Abstract
NeuroD1/beta2 is a basic helix-loop-helix (bHLH) factor expressed in the endocrine cells of the pancreas and in a subset of neurons as they undergo terminal differentiation. We now show that NeuroD1 is expressed in corticotroph cells of the pituitary gland and that it is involved in cell-specific transcription of the proopiomelanocortin (POMC) gene. It was previously shown that corticotroph-specific POMC transcription depends in part on the action of cell-restricted bHLH factors that were characterized as the CUTE (corticotroph upstream transcription element) (M. Therrien and J. Drouin, Mol. Cell. Biol. 13:2342-2353, 1993) complexes. We now demonstrate that these complexes contain NeuroD1 in association with various ubiquitous bHLH dimerization partners. The NeuroD1-containing heterodimers specifically recognize and activate transcription from the POMC promoter E box that confers transcriptional specificity. Interestingly, the NeuroD1 heterodimers activate transcription in synergy with Ptx1, a Bicoid-related homeodomain protein, which also contributes to corticotroph specificity of POMC transcription. In the adult pituitary gland, NeuroD1 transcripts are detected in POMC-expressing corticotroph cells. Taken together with the restricted pattern of Ptx1 expression, these results suggest that these two factors establish the basis of a combinatorial code for the program of corticotroph-specific gene expression.
Full Text
The Full Text of this article is available as a PDF (1.4 MB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Akerblom I. E., Ridgway E. C., Mellon P. L. An alpha-subunit-secreting cell line derived from a mouse thyrotrope tumor. Mol Endocrinol. 1990 Apr;4(4):589–596. doi: 10.1210/mend-4-4-589. [DOI] [PubMed] [Google Scholar]
- Andersen B., Rosenfeld M. G. Pit-1 determines cell types during development of the anterior pituitary gland. A model for transcriptional regulation of cell phenotypes in mammalian organogenesis. J Biol Chem. 1994 Nov 25;269(47):29335–29338. [PubMed] [Google Scholar]
- Aplan P. D., Nakahara K., Orkin S. H., Kirsch I. R. The SCL gene product: a positive regulator of erythroid differentiation. EMBO J. 1992 Nov;11(11):4073–4081. doi: 10.1002/j.1460-2075.1992.tb05500.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Benezra R., Davis R. L., Lockshon D., Turner D. L., Weintraub H. The protein Id: a negative regulator of helix-loop-helix DNA binding proteins. Cell. 1990 Apr 6;61(1):49–59. doi: 10.1016/0092-8674(90)90214-y. [DOI] [PubMed] [Google Scholar]
- Blackwell T. K., Weintraub H. Differences and similarities in DNA-binding preferences of MyoD and E2A protein complexes revealed by binding site selection. Science. 1990 Nov 23;250(4984):1104–1110. doi: 10.1126/science.2174572. [DOI] [PubMed] [Google Scholar]
- Boockfor F. R., Schwarz L. K. Cultures of GH3 cells contain both single and dual hormone secretors. Endocrinology. 1988 Feb;122(2):762–764. doi: 10.1210/endo-122-2-762. [DOI] [PubMed] [Google Scholar]
- Chiaramello A., Neuman K., Palm K., Metsis M., Neuman T. Helix-loop-helix transcription factors mediate activation and repression of the p75LNGFR gene. Mol Cell Biol. 1995 Nov;15(11):6036–6044. doi: 10.1128/mcb.15.11.6036. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
- Cordle S. R., Henderson E., Masuoka H., Weil P. A., Stein R. Pancreatic beta-cell-type-specific transcription of the insulin gene is mediated by basic helix-loop-helix DNA-binding proteins. Mol Cell Biol. 1991 Mar;11(3):1734–1738. doi: 10.1128/mcb.11.3.1734. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Davis R. L., Cheng P. F., Lassar A. B., Weintraub H. The MyoD DNA binding domain contains a recognition code for muscle-specific gene activation. Cell. 1990 Mar 9;60(5):733–746. doi: 10.1016/0092-8674(90)90088-v. [DOI] [PubMed] [Google Scholar]
- Davis R. L., Weintraub H. Acquisition of myogenic specificity by replacement of three amino acid residues from MyoD into E12. Science. 1992 May 15;256(5059):1027–1030. doi: 10.1126/science.1317057. [DOI] [PubMed] [Google Scholar]
- Ellenberger T., Fass D., Arnaud M., Harrison S. C. Crystal structure of transcription factor E47: E-box recognition by a basic region helix-loop-helix dimer. Genes Dev. 1994 Apr 15;8(8):970–980. doi: 10.1101/gad.8.8.970. [DOI] [PubMed] [Google Scholar]
- Fisher F., Goding C. R. Single amino acid substitutions alter helix-loop-helix protein specificity for bases flanking the core CANNTG motif. EMBO J. 1992 Nov;11(11):4103–4109. doi: 10.1002/j.1460-2075.1992.tb05503.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- German M. S., Wang J., Chadwick R. B., Rutter W. J. Synergistic activation of the insulin gene by a LIM-homeo domain protein and a basic helix-loop-helix protein: building a functional insulin minienhancer complex. Genes Dev. 1992 Nov;6(11):2165–2176. doi: 10.1101/gad.6.11.2165. [DOI] [PubMed] [Google Scholar]
- Guillemot F., Lo L. C., Johnson J. E., Auerbach A., Anderson D. J., Joyner A. L. Mammalian achaete-scute homolog 1 is required for the early development of olfactory and autonomic neurons. Cell. 1993 Nov 5;75(3):463–476. doi: 10.1016/0092-8674(93)90381-y. [DOI] [PubMed] [Google Scholar]
- Hasty P., Bradley A., Morris J. H., Edmondson D. G., Venuti J. M., Olson E. N., Klein W. H. Muscle deficiency and neonatal death in mice with a targeted mutation in the myogenin gene. Nature. 1993 Aug 5;364(6437):501–506. doi: 10.1038/364501a0. [DOI] [PubMed] [Google Scholar]
- Henthorn P., McCarrick-Walmsley R., Kadesch T. Sequence of the cDNA encoding ITF-1, a positive-acting transcription factor. Nucleic Acids Res. 1990 Feb 11;18(3):677–677. doi: 10.1093/nar/18.3.677. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ishibashi M., Ang S. L., Shiota K., Nakanishi S., Kageyama R., Guillemot F. Targeted disruption of mammalian hairy and Enhancer of split homolog-1 (HES-1) leads to up-regulation of neural helix-loop-helix factors, premature neurogenesis, and severe neural tube defects. Genes Dev. 1995 Dec 15;9(24):3136–3148. doi: 10.1101/gad.9.24.3136. [DOI] [PubMed] [Google Scholar]
- Ishibashi M., Moriyoshi K., Sasai Y., Shiota K., Nakanishi S., Kageyama R. Persistent expression of helix-loop-helix factor HES-1 prevents mammalian neural differentiation in the central nervous system. EMBO J. 1994 Apr 15;13(8):1799–1805. doi: 10.1002/j.1460-2075.1994.tb06448.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Japón M. A., Rubinstein M., Low M. J. In situ hybridization analysis of anterior pituitary hormone gene expression during fetal mouse development. J Histochem Cytochem. 1994 Aug;42(8):1117–1125. doi: 10.1177/42.8.8027530. [DOI] [PubMed] [Google Scholar]
- Jeannotte L., Trifiro M. A., Plante R. K., Chamberland M., Drouin J. Tissue-specific activity of the pro-opiomelanocortin gene promoter. Mol Cell Biol. 1987 Nov;7(11):4058–4064. doi: 10.1128/mcb.7.11.4058. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kageyama R., Sasai Y., Akazawa C., Ishibashi M., Takebayashi K., Shimizu C., Tomita K., Nakanishi S. Regulation of mammalian neural development by helix-loop-helix transcription factors. Crit Rev Neurobiol. 1995;9(2-3):177–188. [PubMed] [Google Scholar]
- Karlsson O., Edlund T., Moss J. B., Rutter W. J., Walker M. D. A mutational analysis of the insulin gene transcription control region: expression in beta cells is dependent on two related sequences within the enhancer. Proc Natl Acad Sci U S A. 1987 Dec;84(24):8819–8823. doi: 10.1073/pnas.84.24.8819. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kawamura K., Kikuyama S. Induction from posterior hypothalamus is essential for the development of the pituitary proopiomelacortin (POMC) cells of the toad (Bufo japonicus). Cell Tissue Res. 1995 Feb;279(2):233–239. doi: 10.1007/BF00318479. [DOI] [PubMed] [Google Scholar]
- Kikuyama S., Inaco H., Jenks B. G., Kawamura K. Development of the ectopically transplanted primordium of epithelial hypophysis (anterior neural ridge) in Bufo japonicus embryos. J Exp Zool. 1993 Jul 1;266(3):216–220. doi: 10.1002/jez.1402660307. [DOI] [PubMed] [Google Scholar]
- Lamonerie T., Tremblay J. J., Lanctôt C., Therrien M., Gauthier Y., Drouin J. Ptx1, a bicoid-related homeo box transcription factor involved in transcription of the pro-opiomelanocortin gene. Genes Dev. 1996 May 15;10(10):1284–1295. doi: 10.1101/gad.10.10.1284. [DOI] [PubMed] [Google Scholar]
- Lanctôt C., Lamolet B., Drouin J. The bicoid-related homeoprotein Ptx1 defines the most anterior domain of the embryo and differentiates posterior from anterior lateral mesoderm. Development. 1997 Jul;124(14):2807–2817. doi: 10.1242/dev.124.14.2807. [DOI] [PubMed] [Google Scholar]
- Lassar A. B., Davis R. L., Wright W. E., Kadesch T., Murre C., Voronova A., Baltimore D., Weintraub H. Functional activity of myogenic HLH proteins requires hetero-oligomerization with E12/E47-like proteins in vivo. Cell. 1991 Jul 26;66(2):305–315. doi: 10.1016/0092-8674(91)90620-e. [DOI] [PubMed] [Google Scholar]
- Lee J. E., Hollenberg S. M., Snider L., Turner D. L., Lipnick N., Weintraub H. Conversion of Xenopus ectoderm into neurons by NeuroD, a basic helix-loop-helix protein. Science. 1995 May 12;268(5212):836–844. doi: 10.1126/science.7754368. [DOI] [PubMed] [Google Scholar]
- Ma P. C., Rould M. A., Weintraub H., Pabo C. O. Crystal structure of MyoD bHLH domain-DNA complex: perspectives on DNA recognition and implications for transcriptional activation. Cell. 1994 May 6;77(3):451–459. doi: 10.1016/0092-8674(94)90159-7. [DOI] [PubMed] [Google Scholar]
- Ma Q., Kintner C., Anderson D. J. Identification of neurogenin, a vertebrate neuronal determination gene. Cell. 1996 Oct 4;87(1):43–52. doi: 10.1016/s0092-8674(00)81321-5. [DOI] [PubMed] [Google Scholar]
- McCormick M. B., Tamimi R. M., Snider L., Asakura A., Bergstrom D., Tapscott S. J. NeuroD2 and neuroD3: distinct expression patterns and transcriptional activation potentials within the neuroD gene family. Mol Cell Biol. 1996 Oct;16(10):5792–5800. doi: 10.1128/mcb.16.10.5792. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Molkentin J. D., Black B. L., Martin J. F., Olson E. N. Cooperative activation of muscle gene expression by MEF2 and myogenic bHLH proteins. Cell. 1995 Dec 29;83(7):1125–1136. doi: 10.1016/0092-8674(95)90139-6. [DOI] [PubMed] [Google Scholar]
- Murre C., McCaw P. S., Baltimore D. A new DNA binding and dimerization motif in immunoglobulin enhancer binding, daughterless, MyoD, and myc proteins. Cell. 1989 Mar 10;56(5):777–783. doi: 10.1016/0092-8674(89)90682-x. [DOI] [PubMed] [Google Scholar]
- Murre C., McCaw P. S., Vaessin H., Caudy M., Jan L. Y., Jan Y. N., Cabrera C. V., Buskin J. N., Hauschka S. D., Lassar A. B. Interactions between heterologous helix-loop-helix proteins generate complexes that bind specifically to a common DNA sequence. Cell. 1989 Aug 11;58(3):537–544. doi: 10.1016/0092-8674(89)90434-0. [DOI] [PubMed] [Google Scholar]
- Mutoh H., Fung B. P., Naya F. J., Tsai M. J., Nishitani J., Leiter A. B. The basic helix-loop-helix transcription factor BETA2/NeuroD is expressed in mammalian enteroendocrine cells and activates secretin gene expression. Proc Natl Acad Sci U S A. 1997 Apr 15;94(8):3560–3564. doi: 10.1073/pnas.94.8.3560. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nabeshima Y., Hanaoka K., Hayasaka M., Esumi E., Li S., Nonaka I., Nabeshima Y. Myogenin gene disruption results in perinatal lethality because of severe muscle defect. Nature. 1993 Aug 5;364(6437):532–535. doi: 10.1038/364532a0. [DOI] [PubMed] [Google Scholar]
- Naya F. J., Stellrecht C. M., Tsai M. J. Tissue-specific regulation of the insulin gene by a novel basic helix-loop-helix transcription factor. Genes Dev. 1995 Apr 15;9(8):1009–1019. doi: 10.1101/gad.9.8.1009. [DOI] [PubMed] [Google Scholar]
- Nelson C., Shen L. P., Meister A., Fodor E., Rutter W. J. Pan: a transcriptional regulator that binds chymotrypsin, insulin, and AP-4 enhancer motifs. Genes Dev. 1990 Jun;4(6):1035–1043. doi: 10.1101/gad.4.6.1035. [DOI] [PubMed] [Google Scholar]
- Nordeen S. K. Luciferase reporter gene vectors for analysis of promoters and enhancers. Biotechniques. 1988 May;6(5):454–458. [PubMed] [Google Scholar]
- Peers B., Leonard J., Sharma S., Teitelman G., Montminy M. R. Insulin expression in pancreatic islet cells relies on cooperative interactions between the helix loop helix factor E47 and the homeobox factor STF-1. Mol Endocrinol. 1994 Dec;8(12):1798–1806. doi: 10.1210/mend.8.12.7708065. [DOI] [PubMed] [Google Scholar]
- Rudnicki M. A., Schnegelsberg P. N., Stead R. H., Braun T., Arnold H. H., Jaenisch R. MyoD or Myf-5 is required for the formation of skeletal muscle. Cell. 1993 Dec 31;75(7):1351–1359. doi: 10.1016/0092-8674(93)90621-v. [DOI] [PubMed] [Google Scholar]
- Shivdasani R. A., Mayer E. L., Orkin S. H. Absence of blood formation in mice lacking the T-cell leukaemia oncoprotein tal-1/SCL. Nature. 1995 Feb 2;373(6513):432–434. doi: 10.1038/373432a0. [DOI] [PubMed] [Google Scholar]
- Sun X. H., Baltimore D. An inhibitory domain of E12 transcription factor prevents DNA binding in E12 homodimers but not in E12 heterodimers. Cell. 1991 Jan 25;64(2):459–470. doi: 10.1016/0092-8674(91)90653-g. [DOI] [PubMed] [Google Scholar]
- Therrien M., Drouin J. Cell-specific helix-loop-helix factor required for pituitary expression of the pro-opiomelanocortin gene. Mol Cell Biol. 1993 Apr;13(4):2342–2353. doi: 10.1128/mcb.13.4.2342. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Therrien M., Drouin J. Pituitary pro-opiomelanocortin gene expression requires synergistic interactions of several regulatory elements. Mol Cell Biol. 1991 Jul;11(7):3492–3503. doi: 10.1128/mcb.11.7.3492. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Voss J. W., Rosenfeld M. G. Anterior pituitary development: short tales from dwarf mice. Cell. 1992 Aug 21;70(4):527–530. doi: 10.1016/0092-8674(92)90422-9. [DOI] [PubMed] [Google Scholar]
- Weintraub H. The MyoD family and myogenesis: redundancy, networks, and thresholds. Cell. 1993 Dec 31;75(7):1241–1244. doi: 10.1016/0092-8674(93)90610-3. [DOI] [PubMed] [Google Scholar]
- Windle J. J., Weiner R. I., Mellon P. L. Cell lines of the pituitary gonadotrope lineage derived by targeted oncogenesis in transgenic mice. Mol Endocrinol. 1990 Apr;4(4):597–603. doi: 10.1210/mend-4-4-597. [DOI] [PubMed] [Google Scholar]
- Zhang W., Behringer R. R., Olson E. N. Inactivation of the myogenic bHLH gene MRF4 results in up-regulation of myogenin and rib anomalies. Genes Dev. 1995 Jun 1;9(11):1388–1399. doi: 10.1101/gad.9.11.1388. [DOI] [PubMed] [Google Scholar]