Suppressors of the egg-laying defective phenotype of sel-12 presenilin mutants implicate the CoREST corepressor complex in LIN-12/Notch signaling in C. elegans.
Presenilin is an essential component of the LIN-12/Notch signaling pathway and also plays a critical role in the genesis of Alzheimer's disease. Previously, a screen for suppressors of the egg-laying defective phenotype caused by partial loss of presenilin activity in Caenorhabditis elegans identified a number of new spr genes that are potentially involved in the regulation of LIN-12/Notch signaling or presenilin activity. Here we report the molecular identity of two spr genes, spr-1 and spr-5. Our genetic analysis indicates that loss of spr-1 elevates lin-12/Notch gene activity in many different cell fate decisions, suggesting that spr-1 is a negative regulator of LIN-12/Notch signaling. Sequence analysis revealed that spr-1 is an ortholog of human CoREST, a known corepressor. SPR-1 is localized to the nucleus and acts in a cell-autonomous manner; furthermore, human CoREST can substitute for SPR-1 in C. elegans. We also show that spr-5 encodes a homolog of p110b, another known member of the CoREST corepressor complex. Our results suggest that the CoREST corepressor complex might be functionally conserved in worms, and we discuss the potential role of SPR-1 and SPR-5 in the repression of transcription of genes involved in, or downstream of, LIN-12/Notch signal transduction.
Jarriault
Sophie
S
Howard Hughes Medical Institute, Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York 10032, USA.
Greenwald
Iva
I
D000483:Alleles; D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000235:genetics*; D029742:Caenorhabditis elegans Proteins; D002467:Cell Nucleus / Q000378:metabolism; D056970:Co-Repressor Proteins; D055233:Cornified Envelope Proline-Rich Proteins; D017931:DNA Primers / Q000737:chemistry; D004268:DNA-Binding Proteins; D004531:Eggs; D004625:Embryo, Nonmammalian / Q000502:physiology; D005260:Female; D005786:Gene Expression Regulation; D015801:Helminth Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D006801:Humans; D007763:Lac Operon / Q000502:physiology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D009154:Mutation; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D010957:Plasmids; D016133:Polymerase Chain Reaction; D011506:Proteins / Q000378:metabolism*; D012313:RNA / Q000378:metabolism; D022821:RNA Splice Sites; D051880:Receptors, Notch; D011995:Recombination, Genetic; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D019076:Transgenes / Q000502:physiology
D029742:Caenorhabditis elegans Proteins; D056970:Co-Repressor Proteins; D055233:Cornified Envelope Proline-Rich Proteins; D017931:DNA Primers; D004268:DNA-Binding Proteins; C060620:Glp-1 protein, C elegans; D015801:Helminth Proteins; C109040:Hop-1 protein, C elegans; C082460:Lin-12 protein, C elegans; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C491000:NAB2 protein, human; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D011506:Proteins; C121019:RCOR1 protein, human; D022821:RNA Splice Sites; C485650:Rcor2 protein, mouse; D051880:Receptors, Notch; D012097:Repressor Proteins; C095907:SEL-12 protein, C elegans; D012313:RNA