A regulator of transcriptional elongation controls vertebrate neuronal development

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Abstract

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.

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Figure 1: The foggy mutation disrupts neuronal development.
Figure 2: Identification of the foggy gene.
Figure 3: Sequence and domain structure of the Foggy protein.
Figure 4: The V1012D mutation abolishes the negative but not positive function of Foggy in transcription elongation.

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Acknowledgements

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.

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