Single-cell profiling screen identifies microtubule-dependent reduction of variability in signaling

Autores
Pesce, Gustavo C.; Zdraljevic, Stefan; Peria, William J.; Bush, Alan; Repetto, María Victoria; Rockwell, Daniel; Yu, Richard C.; Colman Lerner, Alejandro Ariel; Brent, Roger
Año de publicación
2018
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Populations of isogenic cells often respond coherently to signals, despite differences in protein abundance and cell state. Previously, we uncovered processes in the Saccharomyces cerevisiae pheromone response system (PRS) that reduced cell-to-cell variability in signal strength and cellular response. Here, we screened 1,141 non-essential genes to identify 50 “variability genes”. Most had distinct, separable effects on strength and variability of the PRS, defining these quantities as genetically distinct “axes” of system behavior. Three genes affected cytoplasmic microtubule function: BIM1, GIM2, and GIM4. We used genetic and chemical perturbations to show that, without microtubules, PRS output is reduced but variability is unaffected, while, when microtubules are present but their function is perturbed, output is sometimes lowered, but its variability is always high. The increased variability caused by microtubule perturbations required the PRS MAP kinase Fus3 and a process at or upstream of Ste5, the membrane-localized scaffold to which Fus3 must bind to be activated. Visualization of Ste5 localization dynamics demonstrated that perturbing microtubules destabilized Ste5 at the membrane signaling site. The fact that such microtubule perturbations cause aberrant fate and polarity decisions in mammals suggests that microtubule-dependent signal stabilization might also operate throughout metazoans.
Fil: Pesce, Gustavo C.. Abalone Bio, Inc; Estados Unidos
Fil: Zdraljevic, Stefan. Northwestern University; Estados Unidos
Fil: Peria, William J.. Fred Hutchinson Cancer Research Center; Estados Unidos
Fil: Bush, Alan. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina
Fil: Repetto, María Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina
Fil: Rockwell, Daniel. Abalone Bio Inc; Estados Unidos
Fil: Yu, Richard C.. Abalone Bio Inc; Estados Unidos
Fil: Colman Lerner, Alejandro Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina
Fil: Brent, Roger. Fred Hutchinson Cancer Research Center; Estados Unidos
Materia
CELL-TO-CELL VARIABILITY
GENETIC SCREEN
MAP KINASE
MICROTUBULES
NOISE
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/89279
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/89279
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Single-cell profiling screen identifies microtubule-dependent reduction of variability in signalingPesce, Gustavo C.Zdraljevic, StefanPeria, William J.Bush, AlanRepetto, María VictoriaRockwell, DanielYu, Richard C.Colman Lerner, Alejandro ArielBrent, RogerCELL-TO-CELL VARIABILITYGENETIC SCREENMAP KINASEMICROTUBULESNOISEhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Populations of isogenic cells often respond coherently to signals, despite differences in protein abundance and cell state. Previously, we uncovered processes in the Saccharomyces cerevisiae pheromone response system (PRS) that reduced cell-to-cell variability in signal strength and cellular response. Here, we screened 1,141 non-essential genes to identify 50 “variability genes”. Most had distinct, separable effects on strength and variability of the PRS, defining these quantities as genetically distinct “axes” of system behavior. Three genes affected cytoplasmic microtubule function: BIM1, GIM2, and GIM4. We used genetic and chemical perturbations to show that, without microtubules, PRS output is reduced but variability is unaffected, while, when microtubules are present but their function is perturbed, output is sometimes lowered, but its variability is always high. The increased variability caused by microtubule perturbations required the PRS MAP kinase Fus3 and a process at or upstream of Ste5, the membrane-localized scaffold to which Fus3 must bind to be activated. Visualization of Ste5 localization dynamics demonstrated that perturbing microtubules destabilized Ste5 at the membrane signaling site. The fact that such microtubule perturbations cause aberrant fate and polarity decisions in mammals suggests that microtubule-dependent signal stabilization might also operate throughout metazoans.Fil: Pesce, Gustavo C.. Abalone Bio, Inc; Estados UnidosFil: Zdraljevic, Stefan. Northwestern University; Estados UnidosFil: Peria, William J.. Fred Hutchinson Cancer Research Center; Estados UnidosFil: Bush, Alan. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Repetto, María Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Rockwell, Daniel. Abalone Bio Inc; Estados UnidosFil: Yu, Richard C.. Abalone Bio Inc; Estados UnidosFil: Colman Lerner, Alejandro Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; ArgentinaFil: Brent, Roger. Fred Hutchinson Cancer Research Center; Estados UnidosNature Publishing Group2018-04info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/89279Pesce, Gustavo C.; Zdraljevic, Stefan; Peria, William J.; Bush, Alan; Repetto, María Victoria; et al.; Single-cell profiling screen identifies microtubule-dependent reduction of variability in signaling; Nature Publishing Group; Molecular Systems Biology; 14; 4; 4-2018; 1-201744-4292CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.embopress.org/doi/full/10.15252/msb.20167390info:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5884679/info:eu-repo/semantics/altIdentifier/doi/10.15252/msb.20167390info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-22T12:09:16Zoai:ri.conicet.gov.ar:11336/89279instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-22 12:09:17.169CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Single-cell profiling screen identifies microtubule-dependent reduction of variability in signaling
title Single-cell profiling screen identifies microtubule-dependent reduction of variability in signaling
spellingShingle Single-cell profiling screen identifies microtubule-dependent reduction of variability in signaling
Pesce, Gustavo C.
CELL-TO-CELL VARIABILITY
GENETIC SCREEN
MAP KINASE
MICROTUBULES
NOISE
title_short Single-cell profiling screen identifies microtubule-dependent reduction of variability in signaling
title_full Single-cell profiling screen identifies microtubule-dependent reduction of variability in signaling
title_fullStr Single-cell profiling screen identifies microtubule-dependent reduction of variability in signaling
title_full_unstemmed Single-cell profiling screen identifies microtubule-dependent reduction of variability in signaling
title_sort Single-cell profiling screen identifies microtubule-dependent reduction of variability in signaling
dc.creator.none.fl_str_mv Pesce, Gustavo C.
Zdraljevic, Stefan
Peria, William J.
Bush, Alan
Repetto, María Victoria
Rockwell, Daniel
Yu, Richard C.
Colman Lerner, Alejandro Ariel
Brent, Roger
author Pesce, Gustavo C.
author_facet Pesce, Gustavo C.
Zdraljevic, Stefan
Peria, William J.
Bush, Alan
Repetto, María Victoria
Rockwell, Daniel
Yu, Richard C.
Colman Lerner, Alejandro Ariel
Brent, Roger
author_role author
author2 Zdraljevic, Stefan
Peria, William J.
Bush, Alan
Repetto, María Victoria
Rockwell, Daniel
Yu, Richard C.
Colman Lerner, Alejandro Ariel
Brent, Roger
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv CELL-TO-CELL VARIABILITY
GENETIC SCREEN
MAP KINASE
MICROTUBULES
NOISE
topic CELL-TO-CELL VARIABILITY
GENETIC SCREEN
MAP KINASE
MICROTUBULES
NOISE
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Populations of isogenic cells often respond coherently to signals, despite differences in protein abundance and cell state. Previously, we uncovered processes in the Saccharomyces cerevisiae pheromone response system (PRS) that reduced cell-to-cell variability in signal strength and cellular response. Here, we screened 1,141 non-essential genes to identify 50 “variability genes”. Most had distinct, separable effects on strength and variability of the PRS, defining these quantities as genetically distinct “axes” of system behavior. Three genes affected cytoplasmic microtubule function: BIM1, GIM2, and GIM4. We used genetic and chemical perturbations to show that, without microtubules, PRS output is reduced but variability is unaffected, while, when microtubules are present but their function is perturbed, output is sometimes lowered, but its variability is always high. The increased variability caused by microtubule perturbations required the PRS MAP kinase Fus3 and a process at or upstream of Ste5, the membrane-localized scaffold to which Fus3 must bind to be activated. Visualization of Ste5 localization dynamics demonstrated that perturbing microtubules destabilized Ste5 at the membrane signaling site. The fact that such microtubule perturbations cause aberrant fate and polarity decisions in mammals suggests that microtubule-dependent signal stabilization might also operate throughout metazoans.
Fil: Pesce, Gustavo C.. Abalone Bio, Inc; Estados Unidos
Fil: Zdraljevic, Stefan. Northwestern University; Estados Unidos
Fil: Peria, William J.. Fred Hutchinson Cancer Research Center; Estados Unidos
Fil: Bush, Alan. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina
Fil: Repetto, María Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina
Fil: Rockwell, Daniel. Abalone Bio Inc; Estados Unidos
Fil: Yu, Richard C.. Abalone Bio Inc; Estados Unidos
Fil: Colman Lerner, Alejandro Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Fisiología, Biología Molecular y Neurociencias. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Fisiología, Biología Molecular y Neurociencias; Argentina
Fil: Brent, Roger. Fred Hutchinson Cancer Research Center; Estados Unidos
description Populations of isogenic cells often respond coherently to signals, despite differences in protein abundance and cell state. Previously, we uncovered processes in the Saccharomyces cerevisiae pheromone response system (PRS) that reduced cell-to-cell variability in signal strength and cellular response. Here, we screened 1,141 non-essential genes to identify 50 “variability genes”. Most had distinct, separable effects on strength and variability of the PRS, defining these quantities as genetically distinct “axes” of system behavior. Three genes affected cytoplasmic microtubule function: BIM1, GIM2, and GIM4. We used genetic and chemical perturbations to show that, without microtubules, PRS output is reduced but variability is unaffected, while, when microtubules are present but their function is perturbed, output is sometimes lowered, but its variability is always high. The increased variability caused by microtubule perturbations required the PRS MAP kinase Fus3 and a process at or upstream of Ste5, the membrane-localized scaffold to which Fus3 must bind to be activated. Visualization of Ste5 localization dynamics demonstrated that perturbing microtubules destabilized Ste5 at the membrane signaling site. The fact that such microtubule perturbations cause aberrant fate and polarity decisions in mammals suggests that microtubule-dependent signal stabilization might also operate throughout metazoans.
publishDate 2018
dc.date.none.fl_str_mv 2018-04
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/89279
Pesce, Gustavo C.; Zdraljevic, Stefan; Peria, William J.; Bush, Alan; Repetto, María Victoria; et al.; Single-cell profiling screen identifies microtubule-dependent reduction of variability in signaling; Nature Publishing Group; Molecular Systems Biology; 14; 4; 4-2018; 1-20
1744-4292
CONICET Digital
CONICET
url http://hdl.handle.net/11336/89279
identifier_str_mv Pesce, Gustavo C.; Zdraljevic, Stefan; Peria, William J.; Bush, Alan; Repetto, María Victoria; et al.; Single-cell profiling screen identifies microtubule-dependent reduction of variability in signaling; Nature Publishing Group; Molecular Systems Biology; 14; 4; 4-2018; 1-20
1744-4292
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://www.embopress.org/doi/full/10.15252/msb.20167390
info:eu-repo/semantics/altIdentifier/url/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5884679/
info:eu-repo/semantics/altIdentifier/doi/10.15252/msb.20167390
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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