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1.
Genetics ; 227(3)2024 Jul 08.
Article in English | MEDLINE | ID: mdl-38717968

ABSTRACT

The final step in Notch signaling activation is the transmembrane cleavage of Notch receptor by γ secretase. Thus far, genetic and biochemical evidence indicates that four subunits are essential for γ secretase activity in vivo: presenilin (the catalytic core), APH-1, PEN-2, and APH-2/nicastrin. Although some γ secretase activity has been detected in APH-2/nicastrin-deficient mammalian cell lines, the lack of biological relevance for this activity has left the quaternary γ secretase model unchallenged. Here, we provide the first example of in vivo Notch signal transduction without APH-2/nicastrin. The surprising dispensability of APH-2/nicastrin is observed in Caenorhabditis elegans germline stem cells (GSCs) and contrasts with its essential role in previously described C. elegans Notch signaling events. Depletion of GLP-1/Notch, presenilin, APH-1, or PEN-2 causes a striking loss of GSCs. In contrast, aph-2/nicastrin mutants maintain GSCs and exhibit robust and localized expression of the downstream Notch target sygl-1. Interestingly, APH-2/nicastrin is normally expressed in GSCs and becomes essential under conditions of compromised Notch function. Further insight is provided by reconstituting the C. elegans γ secretase complex in yeast, where we find that APH-2/nicastrin increases but is not essential for γ secretase activity. Together, our results are most consistent with a revised model of γ secretase in which the APH-2/nicastrin subunit has a modulatory, rather than obligatory role. We propose that a trimeric presenilin-APH-1-PEN-2 γ secretase complex can provide a low level of γ secretase activity, and that cellular context determines whether or not APH-2/nicastrin is essential for effective Notch signal transduction.


Subject(s)
Amyloid Precursor Protein Secretases , Caenorhabditis elegans Proteins , Caenorhabditis elegans , Germ Cells , Receptors, Notch , Signal Transduction , Animals , Caenorhabditis elegans/metabolism , Caenorhabditis elegans/genetics , Receptors, Notch/metabolism , Receptors, Notch/genetics , Caenorhabditis elegans Proteins/metabolism , Caenorhabditis elegans Proteins/genetics , Amyloid Precursor Protein Secretases/metabolism , Amyloid Precursor Protein Secretases/genetics , Germ Cells/metabolism , Stem Cells/metabolism , Stem Cells/cytology , Membrane Glycoproteins/metabolism , Membrane Glycoproteins/genetics
2.
Genetics ; 208(2): 745-762, 2018 02.
Article in English | MEDLINE | ID: mdl-29242286

ABSTRACT

Functionally redundant genes present a puzzle as to their evolutionary preservation, and offer an interesting opportunity for molecular specialization. In Caenorhabditis elegans, either one of two presenilin genes (sel-12 or hop-1) facilitate Notch activation, providing the catalytic subunit for the γ secretase proteolytic enzyme complex. For all known Notch signaling events, sel-12 can mediate Notch activation, so the conservation of hop-1 remains a mystery. Here, we uncover a novel "late-onset" germline Notch phenotype in which HOP-1-deficient worms fail to maintain proliferating germline stem cells during adulthood. Either SEL-12 or HOP-1 presenilin can impart sufficient Notch signaling for the establishment and expansion of the germline, but maintenance of an adult stem cell pool relies exclusively on HOP-1-mediated Notch signaling. We also show that HOP-1 is necessary for maximum fecundity and reproductive span. The low-fecundity phenotype of hop-1 mutants can be phenocopied by switching off glp-1/Notch function during the last stage of larval development. We propose that at the end of larval development, dual presenilin usage switches exclusively to HOP-1, perhaps offering opportunities for differential regulation of the germline during adulthood. Additional defects in oocyte size and production rate in hop-1 and glp-1 mutants indicate that the process of oogenesis is compromised when germline Notch signaling is switched off. We calculate that in wild-type adults, as much as 86% of cells derived from the stem cell pool function to support oogenesis. This work suggests that an important role for Notch signaling in the adult germline is to furnish a large and continuous supply of nurse cells to support the efficiency of oogenesis.


Subject(s)
Caenorhabditis elegans/genetics , Germ Cells/metabolism , Membrane Proteins/deficiency , Receptors, Notch/metabolism , Signal Transduction , Alleles , Animals , Caenorhabditis elegans Proteins , Cell Proliferation , Gain of Function Mutation , Glucagon-Like Peptide-1 Receptor/metabolism , Gonads/metabolism , Male , Mutation , Oocytes/metabolism , Oogenesis , Phenotype , Reproduction/genetics
3.
Genetics ; 190(3): 1043-57, 2012 Mar.
Article in English | MEDLINE | ID: mdl-22209900

ABSTRACT

Notch signaling pathways can be regulated through a variety of cellular mechanisms, and genetically compromised systems provide useful platforms from which to search for the responsible modulators. The Caenorhabditis elegans gene aph-1 encodes a component of γ-secretase, which is essential for Notch signaling events throughout development. By looking for suppressors of the incompletely penetrant aph-1(zu147) mutation, we identify a new gene, sao-1 (suppressor of aph-one), that negatively regulates aph-1(zu147) activity in the early embryo. The sao-1 gene encodes a novel protein that contains a GYF protein-protein interaction domain and interacts specifically with SEL-10, an Fbw7 component of SCF E3 ubiquitin ligases. We demonstrate that the embryonic lethality of aph-1(zu147) mutants can be suppressed by removing sao-1 activity or by mutations that disrupt the SAO-1-SEL-10 protein interaction. Decreased sao-1 activity also influences Notch signaling events when they are compromised at different molecular steps of the pathway, such as at the level of the Notch receptor GLP-1 or the downstream transcription factor LAG-1. Combined analysis of the SAO-1-SEL-10 protein interaction and comparisons of sao-1 and sel-10 genetic interactions suggest a possible role for SAO-1 as an accessory protein that participates with SEL-10 in downregulation of Notch signaling. This work provides the first mutant analysis of a GYF-domain protein in either C. elegans or Drosophila and introduces a new type of Fbw7-interacting protein that acts in a subset of Fbw7 functions.


Subject(s)
Caenorhabditis elegans Proteins/genetics , Caenorhabditis elegans Proteins/metabolism , Caenorhabditis elegans/metabolism , Carrier Proteins/genetics , Carrier Proteins/metabolism , Cell Cycle Proteins/metabolism , Receptors, Notch/metabolism , Ubiquitin-Protein Ligases/metabolism , Adaptor Proteins, Signal Transducing , Amino Acid Sequence , Animals , Caenorhabditis elegans/embryology , Caenorhabditis elegans/genetics , Caenorhabditis elegans Proteins/chemistry , Carrier Proteins/chemistry , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Embryonic Development/genetics , Gene Order , Genes, Lethal , Glucagon-Like Peptide-1 Receptor , Homeodomain Proteins/genetics , Homeodomain Proteins/metabolism , Molecular Sequence Data , Mutation , Protein Binding , Protein Structure, Tertiary , Receptors, Glucagon/genetics , Receptors, Glucagon/metabolism , Receptors, Notch/antagonists & inhibitors , Sequence Alignment , Signal Transduction
4.
Dev Cell ; 3(1): 6-7, 2002 Jul.
Article in English | MEDLINE | ID: mdl-12110162

ABSTRACT

Presenilins mediate the gamma-secretase cleavage of Notch transmembrane receptors as well as the transmembrane beta-amyloid precursor protein (betaAPP), but they are not thought to accomplish this alone. Recent genetic screens in C. elegans, presented in this issue of Developmental Cell, identify two genes that are essential to gamma-secretase activity and may interact with presenilins.


Subject(s)
Amyloid beta-Protein Precursor/metabolism , Caenorhabditis elegans Proteins , Cell Membrane/metabolism , Eukaryotic Cells/metabolism , Homeodomain Proteins/metabolism , Membrane Proteins/metabolism , Amyloid beta-Protein Precursor/genetics , Animals , Cell Membrane/ultrastructure , Eukaryotic Cells/ultrastructure , Homeodomain Proteins/genetics , Humans , Membrane Proteins/genetics , Mutation/genetics , Presenilin-1 , Receptors, Notch
5.
Proc Natl Acad Sci U S A ; 99(2): 775-9, 2002 Jan 22.
Article in English | MEDLINE | ID: mdl-11792846

ABSTRACT

Early embryonic cells in Caenorhabditis elegans embryos interact through a signaling pathway closely related to the Notch signaling pathway in Drosophila and vertebrates. Components of this pathway include a ligand, receptor, the presenilin proteins, and a novel protein, APH-2, that is related to the Nicastrin protein in humans. Here we identify the aph-1 gene as a new component of the Notch pathway in Caenorhabditis elegans. aph-1 is predicted to encode a novel, highly conserved multipass membrane protein. We show that aph-1 and the presenilin genes share a similar function in that they are both required for proper cell-surface localization of APH-2/Nicastrin.


Subject(s)
Caenorhabditis elegans Proteins/genetics , Caenorhabditis elegans Proteins/physiology , Caenorhabditis elegans/embryology , Caenorhabditis elegans/genetics , Homeodomain Proteins/genetics , Homeodomain Proteins/physiology , Membrane Proteins/genetics , Membrane Proteins/physiology , Amino Acid Sequence , Amyloid Precursor Protein Secretases , Animals , Cell Membrane/physiology , Genes, Helminth , Helminth Proteins/genetics , Helminth Proteins/physiology , Membrane Glycoproteins/genetics , Membrane Glycoproteins/physiology , Molecular Sequence Data , Mutation , Phenotype , Receptors, Notch , Sequence Homology, Amino Acid , Signal Transduction
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