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The Journal of Neuroscience, September 9, 2009, 29(36):11399-11408; doi:10.1523/JNEUROSCI.0160-09.2009

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Development/Plasticity/Repair
A Genome-Wide Screen for Spatially Restricted Expression Patterns Identifies Transcription Factors That Regulate Glial Development

Hui Fu,^1,12 Jun Cai,^5,6 Hans Clevers,⁷ Eva Fast,⁸ Susan Gray,⁴ Rachel Greenberg,⁹ Mukesh K. Jain,¹⁰ Qiufu Ma,^1,2 Mengsheng Qiu,⁶ David H. Rowitch,¹¹ Christopher M. Taylor,^1,3 and Charles D. Stiles^1,3

¹Department of Cancer Biology, Dana-Farber Cancer Institute, and ²Departments of Neurobiology and ³Microbiology and Molecular Genetics, Harvard Medical School, Boston, Massachusetts 02115, ⁴Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, ⁵Department of Pediatrics, Kosair Children's Hospital Research Institute, and ⁶Department of Anatomical Sciences and Neurobiology, School of Medicine, University of Louisville, Louisville, Kentucky 40202, ⁷Hubrecht Laboratory, 3584 CT Utrecht, The Netherlands, ⁸Department of Biology, Boston University, Boston, Massachusetts 02215, ⁹Department of Biological Sciences, Columbia College, Columbia University, New York, New York 10027, ¹⁰Case Cardiovascular Research Institute, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, ¹¹Departments of Pediatrics and Neurological Surgery and the Institute for Regeneration Medicine, University of California, San Francisco, San Francisco, California 94143, and ¹²Department of Physiology, Basic Medical College of Nanchang University, Nanchang, Jiangxi 330006, China

Correspondence should be addressed to Charles D. Stiles, Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115. Email: Charles_stiles{at}dfci.harvard.edu

Forward genetic screens in genetically accessible invertebrate organisms such as Drosophila melanogaster have shed light on transcription factors that specify formation of neurons in the vertebrate CNS. However, invertebrate models have, to date, been uninformative with respect to genes that specify formation of the vertebrate glial lineages. All recent insights into specification of vertebrate glia have come via monitoring the spatial and temporal expression patterns of individual transcription factors during development. In studies described here, we have taken this approach to the genome scale with an in silico screen of the Mahoney pictorial atlas of transcription factor expression in the developing CNS. From the population of 1445 known or probable transcription factors encoded in the mouse genome, we identify 12 novel transcription factors that are expressed in glial lineage progenitor cells. Entry-level screens for biological function establish one of these transcription factors, Klf15, as sufficient for genesis of precocious GFAP-positive astrocytes in spinal cord explants. Another transcription factor, Tcf4, plays an important role in maturation of oligodendrocyte progenitors.

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Received Jan. 12, 2009; revised Aug. 7, 2009; accepted Aug. 7, 2009.

Correspondence should be addressed to Charles D. Stiles, Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115. Email: Charles_stiles{at}dfci.harvard.edu

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