due to differentia l expression of parental alleles of imprinted genes. Neuronatin (Nnat) is a recently identified paternally expressed imprinted gene that is initially expressed in the rhombomeres and pituitary gland and later m ore widely in the central and peripheral nervous system mainly in post mitotic and differentiating neuroepithelial cells. Nnaf maps to distal chromosome (Chr) 2, which contains an imprinting region that causes m orphological abnormalities and early neonatal lethality. More detailed mapping analysis of Nnat showed that it is located between the T26H a nd T2Wa translocation breakpoints which is, surprisingly, proximal to the reported imprinting region between the T2Wa and T28H translocation breakpoints, suggesting that there may be two distinct imprinting reg ions on distal chromosome 2. To investigate the potential role of Nnaf , we compared normal embryos with those which were PatDp.dist2.T26H (p aternal duplication/maternal deficiency of chromosome 2 distal to the translocation breakpoint T26H) and MatDp.dist2.T26H. Expression of Nna t was detected in the PatDp.dist2.T26H embryos, where both copies of N nat are paternally inherited, and normal embryos but no expression was detected in the MatDp.dist2.T26H embryos with the two maternally inhe rited copies. The differential expression of Nnat was supported by DNA methylation analysis with the paternally inherited alleles being unme thylated and the maternal alleles fully methylated. Although experimen tal embryos appeared grossly similar phenotypically in the structures where expression of Nnat was detected, differences in folding of the c erebellum were observed in neonates, and other more subtle development al or behavioral effects due to gain or loss of Nnat cannot be ruled o ut. (C) 1997 Academic Press.