REST: A mammalian silencer protein that restricts sodium channel gene expression to neurons

Expression of the type II voltage-dependent sodium channel gene is restricted to neurons by a silencer element active in nonneuronal cells. We have cloned cDNA coding for a transcription factor (REST) that binds to this silencer element. Expression of a recombinant REST protein confers the ability to silence type II reporter genes in neuronal cell types lacking the native REST protein, whereas expression of a dominant negative form of REST in nonneuronal cells relieves silencing mediated by the native protein. REST transcripts in developing mouse embryos are detected ubiquitously outside of the nervous system. We propose that expression of the type II sodium channel gene in neurons reflects a default pathway that is blocked in nonneuronal cells by the presence of REST.

[1]  M. Frohman,et al.  Rapid amplification of complementary DNA ends for generation of full-length complementary DNAs: thermal RACE. , 1993, Methods in enzymology.

[2]  J. Bonventre,et al.  The Krüppel-associated box-A (KRAB-A) domain of zinc finger proteins mediates transcriptional repression. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[3]  P. Bartel,et al.  Using the two-hybrid system to detect protein - protein interactions. , 1993 .

[4]  J. Sambrook,et al.  Molecular Cloning: A Laboratory Manual , 2001 .

[5]  Jeremy B. A. Green.  Roads to neuralness: Embryonic neural induction as derepression of a default state , 1994, Cell.

[6]  J. Coleman,et al.  Zinc proteins: enzymes, storage proteins, transcription factors, and replication proteins. , 1992, Annual review of biochemistry.

[7]  U. K. Laemmli,et al.  Cleavage of Structural Proteins during the Assembly of the Head of Bacteriophage T4 , 1970, Nature.

[8]  R. Kornberg,et al.  Accurate initiation at RNA polymerase II promoters in extracts from Saccharomyces cerevisiae. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[9]  I. Herskowitz,et al.  Isolation of ORC6, a component of the yeast origin recognition complex by a one-hybrid system. , 1993, Science.

[10]  G. Fink,et al.  Methods in yeast genetics , 1979 .

[11]  A Klug,et al.  Toward a code for the interactions of zinc fingers with DNA: selection of randomized fingers displayed on phage. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[12]  M. Frohman,et al.  Rapid production of full-length cDNAs from rare transcripts: amplification using a single gene-specific oligonucleotide primer. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[13]  Scott W. Emmons,et al.  A transcription factor controlling development of peripheral sense organs in C. elegans , 1995, Nature.

[14]  W. Moody,et al.  Na+ channel mis‐expression accelerates K+ channel development in embryonic Xenopus laevis skeletal muscle. , 1994, The Journal of physiology.

[15]  J. Diffley,et al.  Interaction of Dbf4, the Cdc7 protein kinase regulatory subunit, with yeast replication origins in vivo. , 1994, Science.

[16]  David J. Anderson,et al.  Analysis of SCG10 gene expression in transgenic mice reveals that neural specificity is achieved through selective derepression , 1990, Neuron.

[17]  R. Renkawitz,et al.  Transcriptional repression in eukaryotes. , 1990, Trends in genetics : TIG.

[18]  M. Frohman,et al.  Isolation of the mouse Hox-2.9 gene; analysis of embryonic expression suggests that positional information along the anterior-posterior axis is specified by mesoderm. , 1990, Development.

[19]  David J. Anderson,et al.  Mammalian achaete-scute homolog 1 is required for the early development of olfactory and autonomic neurons , 1993, Cell.

[20]  G. Mandel,et al.  Silencing the type II sodium channel gene: A model for neural-specific gene regulation , 1992, Neuron.

[21]  F. Sanger,et al.  DNA sequencing with chain-terminating inhibitors. , 1977, Proceedings of the National Academy of Sciences of the United States of America.

[22]  M. Johnston,et al.  Two systems of glucose repression of the GAL1 promoter in Saccharomyces cerevisiae , 1990, Molecular and cellular biology.

[23]  J. Manley,et al.  Functional domains of the Drosophila Engrailed protein. , 1993, The EMBO journal.

[24]  R. Roeder,et al.  Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. , 1983, Nucleic acids research.

[25]  D. Hartley.  Cellular interactions in development : a practical approach , 1993 .

[26]  T. Joh,et al.  Neuron-specific expression of the human dopamine beta-hydroxylase gene requires both the cAMP-response element and a silencer region. , 1993, The Journal of biological chemistry.

[27]  N. Pavletich,et al.  Zinc finger-DNA recognition: crystal structure of a Zif268-DNA complex at 2.1 A , 1991, Science.

[28]  P. Greengard,et al.  Identification of a functional silencer element involved in neuron-specific expression of the synapsin I gene. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[29]  E. Nedivi,et al.  A neural-specific GAP-43 core promoter located between unusual DNA elements that interact to regulate its activity , 1992, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[30]  P. Brehm,et al.  A single pulse of nerve growth factor triggers long-term neuronal excitability through sodium channel gene induction , 1995, Neuron.

[31]  D. Mckinnon,et al.  Molecular basis of neural-specific gene expression. , 1993, Annual review of neuroscience.

[32]  J. Martial,et al.  The evolutionarily conserved Krüppel-associated box domain defines a subfamily of eukaryotic multifingered proteins. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[33]  Jonathan D. Licht,et al.  Drosophila Krüppel protein is a transcriptional represser , 1990, Nature.

[34]  J. Rine,et al.  Silencers, silencing, and heritable transcriptional states. , 1992, Microbiological reviews.

[35]  Y. Jan,et al.  Cell interactions and gene interactions in peripheral neurogenesis. , 1993, Genes & development.

[36]  Robert K. Davis,et al.  The myoD gene family: nodal point during specification of the muscle cell lineage. , 1991, Science.

[37]  B. Lewin.  On neuronal specificity and the molecular basis of perception , 1994, Cell.

[38]  Michael M. Wang,et al.  Molecular cloning of the olfactory neuronal transcription factor Olf-1 by genetic selection in yeast , 1993, Nature.

[39]  L. Greene,et al.  Establishment of a noradrenergic clonal line of rat adrenal pheochromocytoma cells which respond to nerve growth factor. , 1976, Proceedings of the National Academy of Sciences of the United States of America.

[40]  P. Brehm,et al.  Neuronal growth factor regulation of two different sodium channel types through distinct signal transduction pathways , 1993, The Journal of cell biology.

[41]  P. Brehm,et al.  Selective induction of brain type II Na+ channels by nerve growth factor. , 1988, Proceedings of the National Academy of Sciences of the United States of America.

[42]  Y. Jan,et al.  Maggot's hair and bug's eye: Role of cell interactions and intrinsic factors in cell fate specification , 1995, Neuron.

[43]  R. Goodman,et al.  Neuron-specific expression of the rat brain type II sodium channel gene is directed by upstream regulatory elements , 1990, Neuron.

[44]  David J. Anderson,et al.  A common silencer element in the SCG10 and type II Na+ channel genes binds a factor present in nonneuronal cells but not in neuronal cells , 1992, Neuron.

[45]  M. Kozak.  Bifunctional messenger RNAs in eukaryotes , 1986, Cell.