A regulatory code for neurogenic gene expression in the Drosophila embryo

Bioinformatics methods have identified enhancers that mediate restricted expression in the Drosophila embryo. However, only a small fraction of the predicted enhancers actually work when tested in vivo. In the present study, co-regulated neurogenic enhancers that are activated by intermediate levels of the Dorsal regulatory gradient are shown to contain several shared sequence motifs. These motifs permitted the identification of new neurogenic enhancers with high precision: five out of seven predicted enhancers direct restricted expression within ventral regions of the neurogenic ectoderm. Mutations in some of the shared motifs disrupt enhancer function, and evidence is presented that the Twist and Su(H) regulatory proteins are essential for the specification of the ventral neurogenic ectoderm prior to gastrulation. The regulatory model of neurogenic gene expression defined in this study permitted the identification of a neurogenic enhancer in the distant Anopheles genome. We discuss the prospects for deciphering regulatory codes that link primary DNA sequence information with predicted patterns of gene expression.

[1]  R. Tjian,et al.  Transcription regulation and animal diversity , 2003, Nature.

[2]  Paul Richardson,et al.  The Draft Genome of Ciona intestinalis: Insights into Chordate and Vertebrate Origins , 2002, Science.

[3]  Michael Levine,et al.  Whole-Genome Analysis of Dorsal-Ventral Patterning in the Drosophila Embryo , 2002, Cell.

[4]  Michael Levine,et al.  Decoding cis-regulatory DNAs in the Drosophila genome. , 2002, Current opinion in genetics & development.

[5]  Paramvir S. Dehal,et al.  Whole-Genome Shotgun Assembly and Analysis of the Genome of Fugu rubripes , 2002, Science.

[6]  Michael Levine,et al.  Dorsal gradient networks in the Drosophila embryo. , 2002, Developmental biology.

[7]  William H. Majoros,et al.  A Comparison of Whole-Genome Shotgun-Derived Mouse Chromosome 16 and the Human Genome , 2002, Science.

[8]  G. Stormo,et al.  Identification of a novel cis-regulatory element involved in the heat shock response in Caenorhabditis elegans using microarray gene expression and computational methods. , 2002, Genome research.

[9]  Michael Levine,et al.  The Snail repressor positions Notch signaling in the Drosophila embryo. , 2002, Development.

[10]  G. Rubin,et al.  Exploiting transcription factor binding site clustering to identify cis-regulatory modules involved in pattern formation in the Drosophila genome , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[11]  Marc S Halfon,et al.  Computation-based discovery of related transcriptional regulatory modules and motifs using an experimentally validated combinatorial model. , 2002, Genome research.

[12]  Peter W. Markstein,et al.  Genome-wide analysis of clustered Dorsal binding sites identifies putative target genes in the Drosophila embryo , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[13]  M. Baylies,et al.  Dimerization partners determine the activity of the Twist bHLH protein during Drosophila mesoderm development. , 2001, Development.

[14]  F. Schweisguth,et al.  Repression by suppressor of hairless and activation by Notch are required to define a single row of single-minded expressing cells in the Drosophila embryo. , 2000, Genes & development.

[15]  S. Roth,et al.  The role of brinker in mediating the graded response to Dpp in early Drosophila embryos. , 1999, Development.

[16]  M. Leptin,et al.  Identification of novel genes in Drosophila reveals the complex regulation of early gene activity in the mesoderm. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[17]  G. Grumbling,et al.  Vein is a novel component in the Drosophila epidermal growth factor receptor pathway with similarity to the neuregulins. , 1996, Genes & development.

[18]  M. Levine,et al.  Threshold responses to the dorsal regulatory gradient and the subdivision of primary tissue territories in the Drosophila embryo. , 1996, Current opinion in genetics & development.

[19]  A. Mccarthy.  Development , 1996, Current Opinion in Neurobiology.

[20]  J. Posakony,et al.  Suppressor of hairless directly activates transcription of enhancer of split complex genes in response to Notch receptor activity. , 1995, Genes & development.

[21]  M. Levine,et al.  Interactions between dorsal and helix-loop-helix proteins initiate the differentiation of the embryonic mesoderm and neuroectoderm in Drosophila. , 1993, Genes & development.

[22]  G. Gloor,et al.  Type I repressors of P element mobility. , 1993, Genetics.

[23]  Michael Levine,et al.  Binding affinities and cooperative interactions with bHLH activators delimit threshold responses to the dorsal gradient morphogen , 1993, Cell.

[24]  M. Levine,et al.  Regulation of even‐skipped stripe 2 in the Drosophila embryo. , 1992, The EMBO journal.

[25]  M. Levine,et al.  The dorsal gradient morphogen regulates stripes of rhomboid expression in the presumptive neuroectoderm of the Drosophila embryo. , 1992, Genes & development.

[26]  J. Posakony,et al.  Suppressor of Hairless, the Drosophila homolog of the mouse recombination signal-binding protein gene, controls sensory organ cell fates , 1992, Cell.

[27]  P. Lieberman,et al.  Dorsal-ventral patterning in Drosophila: DNA binding of snail protein to the single-minded gene. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[28]  D Kosman,et al.  Establishment of the mesoderm-neuroectoderm boundary in the Drosophila embryo. , 1991, Science.

[29]  D Kosman,et al.  The dorsal morphogen gradient regulates the mesoderm determinant twist in early Drosophila embryos. , 1991, Genes & development.

[30]  B. Thisse,et al.  Sequence-specific transactivation of the Drosophila twist gene by the dorsal gene product , 1991, Cell.

[31]  Y. Jan,et al.  rhomboid, a gene required for dorsoventral axis establishment and peripheral nervous system development in Drosophila melanogaster. , 1990, Genes & development.

[32]  Y. Jan,et al.  Interactions between heterologous helix-loop-helix proteins generate complexes that bind specifically to a common DNA sequence , 1989, Cell.

[33]  B. Thisse,et al.  The twist gene: isolation of a Drosophila zygotic gene necessary for the establishment of dorsoventral pattern. , 1987, Nucleic acids research.

[34]  K. White,et al.  Genetic and developmental analysis of the locus vnd in Drosophila melanogaster. , 1983, Genetics.

[35]  G. Rubin,et al.  Genetic transformation of Drosophila with transposable element vectors. , 1982, Science.