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. 1998 Nov 2;17(21):6316–6326. doi: 10.1093/emboj/17.21.6316

Positive autoregulation of the glial promoting factor glide/gcm.

A A Miller 1, R Bernardoni 1, A Giangrande 1
PMCID: PMC1170956  PMID: 9799239

Abstract

Fly gliogenesis depends on the glial-cell-deficient/glial-cell-missing (glide/gcm) transcription factor. glide/gcm expression is necessary and sufficient to induce the glial fate within and outside the nervous system, indicating that the activity of this gene must be tightly regulated. The current model is that glide/gcm activates the glial fate by inducing the expression of glial-specific genes that are required to maintain such a fate. Previous observations on the null glide/gcmN7-4 allele evoked the possibility that another role of glide/gcm might be to maintain and/or amplify its own expression. Here we show that glide/gcm does positively autoregulate in vitro and in vivo, and that the glide/gcmN7-4 protein is not able to do so. We thereby provide the first direct evidence of both a target and a regulator of glide/gcm. Our data also demonstrate that glide/gcm transcription is regulated at two distinct steps: initiation, which is glide/gcm-independent, and maintenance, which requires glide/gcm. Interestingly, we have found that autoregulation requires the activity of additional cell-specific cofactors. The present results suggest transcriptional autoregulation is a mechanism for glial fate induction.

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Selected References

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  1. Akiyama Y., Hosoya T., Poole A. M., Hotta Y. The gcm-motif: a novel DNA-binding motif conserved in Drosophila and mammals. Proc Natl Acad Sci U S A. 1996 Dec 10;93(25):14912–14916. doi: 10.1073/pnas.93.25.14912. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Altshuller Y., Copeland N. G., Gilbert D. J., Jenkins N. A., Frohman M. A. Gcm1, a mammalian homolog of Drosophila glial cells missing. FEBS Lett. 1996 Sep 16;393(2-3):201–204. doi: 10.1016/0014-5793(96)00890-3. [DOI] [PubMed] [Google Scholar]
  3. Anderson D. J. A molecular switch for the neuron-glia developmental decision. Neuron. 1995 Dec;15(6):1219–1222. doi: 10.1016/0896-6273(95)90001-2. [DOI] [PubMed] [Google Scholar]
  4. Andrews N. C., Faller D. V. A rapid micropreparation technique for extraction of DNA-binding proteins from limiting numbers of mammalian cells. Nucleic Acids Res. 1991 May 11;19(9):2499–2499. doi: 10.1093/nar/19.9.2499. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Baylies M. K., Bate M. twist: a myogenic switch in Drosophila. Science. 1996 Jun 7;272(5267):1481–1484. doi: 10.1126/science.272.5267.1481. [DOI] [PubMed] [Google Scholar]
  6. Bell L. R., Horabin J. I., Schedl P., Cline T. W. Positive autoregulation of sex-lethal by alternative splicing maintains the female determined state in Drosophila. Cell. 1991 Apr 19;65(2):229–239. doi: 10.1016/0092-8674(91)90157-t. [DOI] [PubMed] [Google Scholar]
  7. Bergson C., McGinnis W. An autoregulatory enhancer element of the Drosophila homeotic gene Deformed. EMBO J. 1990 Dec;9(13):4287–4297. doi: 10.1002/j.1460-2075.1990.tb07877.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Bernardoni R., Miller A. A., Giangrande A. Glial differentiation does not require a neural ground state. Development. 1998 Aug;125(16):3189–3200. doi: 10.1242/dev.125.16.3189. [DOI] [PubMed] [Google Scholar]
  9. Bernardoni R., Vivancos V., Giangrande A. glide/gcm is expressed and required in the scavenger cell lineage. Dev Biol. 1997 Nov 1;191(1):118–130. doi: 10.1006/dbio.1997.8702. [DOI] [PubMed] [Google Scholar]
  10. Bienz M. Homeotic genes and positional signalling in the Drosophila viscera. Trends Genet. 1994 Jan;10(1):22–26. doi: 10.1016/0168-9525(94)90015-9. [DOI] [PubMed] [Google Scholar]
  11. Boshart M., Klüppel M., Schmidt A., Schütz G., Luckow B. Reporter constructs with low background activity utilizing the cat gene. Gene. 1992 Jan 2;110(1):129–130. doi: 10.1016/0378-1119(92)90456-y. [DOI] [PubMed] [Google Scholar]
  12. Botas J. Control of morphogenesis and differentiation by HOM/Hox genes. Curr Opin Cell Biol. 1993 Dec;5(6):1015–1022. doi: 10.1016/0955-0674(93)90086-6. [DOI] [PubMed] [Google Scholar]
  13. Brand A. H., Perrimon N. Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. Development. 1993 Jun;118(2):401–415. doi: 10.1242/dev.118.2.401. [DOI] [PubMed] [Google Scholar]
  14. Campbell G., Göring H., Lin T., Spana E., Andersson S., Doe C. Q., Tomlinson A. RK2, a glial-specific homeodomain protein required for embryonic nerve cord condensation and viability in Drosophila. Development. 1994 Oct;120(10):2957–2966. doi: 10.1242/dev.120.10.2957. [DOI] [PubMed] [Google Scholar]
  15. Carter D. A., Murphy D. Circadian rhythms and autoregulatory transcription loops--going round in circles? Mol Cell Endocrinol. 1996 Nov 29;124(1-2):1–5. doi: 10.1016/s0303-7207(96)03962-7. [DOI] [PubMed] [Google Scholar]
  16. Chen R. P., Ingraham H. A., Treacy M. N., Albert V. R., Wilson L., Rosenfeld M. G. Autoregulation of pit-1 gene expression mediated by two cis-active promoter elements. Nature. 1990 Aug 9;346(6284):583–586. doi: 10.1038/346583a0. [DOI] [PubMed] [Google Scholar]
  17. Chouinard S., Kaufman T. C. Control of expression of the homeotic labial (lab) locus of Drosophila melanogaster: evidence for both positive and negative autogenous regulation. Development. 1991 Dec;113(4):1267–1280. doi: 10.1242/dev.113.4.1267. [DOI] [PubMed] [Google Scholar]
  18. Crews S. T. Control of cell lineage-specific development and transcription by bHLH-PAS proteins. Genes Dev. 1998 Mar 1;12(5):607–620. doi: 10.1101/gad.12.5.607. [DOI] [PubMed] [Google Scholar]
  19. Di Nocera P. P., Dawid I. B. Transient expression of genes introduced into cultured cells of Drosophila. Proc Natl Acad Sci U S A. 1983 Dec;80(23):7095–7098. doi: 10.1073/pnas.80.23.7095. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. DiMattia G. E., Rhodes S. J., Krones A., Carrière C., O'Connell S., Kalla K., Arias C., Sawchenko P., Rosenfeld M. G. The Pit-1 gene is regulated by distinct early and late pituitary-specific enhancers. Dev Biol. 1997 Feb 1;182(1):180–190. doi: 10.1006/dbio.1996.8472. [DOI] [PubMed] [Google Scholar]
  21. Doe C. Q., Chu-LaGraff Q., Wright D. M., Scott M. P. The prospero gene specifies cell fates in the Drosophila central nervous system. Cell. 1991 May 3;65(3):451–464. doi: 10.1016/0092-8674(91)90463-9. [DOI] [PubMed] [Google Scholar]
  22. Duffy J. B., Gergen J. P. Sex, segments, and the central nervous system: common genetic mechanisms of cell fate determination. Adv Genet. 1994;31:1–28. doi: 10.1016/s0065-2660(08)60394-6. [DOI] [PubMed] [Google Scholar]
  23. Fischer J. A., Giniger E., Maniatis T., Ptashne M. GAL4 activates transcription in Drosophila. Nature. 1988 Apr 28;332(6167):853–856. doi: 10.1038/332853a0. [DOI] [PubMed] [Google Scholar]
  24. Foulkes N. S., Borjigin J., Snyder S. H., Sassone-Corsi P. Transcriptional control of circadian hormone synthesis via the CREM feedback loop. Proc Natl Acad Sci U S A. 1996 Nov 26;93(24):14140–14145. doi: 10.1073/pnas.93.24.14140. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Frasch M., Warrior R., Tugwood J., Levine M. Molecular analysis of even-skipped mutants in Drosophila development. Genes Dev. 1988 Dec;2(12B):1824–1838. doi: 10.1101/gad.2.12b.1824. [DOI] [PubMed] [Google Scholar]
  26. Giangrande A. Development and organization of glial cells in Drosophila melanogaster. Int J Dev Biol. 1996 Oct;40(5):917–927. [PubMed] [Google Scholar]
  27. Giesen K., Hummel T., Stollewerk A., Harrison S., Travers A., Klämbt C. Glial development in the Drosophila CNS requires concomitant activation of glial and repression of neuronal differentiation genes. Development. 1997 Jun;124(12):2307–2316. doi: 10.1242/dev.124.12.2307. [DOI] [PubMed] [Google Scholar]
  28. Guichet A., Copeland J. W., Erdélyi M., Hlousek D., Závorszky P., Ho J., Brown S., Percival-Smith A., Krause H. M., Ephrussi A. The nuclear receptor homologue Ftz-F1 and the homeodomain protein Ftz are mutually dependent cofactors. Nature. 1997 Feb 6;385(6616):548–552. doi: 10.1038/385548a0. [DOI] [PubMed] [Google Scholar]
  29. Halter D. A., Urban J., Rickert C., Ner S. S., Ito K., Travers A. A., Technau G. M. The homeobox gene repo is required for the differentiation and maintenance of glia function in the embryonic nervous system of Drosophila melanogaster. Development. 1995 Feb;121(2):317–332. doi: 10.1242/dev.121.2.317. [DOI] [PubMed] [Google Scholar]
  30. Harrison S. D., Travers A. A. The tramtrack gene encodes a Drosophila finger protein that interacts with the ftz transcriptional regulatory region and shows a novel embryonic expression pattern. EMBO J. 1990 Jan;9(1):207–216. doi: 10.1002/j.1460-2075.1990.tb08097.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Hiromi Y., Gehring W. J. Regulation and function of the Drosophila segmentation gene fushi tarazu. Cell. 1987 Sep 11;50(6):963–974. doi: 10.1016/0092-8674(87)90523-x. [DOI] [PubMed] [Google Scholar]
  32. Hosoya T., Takizawa K., Nitta K., Hotta Y. glial cells missing: a binary switch between neuronal and glial determination in Drosophila. Cell. 1995 Sep 22;82(6):1025–1036. doi: 10.1016/0092-8674(95)90281-3. [DOI] [PubMed] [Google Scholar]
  33. Jiang J., Hoey T., Levine M. Autoregulation of a segmentation gene in Drosophila: combinatorial interaction of the even-skipped homeo box protein with a distal enhancer element. Genes Dev. 1991 Feb;5(2):265–277. doi: 10.1101/gad.5.2.265. [DOI] [PubMed] [Google Scholar]
  34. Johnson D. G., Ohtani K., Nevins J. R. Autoregulatory control of E2F1 expression in response to positive and negative regulators of cell cycle progression. Genes Dev. 1994 Jul 1;8(13):1514–1525. doi: 10.1101/gad.8.13.1514. [DOI] [PubMed] [Google Scholar]
  35. Jones B. W., Fetter R. D., Tear G., Goodman C. S. glial cells missing: a genetic switch that controls glial versus neuronal fate. Cell. 1995 Sep 22;82(6):1013–1023. doi: 10.1016/0092-8674(95)90280-5. [DOI] [PubMed] [Google Scholar]
  36. Keyes L. N., Cline T. W., Schedl P. The primary sex determination signal of Drosophila acts at the level of transcription. Cell. 1992 Mar 6;68(5):933–943. doi: 10.1016/0092-8674(92)90036-c. [DOI] [PubMed] [Google Scholar]
  37. Klaes A., Menne T., Stollewerk A., Scholz H., Klämbt C. The Ets transcription factors encoded by the Drosophila gene pointed direct glial cell differentiation in the embryonic CNS. Cell. 1994 Jul 15;78(1):149–160. doi: 10.1016/0092-8674(94)90581-9. [DOI] [PubMed] [Google Scholar]
  38. Klämbt C., Hummel T., Menne T., Sadlowski E., Scholz H., Stollewerk A. Development and function of embryonic central nervous system glial cells in Drosophila. Dev Genet. 1996;18(1):40–49. doi: 10.1002/(SICI)1520-6408(1996)18:1<40::AID-DVG5>3.0.CO;2-1. [DOI] [PubMed] [Google Scholar]
  39. Klämbt C. The Drosophila gene pointed encodes two ETS-like proteins which are involved in the development of the midline glial cells. Development. 1993 Jan;117(1):163–176. doi: 10.1242/dev.117.1.163. [DOI] [PubMed] [Google Scholar]
  40. Krasnow M. A., Saffman E. E., Kornfeld K., Hogness D. S. Transcriptional activation and repression by Ultrabithorax proteins in cultured Drosophila cells. Cell. 1989 Jun 16;57(6):1031–1043. doi: 10.1016/0092-8674(89)90341-3. [DOI] [PubMed] [Google Scholar]
  41. Kuziora M. A., McGinnis W. Autoregulation of a Drosophila homeotic selector gene. Cell. 1988 Nov 4;55(3):477–485. doi: 10.1016/0092-8674(88)90034-7. [DOI] [PubMed] [Google Scholar]
  42. Lam E. W., La Thangue N. B. DP and E2F proteins: coordinating transcription with cell cycle progression. Curr Opin Cell Biol. 1994 Dec;6(6):859–866. doi: 10.1016/0955-0674(94)90057-4. [DOI] [PubMed] [Google Scholar]
  43. Lane M. E., Kalderon D. Genetic investigation of cAMP-dependent protein kinase function in Drosophila development. Genes Dev. 1993 Jul;7(7A):1229–1243. doi: 10.1101/gad.7.7a.1229. [DOI] [PubMed] [Google Scholar]
  44. Lawrence P. A., Johnston P. Pattern formation in the Drosophila embryo: allocation of cells to parasegments by even-skipped and fushi tarazu. Development. 1989 Apr;105(4):761–767. doi: 10.1242/dev.105.4.761. [DOI] [PubMed] [Google Scholar]
  45. Li S., Crenshaw E. B., 3rd, Rawson E. J., Simmons D. M., Swanson L. W., Rosenfeld M. G. Dwarf locus mutants lacking three pituitary cell types result from mutations in the POU-domain gene pit-1. Nature. 1990 Oct 11;347(6293):528–533. doi: 10.1038/347528a0. [DOI] [PubMed] [Google Scholar]
  46. Lou L., Bergson C., McGinnis W. Deformed expression in the Drosophila central nervous system is controlled by an autoactivated intronic enhancer. Nucleic Acids Res. 1995 Sep 11;23(17):3481–3487. doi: 10.1093/nar/23.17.3481. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Mlodzik M., Baker N. E., Rubin G. M. Isolation and expression of scabrous, a gene regulating neurogenesis in Drosophila. Genes Dev. 1990 Nov;4(11):1848–1861. doi: 10.1101/gad.4.11.1848. [DOI] [PubMed] [Google Scholar]
  48. Pfrieger F. W., Barres B. A. What the fly's glia tell the fly's brain. Cell. 1995 Dec 1;83(5):671–674. doi: 10.1016/0092-8674(95)90178-7. [DOI] [PubMed] [Google Scholar]
  49. Pick L., Schier A., Affolter M., Schmidt-Glenewinkel T., Gehring W. J. Analysis of the ftz upstream element: germ layer-specific enhancers are independently autoregulated. Genes Dev. 1990 Jul;4(7):1224–1239. doi: 10.1101/gad.4.7.1224. [DOI] [PubMed] [Google Scholar]
  50. Pines J. Cell proliferation and control. Curr Opin Cell Biol. 1992 Apr;4(2):144–148. doi: 10.1016/0955-0674(92)90024-7. [DOI] [PubMed] [Google Scholar]
  51. Regulski M., Dessain S., McGinnis N., McGinnis W. High-affinity binding sites for the Deformed protein are required for the function of an autoregulatory enhancer of the Deformed gene. Genes Dev. 1991 Feb;5(2):278–286. doi: 10.1101/gad.5.2.278. [DOI] [PubMed] [Google Scholar]
  52. Sassone-Corsi P. Molecular clocks: mastering time by gene regulation. Nature. 1998 Apr 30;392(6679):871–874. doi: 10.1038/31821. [DOI] [PubMed] [Google Scholar]
  53. Schier A. F., Gehring W. J. Direct homeodomain-DNA interaction in the autoregulation of the fushi tarazu gene. Nature. 1992 Apr 30;356(6372):804–807. doi: 10.1038/356804a0. [DOI] [PubMed] [Google Scholar]
  54. Schneider I. Cell lines derived from late embryonic stages of Drosophila melanogaster. J Embryol Exp Morphol. 1972 Apr;27(2):353–365. [PubMed] [Google Scholar]
  55. Schreiber J., Enderich J., Wegner M. Structural requirements for DNA binding of GCM proteins. Nucleic Acids Res. 1998 May 15;26(10):2337–2343. doi: 10.1093/nar/26.10.2337. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Schreiber J., Sock E., Wegner M. The regulator of early gliogenesis glial cells missing is a transcription factor with a novel type of DNA-binding domain. Proc Natl Acad Sci U S A. 1997 Apr 29;94(9):4739–4744. doi: 10.1073/pnas.94.9.4739. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Shan B., Chang C. Y., Jones D., Lee W. H. The transcription factor E2F-1 mediates the autoregulation of RB gene expression. Mol Cell Biol. 1994 Jan;14(1):299–309. doi: 10.1128/mcb.14.1.299. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Siegfried E., Chou T. B., Perrimon N. wingless signaling acts through zeste-white 3, the Drosophila homolog of glycogen synthase kinase-3, to regulate engrailed and establish cell fate. Cell. 1992 Dec 24;71(7):1167–1179. doi: 10.1016/s0092-8674(05)80065-0. [DOI] [PubMed] [Google Scholar]
  59. Thüringer F., Cohen S. M., Bienz M. Dissection of an indirect autoregulatory response of a homeotic Drosophila gene. EMBO J. 1993 Jun;12(6):2419–2430. doi: 10.1002/j.1460-2075.1993.tb05896.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Vaessin H., Grell E., Wolff E., Bier E., Jan L. Y., Jan Y. N. prospero is expressed in neuronal precursors and encodes a nuclear protein that is involved in the control of axonal outgrowth in Drosophila. Cell. 1991 Nov 29;67(5):941–953. doi: 10.1016/0092-8674(91)90367-8. [DOI] [PubMed] [Google Scholar]
  61. Vervoort M., Dambly-Chaudière C., Ghysen A. Cell fate determination in Drosophila. Curr Opin Neurobiol. 1997 Feb;7(1):21–28. doi: 10.1016/s0959-4388(97)80116-x. [DOI] [PubMed] [Google Scholar]
  62. Vincent S., Vonesch J. L., Giangrande A. Glide directs glial fate commitment and cell fate switch between neurones and glia. Development. 1996 Jan;122(1):131–139. doi: 10.1242/dev.122.1.131. [DOI] [PubMed] [Google Scholar]
  63. Warrior R., Levine M. Dose-dependent regulation of pair-rule stripes by gap proteins and the initiation of segment polarity. Development. 1990 Nov;110(3):759–767. doi: 10.1242/dev.110.3.759. [DOI] [PubMed] [Google Scholar]
  64. Weintraub H., Davis R., Tapscott S., Thayer M., Krause M., Benezra R., Blackwell T. K., Turner D., Rupp R., Hollenberg S. The myoD gene family: nodal point during specification of the muscle cell lineage. Science. 1991 Feb 15;251(4995):761–766. doi: 10.1126/science.1846704. [DOI] [PubMed] [Google Scholar]
  65. Wu X., Bayle J. H., Olson D., Levine A. J. The p53-mdm-2 autoregulatory feedback loop. Genes Dev. 1993 Jul;7(7A):1126–1132. doi: 10.1101/gad.7.7a.1126. [DOI] [PubMed] [Google Scholar]
  66. Xiong W. C., Okano H., Patel N. H., Blendy J. A., Montell C. repo encodes a glial-specific homeo domain protein required in the Drosophila nervous system. Genes Dev. 1994 Apr 15;8(8):981–994. doi: 10.1101/gad.8.8.981. [DOI] [PubMed] [Google Scholar]
  67. Yin X. M., Oltvai Z. N., Veis-Novack D. J., Linette G. P., Korsmeyer S. J. Bcl-2 gene family and the regulation of programmed cell death. Cold Spring Harb Symp Quant Biol. 1994;59:387–393. doi: 10.1101/sqb.1994.059.01.043. [DOI] [PubMed] [Google Scholar]
  68. Yoffe K. B., Manoukian A. S., Wilder E. L., Brand A. H., Perrimon N. Evidence for engrailed-independent wingless autoregulation in Drosophila. Dev Biol. 1995 Aug;170(2):636–650. doi: 10.1006/dbio.1995.1243. [DOI] [PubMed] [Google Scholar]
  69. Yu Y., Li W., Su K., Yussa M., Han W., Perrimon N., Pick L. The nuclear hormone receptor Ftz-F1 is a cofactor for the Drosophila homeodomain protein Ftz. Nature. 1997 Feb 6;385(6616):552–555. doi: 10.1038/385552a0. [DOI] [PubMed] [Google Scholar]

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