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. 1996 Oct;16(10):5792–5800. doi: 10.1128/mcb.16.10.5792

NeuroD2 and neuroD3: distinct expression patterns and transcriptional activation potentials within the neuroD gene family.

M B McCormick 1, R M Tamimi 1, L Snider 1, A Asakura 1, D Bergstrom 1, S J Tapscott 1
PMCID: PMC231580  PMID: 8816493

Abstract

We have identified two new genes, neuroD2 and neuroD3, on the basis of their similarity to the neurogenic basic-helix-loop-helix (bHLH) gene neuroD. The predicted amino acid sequence of neuroD2 shows a high degree of homology to neuroD and MATH-2/NEX-1 in the bHLH region, whereas neuroD3 is a more distantly related family member. neuroD3 is expressed transiently during embryonic development, with the highest levels of expression between days 10 and 12. neuroD2 is initially expressed at embryonic day 11, with persistent expression in the adult nervous system. In situ and Northern (RNA) analyses demonstrate that different regions of the adult nervous system have different relative amounts of neuroD and neuroD2 RNA. Similar to neuroD, expression of neuroD2 in developing Xenopus laevis embryos results in ectopic neurogenesis, indicating that neuroD2 mediates neuronal differentiation. Transfection of vectors expressing neuroD and neuroD2 into P19 cells shows that both can activate expression through simple E-box-driven reporter constructs and can activate a reporter driven by the neuroD2 promoter region, but the GAP-43 promoter is preferentially activated by neuroD2. The noncongruent expression pattern and target gene specificity of these highly related neurogenic bHLH proteins make them candidates for conferring specific aspects of the neuronal phenotype.

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Selected References

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  1. Akazawa C., Ishibashi M., Shimizu C., Nakanishi S., Kageyama R. A mammalian helix-loop-helix factor structurally related to the product of Drosophila proneural gene atonal is a positive transcriptional regulator expressed in the developing nervous system. J Biol Chem. 1995 Apr 14;270(15):8730–8738. doi: 10.1074/jbc.270.15.8730. [DOI] [PubMed] [Google Scholar]
  2. Anderson D. J. Neural development. Spinning skin into neurons. Curr Biol. 1995 Nov 1;5(11):1235–1238. doi: 10.1016/s0960-9822(95)00246-6. [DOI] [PubMed] [Google Scholar]
  3. Asakura A., Fujisawa-Sehara A., Komiya T., Nabeshima Y., Nabeshima Y. MyoD and myogenin act on the chicken myosin light-chain 1 gene as distinct transcriptional factors. Mol Cell Biol. 1993 Nov;13(11):7153–7162. doi: 10.1128/mcb.13.11.7153. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Asakura A., Lyons G. E., Tapscott S. J. The regulation of MyoD gene expression: conserved elements mediate expression in embryonic axial muscle. Dev Biol. 1995 Oct;171(2):386–398. doi: 10.1006/dbio.1995.1290. [DOI] [PubMed] [Google Scholar]
  5. Balak K., Jacobson M., Sunshine J., Rutishauser U. Neural cell adhesion molecule expression in Xenopus embryos. Dev Biol. 1987 Feb;119(2):540–550. doi: 10.1016/0012-1606(87)90057-1. [DOI] [PubMed] [Google Scholar]
  6. Bartholomä A., Nave K. A. NEX-1: a novel brain-specific helix-loop-helix protein with autoregulation and sustained expression in mature cortical neurons. Mech Dev. 1994 Dec;48(3):217–228. doi: 10.1016/0925-4773(94)90061-2. [DOI] [PubMed] [Google Scholar]
  7. Burgess R., Cserjesi P., Ligon K. L., Olson E. N. Paraxis: a basic helix-loop-helix protein expressed in paraxial mesoderm and developing somites. Dev Biol. 1995 Apr;168(2):296–306. doi: 10.1006/dbio.1995.1081. [DOI] [PubMed] [Google Scholar]
  8. Campuzano S., Modolell J. Patterning of the Drosophila nervous system: the achaete-scute gene complex. Trends Genet. 1992 Jun;8(6):202–208. doi: 10.1016/0168-9525(92)90234-u. [DOI] [PubMed] [Google Scholar]
  9. Cross J. C., Flannery M. L., Blanar M. A., Steingrimsson E., Jenkins N. A., Copeland N. G., Rutter W. J., Werb Z. Hxt encodes a basic helix-loop-helix transcription factor that regulates trophoblast cell development. Development. 1995 Aug;121(8):2513–2523. doi: 10.1242/dev.121.8.2513. [DOI] [PubMed] [Google Scholar]
  10. Cserjesi P., Brown D., Ligon K. L., Lyons G. E., Copeland N. G., Gilbert D. J., Jenkins N. A., Olson E. N. Scleraxis: a basic helix-loop-helix protein that prefigures skeletal formation during mouse embryogenesis. Development. 1995 Apr;121(4):1099–1110. doi: 10.1242/dev.121.4.1099. [DOI] [PubMed] [Google Scholar]
  11. 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]
  12. 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]
  13. 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]
  14. Hollenberg S. M., Sternglanz R., Cheng P. F., Weintraub H. Identification of a new family of tissue-specific basic helix-loop-helix proteins with a two-hybrid system. Mol Cell Biol. 1995 Jul;15(7):3813–3822. doi: 10.1128/mcb.15.7.3813. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Hughes S. M., Taylor J. M., Tapscott S. J., Gurley C. M., Carter W. J., Peterson C. A. Selective accumulation of MyoD and myogenin mRNAs in fast and slow adult skeletal muscle is controlled by innervation and hormones. Development. 1993 Aug;118(4):1137–1147. doi: 10.1242/dev.118.4.1137. [DOI] [PubMed] [Google Scholar]
  16. Jarman A. P., Grau Y., Jan L. Y., Jan Y. N. atonal is a proneural gene that directs chordotonal organ formation in the Drosophila peripheral nervous system. Cell. 1993 Jul 2;73(7):1307–1321. doi: 10.1016/0092-8674(93)90358-w. [DOI] [PubMed] [Google Scholar]
  17. Jones-Villeneuve E. M., Rudnicki M. A., Harris J. F., McBurney M. W. Retinoic acid-induced neural differentiation of embryonal carcinoma cells. Mol Cell Biol. 1983 Dec;3(12):2271–2279. doi: 10.1128/mcb.3.12.2271. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Krieg P. A., Melton D. A. In vitro RNA synthesis with SP6 RNA polymerase. Methods Enzymol. 1987;155:397–415. doi: 10.1016/0076-6879(87)55027-3. [DOI] [PubMed] [Google Scholar]
  19. Kume H., Maruyama K., Tomita T., Iwatsubo T., Saido T. C., Obata K. Molecular cloning of a novel basic helix-loop-helix protein from the rat brain. Biochem Biophys Res Commun. 1996 Feb 15;219(2):526–530. doi: 10.1006/bbrc.1996.0267. [DOI] [PubMed] [Google Scholar]
  20. 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]
  21. Lo L. C., Johnson J. E., Wuenschell C. W., Saito T., Anderson D. J. Mammalian achaete-scute homolog 1 is transiently expressed by spatially restricted subsets of early neuroepithelial and neural crest cells. Genes Dev. 1991 Sep;5(9):1524–1537. doi: 10.1101/gad.5.9.1524. [DOI] [PubMed] [Google Scholar]
  22. Masters B. A., Quaife C. J., Erickson J. C., Kelly E. J., Froelick G. J., Zambrowicz B. P., Brinster R. L., Palmiter R. D. Metallothionein III is expressed in neurons that sequester zinc in synaptic vesicles. J Neurosci. 1994 Oct;14(10):5844–5857. doi: 10.1523/JNEUROSCI.14-10-05844.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. 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]
  24. 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]
  25. Nedivi E., Basi G. S., Akey I. V., Skene J. H. A neural-specific GAP-43 core promoter located between unusual DNA elements that interact to regulate its activity. J Neurosci. 1992 Mar;12(3):691–704. doi: 10.1523/JNEUROSCI.12-03-00691.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. 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]
  27. Shen C. P., Kadesch T. B-cell-specific DNA binding by an E47 homodimer. Mol Cell Biol. 1995 Aug;15(8):4518–4524. doi: 10.1128/mcb.15.8.4518. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Shimizu C., Akazawa C., Nakanishi S., Kageyama R. MATH-2, a mammalian helix-loop-helix factor structurally related to the product of Drosophila proneural gene atonal, is specifically expressed in the nervous system. Eur J Biochem. 1995 Apr 1;229(1):239–248. doi: 10.1111/j.1432-1033.1995.tb20461.x. [DOI] [PubMed] [Google Scholar]
  29. Tamimi R., Steingrimsson E., Copeland N. G., Dyer-Montgomery K., Lee J. E., Hernandez R., Jenkins N. A., Tapscott S. J. The NEUROD gene maps to human chromosome 2q32 and mouse chromosome 2. Genomics. 1996 Jun 15;34(3):418–421. doi: 10.1006/geno.1996.0306. [DOI] [PubMed] [Google Scholar]
  30. Tamura M., Noda M. Identification of a DNA sequence involved in osteoblast-specific gene expression via interaction with helix-loop-helix (HLH)-type transcription factors. J Cell Biol. 1994 Aug;126(3):773–782. doi: 10.1083/jcb.126.3.773. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Tapscott S. J., Thayer M. J., Weintraub H. Deficiency in rhabdomyosarcomas of a factor required for MyoD activity and myogenesis. Science. 1993 Mar 5;259(5100):1450–1453. doi: 10.1126/science.8383879. [DOI] [PubMed] [Google Scholar]
  32. Tassabehji M., Newton V. E., Read A. P. Waardenburg syndrome type 2 caused by mutations in the human microphthalmia (MITF) gene. Nat Genet. 1994 Nov;8(3):251–255. doi: 10.1038/ng1194-251. [DOI] [PubMed] [Google Scholar]
  33. Turner D. L., Weintraub H. Expression of achaete-scute homolog 3 in Xenopus embryos converts ectodermal cells to a neural fate. Genes Dev. 1994 Jun 15;8(12):1434–1447. doi: 10.1101/gad.8.12.1434. [DOI] [PubMed] [Google Scholar]
  34. Venuti J. M., Morris J. H., Vivian J. L., Olson E. N., Klein W. H. Myogenin is required for late but not early aspects of myogenesis during mouse development. J Cell Biol. 1995 Feb;128(4):563–576. doi: 10.1083/jcb.128.4.563. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Weintraub H., Davis R., Lockshon D., Lassar A. MyoD binds cooperatively to two sites in a target enhancer sequence: occupancy of two sites is required for activation. Proc Natl Acad Sci U S A. 1990 Aug;87(15):5623–5627. doi: 10.1073/pnas.87.15.5623. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. 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]
  37. Weintraub H., Dwarki V. J., Verma I., Davis R., Hollenberg S., Snider L., Lassar A., Tapscott S. J. Muscle-specific transcriptional activation by MyoD. Genes Dev. 1991 Aug;5(8):1377–1386. doi: 10.1101/gad.5.8.1377. [DOI] [PubMed] [Google Scholar]
  38. 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]
  39. Yasunami M., Suzuki K., Maruyama H., Kawakami H., Nagai Y., Hagiwara M., Ohkubo H. Molecular cloning and characterization of a cDNA encoding a novel basic helix-loop-helix protein structurally related to Neuro-D/BHF1. Biochem Biophys Res Commun. 1996 Mar 27;220(3):754–758. doi: 10.1006/bbrc.1996.0476. [DOI] [PubMed] [Google Scholar]
  40. Zhuang Y., Soriano P., Weintraub H. The helix-loop-helix gene E2A is required for B cell formation. Cell. 1994 Dec 2;79(5):875–884. doi: 10.1016/0092-8674(94)90076-0. [DOI] [PubMed] [Google Scholar]

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