Alternative splicing controls pan-neuronal homeobox gene expression

The pan-neuronally expressed and phylogenetically conserved CUT homeobox gene ceh-44/CUX orchestrates pan-neuronal gene expression throughout the nervous system of Caenorhabditis elegans. As in many other species, including humans, ceh-44/CUX is encoded by a complex locus that also codes for a Golgi...

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Autores: Leyva-Díaz, Eduardo, Cesar, Michael, Pe, Karinna, Jordá-Llorens, José Ignacio, Valdivia, Jessica, Hobert, Oliver
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2025
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/385552
Acceso en línea:http://hdl.handle.net/10261/385552
https://api.elsevier.com/content/abstract/scopus_id/85217102089
Access Level:acceso abierto
Palabra clave:C. elegans
Alternative splicing
Homeobox
Neuronal cell fate
Pan-neuronal gene expression
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spelling Alternative splicing controls pan-neuronal homeobox gene expressionLeyva-Díaz, EduardoCesar, MichaelPe, KarinnaJordá-Llorens, José IgnacioValdivia, JessicaHobert, OliverC. elegansAlternative splicingHomeoboxNeuronal cell fatePan-neuronal gene expressionThe pan-neuronally expressed and phylogenetically conserved CUT homeobox gene ceh-44/CUX orchestrates pan-neuronal gene expression throughout the nervous system of Caenorhabditis elegans. As in many other species, including humans, ceh-44/CUX is encoded by a complex locus that also codes for a Golgi-localized protein, called CASP (Cux1 alternatively spliced product) in humans and CONE-1 ("CASP of nematodes") in C. elegans How gene expression from this complex locus is controlled-and, in C. elegans, directed to all cells of the nervous system-has not been investigated. We show here that pan-neuronal expression of CEH-44/CUX is controlled by a pan-neuronal RNA splicing factor, UNC-75, the C. elegans homolog of vertebrate CELF proteins. During embryogenesis, the cone-1&ceh-44 locus exclusively produces the Golgi-localized CONE-1/CASP protein in all tissues, but upon the onset of postmitotic terminal differentiation of neurons, UNC-75/CELF induces the production of the alternative CEH-44/CUX CUT homeobox gene-encoding transcript exclusively in the nervous system. Hence, UNC-75/CELF-mediated alternative splicing not only directs pan-neuronal gene expression but also excludes a phylogenetically deeply conserved golgin from the nervous system, paralleling surprising spatial specificities of another golgin that we describe here as well. Our findings provide novel insights into how all cells in a nervous system acquire pan-neuronal identity features and reveal unanticipated cellular specificities in Golgi apparatus composition.We thank Chi Chen for generating transgenic strains; John Calarco for sharing unpublished data; Barth Grant for shar ing the aman-2 reporter (RT2745 strain); Alberto Stolfi for discussion; HaoSheng Sun, Nuria Flames, and members of the Hobert laboratory and Leyva-Díaz laboratory for com menting on the manuscript; WormBase (Sternberg et al. 2024) and Caenorhabditis Genetics Center (funded by the National Institutes of Health Office of Research Infrastruc ture Programs, P40 OD010440) for providing resources and reagents. This work was funded by the Howard Hughes Medical Institute (O.H.) and by a GENT program grant for the Contratación de Investigadores Doctores de Excelencia from Generalitat Valenciana (CIDEXG/2022/30) (E.L.-D.). Author contributions: E.L.-D. and O.H. conceived the project and designed the experiments. E.L.-D. and M.C. performed all the experiments, imaging, and quantifica tions, except for those specified. K.P. conducted the exper iments, imaging, and quantifications shown in Figure 4B and Supplemental Figure S5A. J.I.J.-L. and J.V. performed the quantifications shown in Figures 1D and 2E. The man uscript was prepared by E.L.-D., M.C., and O.H.Peer reviewedCold Spring Harbor Laboratory PressHoward Hughes Medical InstituteGeneralitat ValencianaNational Institutes of Health (US)Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202520252025info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/385552https://api.elsevier.com/content/abstract/scopus_id/85217102089reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)InglésLeyva-Díaz, Eduardo; Cesar, Michael; Pe, Karinna; Jordá-Llorens, José Ignacio; Valdivia, Jessica; Hobert, Oliver; 2025; Supplemental material: Alternative splicing controls pan-neuronal homeobox gene expression; Cold Spring Harbor Laboratory Press; http://dx.doi.org/10.1101/gad.352184.124http://dx.doi.org/10.1101/gad.352184.124Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/3855522026-05-22T06:33:51Z
dc.title.none.fl_str_mv Alternative splicing controls pan-neuronal homeobox gene expression
title Alternative splicing controls pan-neuronal homeobox gene expression
spellingShingle Alternative splicing controls pan-neuronal homeobox gene expression
Leyva-Díaz, Eduardo
C. elegans
Alternative splicing
Homeobox
Neuronal cell fate
Pan-neuronal gene expression
title_short Alternative splicing controls pan-neuronal homeobox gene expression
title_full Alternative splicing controls pan-neuronal homeobox gene expression
title_fullStr Alternative splicing controls pan-neuronal homeobox gene expression
title_full_unstemmed Alternative splicing controls pan-neuronal homeobox gene expression
title_sort Alternative splicing controls pan-neuronal homeobox gene expression
dc.creator.none.fl_str_mv Leyva-Díaz, Eduardo
Cesar, Michael
Pe, Karinna
Jordá-Llorens, José Ignacio
Valdivia, Jessica
Hobert, Oliver
author Leyva-Díaz, Eduardo
author_facet Leyva-Díaz, Eduardo
Cesar, Michael
Pe, Karinna
Jordá-Llorens, José Ignacio
Valdivia, Jessica
Hobert, Oliver
author_role author
author2 Cesar, Michael
Pe, Karinna
Jordá-Llorens, José Ignacio
Valdivia, Jessica
Hobert, Oliver
author2_role author
author
author
author
author
dc.contributor.none.fl_str_mv Howard Hughes Medical Institute
Generalitat Valenciana
National Institutes of Health (US)
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv C. elegans
Alternative splicing
Homeobox
Neuronal cell fate
Pan-neuronal gene expression
topic C. elegans
Alternative splicing
Homeobox
Neuronal cell fate
Pan-neuronal gene expression
description The pan-neuronally expressed and phylogenetically conserved CUT homeobox gene ceh-44/CUX orchestrates pan-neuronal gene expression throughout the nervous system of Caenorhabditis elegans. As in many other species, including humans, ceh-44/CUX is encoded by a complex locus that also codes for a Golgi-localized protein, called CASP (Cux1 alternatively spliced product) in humans and CONE-1 ("CASP of nematodes") in C. elegans How gene expression from this complex locus is controlled-and, in C. elegans, directed to all cells of the nervous system-has not been investigated. We show here that pan-neuronal expression of CEH-44/CUX is controlled by a pan-neuronal RNA splicing factor, UNC-75, the C. elegans homolog of vertebrate CELF proteins. During embryogenesis, the cone-1&ceh-44 locus exclusively produces the Golgi-localized CONE-1/CASP protein in all tissues, but upon the onset of postmitotic terminal differentiation of neurons, UNC-75/CELF induces the production of the alternative CEH-44/CUX CUT homeobox gene-encoding transcript exclusively in the nervous system. Hence, UNC-75/CELF-mediated alternative splicing not only directs pan-neuronal gene expression but also excludes a phylogenetically deeply conserved golgin from the nervous system, paralleling surprising spatial specificities of another golgin that we describe here as well. Our findings provide novel insights into how all cells in a nervous system acquire pan-neuronal identity features and reveal unanticipated cellular specificities in Golgi apparatus composition.
publishDate 2025
dc.date.none.fl_str_mv 2025
2025
2025
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/385552
https://api.elsevier.com/content/abstract/scopus_id/85217102089
url http://hdl.handle.net/10261/385552
https://api.elsevier.com/content/abstract/scopus_id/85217102089
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Leyva-Díaz, Eduardo; Cesar, Michael; Pe, Karinna; Jordá-Llorens, José Ignacio; Valdivia, Jessica; Hobert, Oliver; 2025; Supplemental material: Alternative splicing controls pan-neuronal homeobox gene expression; Cold Spring Harbor Laboratory Press; http://dx.doi.org/10.1101/gad.352184.124
http://dx.doi.org/10.1101/gad.352184.124
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Cold Spring Harbor Laboratory Press
publisher.none.fl_str_mv Cold Spring Harbor Laboratory Press
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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