Whether normal somatic cell differentiation generally involves irreversible genetic changes is not known. In vertebrates the only known case of directed DNA rearrangements and nucleotide losses concomitant with cell differentiation occurs in some of the lymphocyte genes. However, this laboratory has shown that nuclei of terminally differentiated frog erythrocytes transplanted into first meiotic oocytes can direct the development of feeding tadpoles, the most extensive development obtained from differentiated nuclei. These results demonstrate genetic multipotentiality and widespread activation of the erythrocyte genome. ln this application we propose to transplant erythrocyte nuclei into diplotene oocytes. It is hypothesized that exposure of the nuclei to the molecular components of this earlier stage will result in chromatin remodeled so as to permit more extensive genomic activation and more advanced development, possibly even fertile frogs. In the same system the developmental potential of the totipotent spermatogonial nucleus will be compared to that of the somatic nucleus. Also, some parameters of the molecular basis of genomic activation in nuclear transplants will be examined by studying hemoglobin types and the effect of reduced methylation. Finally, the diplotene oocyte should provide a system for the rigorous analysis of the molecular mechanisms involved not only in the activation of specific genes, but also of an entire genome. Such knowledge could be applied ultimately to controlling cellular disorders in cancer and aging and to enhancing the limited regeneration in humans.

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National Institute of General Medical Sciences (NIGMS)
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Allegheny University of Health Sciences
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Di Berardino, M A (1997) Jean Brachet Memorial Lecture to the Ninth International Conference of the International Society of differentiation: genomic potential--Acetabularia to mammals. J Cell Physiol 173:119-23
Di Berardino, M A; Orr, N H (1992) Genomic potential of erythroid and leukocytic cells of Rana pipiens analyzed by nuclear transfer into diplotene and maturing oocytes. Differentiation 50:1-13
DiBerardino, M A (1989) Genomic activation in differentiated somatic cells. Dev Biol (N Y 1985) 6:175-98
DiBerardino, M A (1988) Genomic multipotentiality of differentiated somatic cells. Cell Differ Dev 25 Suppl:129-36
Orr, N H; DiBerardino, M A; McKinnell, R G (1986) The genome of frog erythrocytes displays centuplicate replications. Proc Natl Acad Sci U S A 83:1369-73
DiBerardino, M A; Orr, N H; McKinnell, R G (1986) Feeding tadpoles cloned from Rana erythrocyte nuclei. Proc Natl Acad Sci U S A 83:8231-4