The development of distinct vertebrate neurons is defined by the unique profiles of genes that neurons express. It is accepted that neural genes are regulated at the point of transcription initiation, but the role of messenger RNA elongation in neural gene regulation has not been examined1,2,3. Here we describe the mutant foggy, identified in a genetic screen for mutations that affect neuronal development in zebrafish4, that displayed a reduction of dopamine-containing neurons and a corresponding surplus of serotonin-containing neurons in the hypothalamus. Positional cloning disclosed that Foggy is a brain-enriched nuclear protein that is structurally related to the transcription elongation factor Spt5 (refs 5,6,7,8,9,10,11 ,12). Foggy is not part of the basic transcription apparatus but a phosphorylation-dependent, dual regulator of transcription elongation. The mutation disrupts its repressive but not its stimulatory activity. Our results provide molecular, genetic and biochemical evidence that negative regulators of transcription elongation control key aspects of neuronal development.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Greenblatt, J. RNA polmerase II holoenzyme and transciptional regulation. Curr. Opin. Cell Biol. 9, 310–319 (1997).
Shilatifard, A., Conaway, J. W. & Conaway, R. C. Mechanism and regulation of transcriptional elongation and termination by RNA polymerase II. Curr. Opin. Genet. Dev. 7, 199–204 (1997).
Uptain, S. M., Kane, C. M. & Chamberlain, M. J. Basic mechanisms of transcript elongation and its regulation. Annu. Rev. Biochem. 66, 117– 172 (1997).
Guo, S. et al. Mutations in the zebrafish unmask shared regulatory pathways controlling the development of catecholaminergic neurons. Dev. Biol. 208, 473–487 (1999).
Swanson, M. S., Malone, E. A. & Winston, F. SPT5, an essential gene important for normal transcription in Saccharomyces cerevisiae encodes an acidic nuclear protein with a carboxy-terminal repeat. Mol. Cell Biol. 11, 3009–3019 (1991).
Swanson, M. S. & Winston, F. SPT4, SPT5 and SPT6 interactions: effects on transcription and viability in Saccharomyces cerevisiae. Genetics 132, 325–326 (1992).
Hartzog, G. A., Wada, T., Handa, H. & Winston, F. Evidence that Spt4, Spt5, and Spt6 control transcription elongation by RNA polymerase II in Saccharomyces cerevisiae. Genes Dev. 12, 357–369 (1998).
Wada, T., Takagi, T., Yamaguchi, Y., Watanabe, D. & Hande, H. Evidence that P-TEFb alleviates the negative effect of DSIF on RNA polymerase II-dependent transcription in vitro. EMBO J. 17, 7395– 7403 (1998).
Yamaguchi, Y. et al. NELF, a multisubunit complex containing RD, cooperates with DSIF to repress RNA polymerase II elongation. Cell 97, 41–51 (1999).
Yamaguchi, Y. et al. Structure and function of the human transcription elongation factor DSIF. J. Biol. Chem. 274, 8085– 8092 (1999).
Wada, T. et al. DSFI, a novel transcription elongation factor that regulates RNA polymerase II processivity, is composed of human Spt4 and Spt5 homologs. Genes Dev. 12, 343–356 (1998).
Yamaguchi, Y., Wada, T. & Handa, H. Interplay between positive and negative elongation factors: drawing a new view of DRB. Genes Cells 3, 9– 15 (1998).
Cepko, C. L. The roles of intrinsic and extrinsic cues and bHLH genes in the determination of retinal cell fates. Curr. Opin. Neurobiol. 9, 37–46 (1999).
Vos, P. et al. AFLP: a new technique for DNA fingerprinting. Nucleic Acids Res. 23, 4407–4414 (1995).
Higashijima, S., Okamoto, H., Ueno, N., Hotta, Y. & Eguchi, G. High-frequency generation of transgenic zebrafish which reliably express GFP in whole muscles of the whole body by using promoters of zebrafish origin. Dev. Biol. 192, 289 –299 (1997).
Sullivan, S. L. & Gottesman, M. E. Requirement for E. coli NusG protein in factor-dependent transcription termination. Cell 68, 989–994 (1992).
Sullivan, S. L., Ward, D. F. & Gottesman, M. E. Effect of Escherichia coli nusG function on lambda N-mediated transcription antitermination. J. Bacteriol. 174, 1339–1344 ( 1992).
Kyrpides, N. C., Woese, C. R. & Ouzounis, C. A. KOW: a novel motif linking a bacterial transcription factor with ribosomal proteins. Trends Biochem. 21, 425–426 (1996).
Hubbard, E. J., Dong, Q., Greenwald, I. Evidence for physical and functional association between EMB-5 and LIN-12 in Caenorhabditis elegans. Science 273, 112–115 (1996).
Schoenherr, C. J. & Anderson, D. J. The neuron-restrictive silencer factor (NRSF): a coordinate repressor of multiple neuron-specific genes. Science 267, 1360– 1363 (1995).
Chen, Z. F., Paquette, A. J. & Anderson, D. J. NRSF/REST is required in vivo for repression of multiple neuronal target genes during embryogenesis. Nature Genet. 20, 136–142 ( 1998).
Anderson, D. J. & Jan, Y. N. in Molecular and Cellular Approaches to Neural Development (ed. Cowan, W. M.) 26 –63 (Oxford Univ. Press, New York, 1997).
Zorick, T. S., Syroid, D. E., Brown, A., Gridley, T. & Lemke, G. Krox-20 controls SCIP expression, cell cycle exit and susceptibility to apoptosis in developing myelinating Schwann cells. Development 126, 1397–1406 (1999).
Turner, C. A. Jr, Mack, D. H. & Davis, M. M. Blimp-1, a novel zinc finger-containing protein that can drive the maturation of B lymphocytes into immunoglobulin-secreting cells. Cell 77, 297–306 (1994).
Persons, D. A. et al. Enforced expression of the GATA-2 transcription factor blocks normal hematopoiesis. Blood 93, 488– 499 (1999).
We thank E. Chen and P. Ma for help with the AFLP analysis; Y. Yan and J. Postlethwait for anchoring our AFLP markers to the zebrafish genetic map; A. Greenleaf and D. Price for providing the plasmid pSLG402; M. Hynes, J. Lin, B. Lu M. Tessier Lavigne, B. Barres and S. Wilson for critically reading the manuscript; D. Anderson for helpful information; and J. Ligos, A Bruce and V. Goodwin for help with graphics. Y.Y. is a JSPS Research Fellow. This work was supported in part by a grant-in-aid for Scientific Research on Priority Areas from the Ministry of Education, Sciences, Sports, and Culture of Japan, and a grant from NEDO to H.H.
About this article
Animal Cells and Systems (2019)
Genes & Development (2019)
Nature Communications (2019)
Structure and nucleic acid binding properties of KOW domains 4 and 6–7 of human transcription elongation factor DSIF
Scientific Reports (2018)
Nature Structural & Molecular Biology (2017)