Activation of Dormant Genes in Specialized Cells

DiBerardino, Marie A.; Hoffner, Nancy J.; Etkin, Laurence D.

doi:10.1126/science.6719127

Cited by 84 publications

(15 citation statements)

References 74 publications

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“…Although the functional diversity of mammalian lymphocytes is due to DNA rearrangements (2), other specialized somatic cell types that do not require phenotypic diversity in metazoans may retain the same genomic repertoire and arrangement of DNA sequences as the zygote nucleus. Thus, genetic totipotency of some somatic specialized cell types still remains a possibility because the activation of dormant genes in specialized cells is a relatively common phenomenon, that has been consistently demonstrated in several experimental systems (33).…”

Section: Discussionmentioning

confidence: 99%

Feeding tadpoles cloned from Rana erythrocyte nuclei.

DiBerardino¹,

Orr²,

McKinnell³

1986

Proc. Natl. Acad. Sci. U.S.A.

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Diploid frog nuclei from differentiated somatic cells, transplanted into enucleated eggs to determine whether cell specialization generally involves irreversible genetic changes, have shown that nuclei from specialized somatic cells still contain the genes specifying the cell types and organ systems of swimming tadpoles. However, those tadpoles failed to feed and did not survive beyond the initial tadpole stages. Here we report that, after incubation in oocytes, triploid erythrocyte nuclei from juvenile frogs of Rana pipwns directed the formation of feeding tadpoles that survived up to a month and had differentiated hind limb buds. These tadpoles occurred at a high yield and showed the most extensive development so far obtained from documented differentiated somatic nuclei.Whether or not cell specialization generally involves irreversible genetic changes has not been determined. In principle, DNA losses would be irreversible, but at the present time these losses occur as a regular event in only a few species, e.g., in some protozoans, nematodes, and insects (1), as well as in the genetic rearrangement of mammalian immunoglobulin genes (2). However, it has not yet been shown that nuclei of specialized somatic cell types are genetically totipotent.A rigorous test of the gene content in cells is to transfer a living nucleus into an enucleated egg and allow development to proceed. The extent of development and differentiation that ensues reveals the gene content present in the transplanted nucleus. Such experiments were performed originally with early embryonic nuclei in the anuran amphibian Rana pipiens (3, 4) and later extended to other species (reviewed in refs. 5-8). Since normal adults developed, these results signified that all the genes required for normal development are present and functional in young embryonic nuclei.In later years numerous heroic attempts were made to test the developmental potential of frog nuclei from specialized somatic tissues of Xenopus laevis. Three metamorphosed frogs were obtained from nuclei ofcells cultured from minced hatching tadpoles (9). Also one metamorphosed (10) and two fertile frogs (11) were derived from nuclei of larval intestine. However, the interpretation of these results remained equivocal, because the technical procedures at that time precluded distinction between undifferentiated stem cells and differentiated cells in the tissues employed. Later, procedures became available for estimating the purity of the donor cell population, and evidence has now been accumulated that some specialized diploid somatic nuclei can direct the formation of swimming tadpoles. These cases include adult nuclei from Xenopus skin (12), spleen cells (13), and embryonic myotome cells tested in eggs (14), as well as adult erythrocyte nuclei tested in Rana oocytes (15). In all these cases, the nuclear transplant tadpoles constructed the various organ systems, tissues, and cell types normally found in tadpoles, thus demonstrating the important conclusion that at least some of the tes...

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Section: Discussionmentioning

confidence: 99%

Feeding tadpoles cloned from Rana erythrocyte nuclei.

DiBerardino¹,

Orr²,

McKinnell³

1986

Proc. Natl. Acad. Sci. U.S.A.

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“…The factor(s) responsible for the switching off of hepatocyte lineage during the development may be removed as a result of massive pancreatic acinar cell depletion, thus enabling duct cells to proliferate and change their com- Mechanism o f Hepatocyte Transformation. The sta bility of the differentiated state is dependent on contin uous interaction between the DNA and its microenvi ronment, DNA alterations and cell-cell interactions [35,36], The development of hepatocytes in rats is probably multifactorial. In the copper-deficient diet model, con version to hepatocytes in the pancreas may be due to global necrosis of acinar cells, thus disturbing cell-cell interaction.…”

Section: Pancreatic Hepalocyle Cell Lineage: Plasticity O F Exocrine mentioning

confidence: 99%

Differentiation and Cell Proliferation Patterns in Rat Exocrine Pancreas: Role of Type I and Type II Injury

Ms¹,

Av²,

Jk³

1990

Pathobiology

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Fully differentiated and functionally specialized acinar cells of the rat pancreas are versatile and adaptable. Acinar cells can be stimulated to divide following administration of a mitogen or after inducing acinar cell necrosis. The degree of compensatory hyperplasia is dependent upon the extent of acinar cell necrosis. Type I injury (subtotal acinar cell necrosis) is followed by marked proliferation of acinar cells leading to complete restitution of the pancreas, whereas subsequent to type II injury (global acinar cell necrosis) there is no restitution of the pancreas because of lack of enough viable cells that have served as precursor cells. Associated with type II injury there is proliferation of ductular and periductular cells followed by the development of hepatocytes. In addition, during adverse conditions acinar cells undergo dedifferentiation and form pseudoductular structures. In rats, acinar tissue is a prime target for carcinogens. Transformed acinar cells form foci which are morphologically classified as acidophilic and basophilic lesions. Acidophilic foci which show increased cell proliferation progress to form nodules and acinar cell carcinomas.

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“…The effect of these regulatory genes appears to be independent of species barriers, as assessed in somatic cell hybrids, and may relate to the different stages of differentiation of the parent cells of the hybrids (reviewed in ref. 21).…”

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confidence: 99%

Reactivation by a trans-acting factor of human major histocompatibility complex Ia gene expression in interspecies hybrids between an Ia-negative human B-cell variant and an Ia-positive mouse B-cell lymphoma.

Accolla¹,

Carrà²,

Guardiola³

1985

Proc. Natl. Acad. Sci. U.S.A.

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Raji, a human B-lymphoma cell line, expresses high levels of class II (Ia) antigens. The expression of Ta antigens is totally abolished at the level of specific mRNA accumulation in RJ 2.2.5, a variant cell line derived from Raji after mutagenesis and immunoselection. We report here that the human Ta antigen expression can be restored in interspecies somatic cell hybrids between RJ 2.2.5 cells and BALB/cderived M12.4.1 (I-A', I-E+) B-lymphoma cells. Two hybrid clones were studied in detail. In both clones Ta molecules of the DR and NG2 type were easily detected by cell surface immunofluorescence and specific immunoprecipitation. In contrast, the DQ1 molecules were not detected with the above technique. DNA hybridization experiments using specific probes indicated that a-chain DR and (3-chain DQ genes were present in the hybrids. However, RNA hybridization experiments revealed that (3-chain DQ mRNA was present in the hybrids at very low amount compared to a-chain DR-specific mRNA. These results indicate that at least several genes of the class II gene cluster are coordinately regulated by trans-acting factor(s) that operate across species barriers. The basis of the mechanisms controlling the expression of class II antigens in these human-mouse hybrids might be related to the extinction

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Activation of Dormant Genes in Specialized Cells

Cited by 84 publications

References 74 publications

Feeding tadpoles cloned from Rana erythrocyte nuclei.

Feeding tadpoles cloned from Rana erythrocyte nuclei.

Differentiation and Cell Proliferation Patterns in Rat Exocrine Pancreas: Role of Type I and Type II Injury

Reactivation by a trans-acting factor of human major histocompatibility complex Ia gene expression in interspecies hybrids between an Ia-negative human B-cell variant and an Ia-positive mouse B-cell lymphoma.

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