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Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1986 Feb;83(3):679–683. doi: 10.1073/pnas.83.3.679

Determinator-inhibitor pairs as a mechanism for threshold setting in development: a possible function for pseudogenes.

J R McCarrey, A D Riggs
PMCID: PMC322927  PMID: 2418440

Abstract

Thresholds are frequently thought to be involved in the development of discrete structures in response to a shallow, monotonic gradient of morphogenetic information. We propose a mechanism for threshold setting that incorporates two essential components: (i) determinator genes that produce intracellular "determinators" that control cellular differentiation during development and (ii) intracellular "inhibitors" that bind tightly and specifically to the determinators to form "determinator-inhibitor pairs" that are inactive with respect to determinator function. The interaction of these components amplifies the intracellular response to an extra-cellular morphogen, thus producing a sharp transition in determinator gene activity. This system could operate at either the RNA level with the determinator-inhibitor pairs taking the form of sense-antisense RNAs or at the protein level via a competitive inhibition mechanism. In either case this model suggests a possible role for pseudogenes in development as a source of the intracellular inhibitors.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ambros V., Horvitz H. R. Heterochronic mutants of the nematode Caenorhabditis elegans. Science. 1984 Oct 26;226(4673):409–416. doi: 10.1126/science.6494891. [DOI] [PubMed] [Google Scholar]
  2. Bender W., Akam M., Karch F., Beachy P. A., Peifer M., Spierer P., Lewis E. B., Hogness D. S. Molecular Genetics of the Bithorax Complex in Drosophila melanogaster. Science. 1983 Jul 1;221(4605):23–29. doi: 10.1126/science.221.4605.23. [DOI] [PubMed] [Google Scholar]
  3. Coleman J., Green P. J., Inouye M. The use of RNAs complementary to specific mRNAs to regulate the expression of individual bacterial genes. Cell. 1984 Jun;37(2):429–436. doi: 10.1016/0092-8674(84)90373-8. [DOI] [PubMed] [Google Scholar]
  4. Farnham P. J., Abrams J. M., Schimke R. T. Opposite-strand RNAs from the 5' flanking region of the mouse dihydrofolate reductase gene. Proc Natl Acad Sci U S A. 1985 Jun;82(12):3978–3982. doi: 10.1073/pnas.82.12.3978. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Izant J. G., Weintraub H. Constitutive and conditional suppression of exogenous and endogenous genes by anti-sense RNA. Science. 1985 Jul 26;229(4711):345–352. doi: 10.1126/science.2990048. [DOI] [PubMed] [Google Scholar]
  6. Izant J. G., Weintraub H. Inhibition of thymidine kinase gene expression by anti-sense RNA: a molecular approach to genetic analysis. Cell. 1984 Apr;36(4):1007–1015. doi: 10.1016/0092-8674(84)90050-3. [DOI] [PubMed] [Google Scholar]
  7. Kauffman S. A. Pattern formation in the Drosophila embryo. Philos Trans R Soc Lond B Biol Sci. 1981 Oct 7;295(1078):567–594. doi: 10.1098/rstb.1981.0161. [DOI] [PubMed] [Google Scholar]
  8. Kauffman S. A., Shymko R. M., Trabert K. Control of sequential compartment formation in Drosophila. Science. 1978 Jan 20;199(4326):259–270. doi: 10.1126/science.413193. [DOI] [PubMed] [Google Scholar]
  9. Kaufman T. C., Lewis R., Wakimoto B. Cytogenetic Analysis of Chromosome 3 in DROSOPHILA MELANOGASTER: The Homoeotic Gene Complex in Polytene Chromosome Interval 84a-B. Genetics. 1980 Jan;94(1):115–133. doi: 10.1093/genetics/94.1.115. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Lewis E. B. A gene complex controlling segmentation in Drosophila. Nature. 1978 Dec 7;276(5688):565–570. doi: 10.1038/276565a0. [DOI] [PubMed] [Google Scholar]
  11. Lewis J., Slack J. M., Wolpert L. Thresholds in development. J Theor Biol. 1977 Apr 7;65(3):579–590. doi: 10.1016/0022-5193(77)90216-8. [DOI] [PubMed] [Google Scholar]
  12. Lin S., Riggs A. D. The general affinity of lac repressor for E. coli DNA: implications for gene regulation in procaryotes and eucaryotes. Cell. 1975 Feb;4(2):107–111. doi: 10.1016/0092-8674(75)90116-6. [DOI] [PubMed] [Google Scholar]
  13. Marx J. L. New ways to "mutate" genes. Science. 1984 Aug 24;225(4664):819–819. doi: 10.1126/science.6474154. [DOI] [PubMed] [Google Scholar]
  14. McGinnis W., Levine M. S., Hafen E., Kuroiwa A., Gehring W. J. A conserved DNA sequence in homoeotic genes of the Drosophila Antennapedia and bithorax complexes. 1984 Mar 29-Apr 4Nature. 308(5958):428–433. doi: 10.1038/308428a0. [DOI] [PubMed] [Google Scholar]
  15. Mizuno T., Chou M. Y., Inouye M. A unique mechanism regulating gene expression: translational inhibition by a complementary RNA transcript (micRNA). Proc Natl Acad Sci U S A. 1984 Apr;81(7):1966–1970. doi: 10.1073/pnas.81.7.1966. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Newport J., Kirschner M. A major developmental transition in early Xenopus embryos: II. Control of the onset of transcription. Cell. 1982 Oct;30(3):687–696. doi: 10.1016/0092-8674(82)90273-2. [DOI] [PubMed] [Google Scholar]
  17. Riggs A. D., Jones P. A. 5-methylcytosine, gene regulation, and cancer. Adv Cancer Res. 1983;40:1–30. doi: 10.1016/s0065-230x(08)60678-8. [DOI] [PubMed] [Google Scholar]
  18. Saito H., Richardson C. C. Processing of mRNA by ribonuclease III regulates expression of gene 1.2 of bacteriophage T7. Cell. 1981 Dec;27(3 Pt 2):533–542. doi: 10.1016/0092-8674(81)90395-0. [DOI] [PubMed] [Google Scholar]
  19. Simons R. W., Kleckner N. Translational control of IS10 transposition. Cell. 1983 Sep;34(2):683–691. doi: 10.1016/0092-8674(83)90401-4. [DOI] [PubMed] [Google Scholar]
  20. Slack J. M. Control of anteroposterior pattern in the axolotl forelimb by a smoothly graded signal. J Embryol Exp Morphol. 1977 Jun;39:169–182. [PubMed] [Google Scholar]
  21. Stephenson M. L., Zamecnik P. C. Inhibition of Rous sarcoma viral RNA translation by a specific oligodeoxyribonucleotide. Proc Natl Acad Sci U S A. 1978 Jan;75(1):285–288. doi: 10.1073/pnas.75.1.285. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Summerbell D., Lewis J. H., Wolpert L. Positional information in chick limb morphogenesis. Nature. 1973 Aug 24;244(5417):492–496. doi: 10.1038/244492a0. [DOI] [PubMed] [Google Scholar]
  23. Wolpert L. Positional information and pattern formation. Curr Top Dev Biol. 1971;6(6):183–224. doi: 10.1016/s0070-2153(08)60641-9. [DOI] [PubMed] [Google Scholar]
  24. Wolpert L. Positional information and the spatial pattern of cellular differentiation. J Theor Biol. 1969 Oct;25(1):1–47. doi: 10.1016/s0022-5193(69)80016-0. [DOI] [PubMed] [Google Scholar]
  25. Zamecnik P. C., Stephenson M. L. Inhibition of Rous sarcoma virus replication and cell transformation by a specific oligodeoxynucleotide. Proc Natl Acad Sci U S A. 1978 Jan;75(1):280–284. doi: 10.1073/pnas.75.1.280. [DOI] [PMC free article] [PubMed] [Google Scholar]

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