Genesis, a Winged Helix transcriptional repressor, has embryonic expression limited to the neural crest, and stimulates proliferation in vitro in a neural development model.
A novel repressor of the Winged Helix (formerly HNF-3/Forkhead) transcriptional regulatory family, termed Genesis (also called HFH2), was previously found to be exclusively expressed in primitive embryonic cell lines. In this study in situ cRNA hybridization experiments revealed that Genesis was expressed during embryogenesis only in developing neural crest cells. Its expression diminished upon their terminal differentiation into sympathetic and parasympathetic neurons. Based on that finding, Genesis was retrovirally transduced into pluripotent N-Tera-2 clone D1 (NT2/D1) teratocarcinoma cells, which are a well-described in vitro model of neural development. Retinoic acid (RA) treatment will drive these cells to differentiation toward the neuronal lineage and cause an increase in expression of the cyclin-dependent kinase inhibitor p21 protein, which leads to an inhibition in cellular proliferation. Although RA-induced expression of neuronal differentiation markers was not influenced by forced overexpression of Genesis in NT2-D1 cells, proliferation of Genesis-transduced cells continued following RA treatment. RA was unable to induce the expression of the cyclin-dependent kinase inhibitor p21 in the Genesis-transduced cells, but Go/G1 tumor suppressor p53 expression was induced normally. Therefore, Genesis may play a role in the regulation of primitive neural crest development by preventing terminal quiescence through inhibition of p21 protein expression. These data also lend evidence for the hypothesis that proliferation and differentiation pathways are not irrevocably linked, but can function independently.
Hromas
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Division of Hematology/Oncology and the Walther Oncology Center, IB 442, Indiana University Medical Center, 975 W. Walnut St., Indianapolis, IN 46202-5121, USA. rhromas@iupui.edu
Ye
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Spinella
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Dmitrovsky
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Xu
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Costa
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D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D002455:Cell Division / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D005314:Embryonic and Fetal Development / Q000235:genetics; D051858:Forkhead Transcription Factors; D018507:Gene Expression Regulation, Developmental; D019077:Helix-Turn-Helix Motifs / Q000235:genetics; D051379:Mice; D009432:Neural Crest / Q000196:embryology*; D009928:Organ Specificity; D012097:Repressor Proteins / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics
D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; C101757:Foxd3 protein, mouse; D012097:Repressor Proteins; D015534:Trans-Activators