DIAPH3 deficiency links microtubules to mitotic errors, defective neurogenesis, and brain dysfunction
<div><p>Diaphanous (DIAPH) three (DIAPH3) is a member of the formin proteins that have the capacity to nucleate and elongate actin filaments and, therefore, to remodel the cytoskeleton. DIAPH3 is essential for cytokinesis as its dysfunction impairs the contractile ring and produces multi...
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| مؤلفون آخرون: | , , , , , , , , , |
| منشور في: |
2021
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| _version_ | 1864513515340955648 |
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| author | Eva On-Chai Lau (18589432) |
| author2 | Devid Damiani (18589435) Georges Chehade (18007084) Nuria Ruiz-Reig (14434026) Rana Saade (18589438) Yves Jossin (18589441) Mohamed Aittaleb (18007087) Olivier Schakman (113533) Nicolas Tajeddine (18007099) Philippe Gailly (113548) Fadel Tissir (245153) |
| author2_role | author author author author author author author author author author |
| author_facet | Eva On-Chai Lau (18589432) Devid Damiani (18589435) Georges Chehade (18007084) Nuria Ruiz-Reig (14434026) Rana Saade (18589438) Yves Jossin (18589441) Mohamed Aittaleb (18007087) Olivier Schakman (113533) Nicolas Tajeddine (18007099) Philippe Gailly (113548) Fadel Tissir (245153) |
| author_role | author |
| dc.creator.none.fl_str_mv | Eva On-Chai Lau (18589432) Devid Damiani (18589435) Georges Chehade (18007084) Nuria Ruiz-Reig (14434026) Rana Saade (18589438) Yves Jossin (18589441) Mohamed Aittaleb (18007087) Olivier Schakman (113533) Nicolas Tajeddine (18007099) Philippe Gailly (113548) Fadel Tissir (245153) |
| dc.date.none.fl_str_mv | 2021-04-26T03:00:00Z |
| dc.identifier.none.fl_str_mv | 10.7554/elife.61974 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/DIAPH3_deficiency_links_microtubules_to_mitotic_errors_defective_neurogenesis_and_brain_dysfunction/25867684 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biological sciences Biochemistry and cell biology Biomedical and clinical sciences Neurosciences Diaphanous DIAPH3 Formin proteins Actin filaments Cytoskeleton remodeling Cytokinesis Contractile ring Centrosome |
| dc.title.none.fl_str_mv | DIAPH3 deficiency links microtubules to mitotic errors, defective neurogenesis, and brain dysfunction |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <div><p>Diaphanous (DIAPH) three (DIAPH3) is a member of the formin proteins that have the capacity to nucleate and elongate actin filaments and, therefore, to remodel the cytoskeleton. DIAPH3 is essential for cytokinesis as its dysfunction impairs the contractile ring and produces multinucleated cells. Here, we report that DIAPH3 localizes at the centrosome during mitosis and regulates the assembly and bipolarity of the mitotic spindle. DIAPH3-deficient cells display disorganized cytoskeleton and multipolar spindles. DIAPH3 deficiency disrupts the expression and/or stability of several proteins including the kinetochore-associated protein SPAG5. DIAPH3 and SPAG5 have similar expression patterns in the developing brain and overlapping subcellular localization during mitosis. Knockdown of SPAG5 phenocopies DIAPH3 deficiency, whereas its overexpression rescues the DIAHP3 knockdown phenotype. Conditional inactivation of Diaph3 in mouse cerebral cortex profoundly disrupts neurogenesis, depleting cortical progenitors and neurons, leading to cortical malformation and autistic-like behavior. Our data uncover the uncharacterized functions of DIAPH3 and provide evidence that this protein belongs to a molecular toolbox that links microtubule dynamics during mitosis to aneuploidy, cell death, fate determination defects, and cortical malformation.</p><p> </p></div><h2>Other Information</h2> <p> Published in: eLife<br> License: <a href="http://creativecommons.org/licenses/by/4.0/" target="_blank">http://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.7554/elife.61974" target="_blank">https://dx.doi.org/10.7554/elife.61974</a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_35301ccc312fe6e5c1a44f618b5016db |
| identifier_str_mv | 10.7554/elife.61974 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/25867684 |
| publishDate | 2021 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | DIAPH3 deficiency links microtubules to mitotic errors, defective neurogenesis, and brain dysfunctionEva On-Chai Lau (18589432)Devid Damiani (18589435)Georges Chehade (18007084)Nuria Ruiz-Reig (14434026)Rana Saade (18589438)Yves Jossin (18589441)Mohamed Aittaleb (18007087)Olivier Schakman (113533)Nicolas Tajeddine (18007099)Philippe Gailly (113548)Fadel Tissir (245153)Biological sciencesBiochemistry and cell biologyBiomedical and clinical sciencesNeurosciencesDiaphanousDIAPH3Formin proteinsActin filamentsCytoskeleton remodelingCytokinesisContractile ringCentrosome<div><p>Diaphanous (DIAPH) three (DIAPH3) is a member of the formin proteins that have the capacity to nucleate and elongate actin filaments and, therefore, to remodel the cytoskeleton. DIAPH3 is essential for cytokinesis as its dysfunction impairs the contractile ring and produces multinucleated cells. Here, we report that DIAPH3 localizes at the centrosome during mitosis and regulates the assembly and bipolarity of the mitotic spindle. DIAPH3-deficient cells display disorganized cytoskeleton and multipolar spindles. DIAPH3 deficiency disrupts the expression and/or stability of several proteins including the kinetochore-associated protein SPAG5. DIAPH3 and SPAG5 have similar expression patterns in the developing brain and overlapping subcellular localization during mitosis. Knockdown of SPAG5 phenocopies DIAPH3 deficiency, whereas its overexpression rescues the DIAHP3 knockdown phenotype. Conditional inactivation of Diaph3 in mouse cerebral cortex profoundly disrupts neurogenesis, depleting cortical progenitors and neurons, leading to cortical malformation and autistic-like behavior. Our data uncover the uncharacterized functions of DIAPH3 and provide evidence that this protein belongs to a molecular toolbox that links microtubule dynamics during mitosis to aneuploidy, cell death, fate determination defects, and cortical malformation.</p><p> </p></div><h2>Other Information</h2> <p> Published in: eLife<br> License: <a href="http://creativecommons.org/licenses/by/4.0/" target="_blank">http://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.7554/elife.61974" target="_blank">https://dx.doi.org/10.7554/elife.61974</a></p>2021-04-26T03:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.7554/elife.61974https://figshare.com/articles/journal_contribution/DIAPH3_deficiency_links_microtubules_to_mitotic_errors_defective_neurogenesis_and_brain_dysfunction/25867684CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/258676842021-04-26T03:00:00Z |
| spellingShingle | DIAPH3 deficiency links microtubules to mitotic errors, defective neurogenesis, and brain dysfunction Eva On-Chai Lau (18589432) Biological sciences Biochemistry and cell biology Biomedical and clinical sciences Neurosciences Diaphanous DIAPH3 Formin proteins Actin filaments Cytoskeleton remodeling Cytokinesis Contractile ring Centrosome |
| status_str | publishedVersion |
| title | DIAPH3 deficiency links microtubules to mitotic errors, defective neurogenesis, and brain dysfunction |
| title_full | DIAPH3 deficiency links microtubules to mitotic errors, defective neurogenesis, and brain dysfunction |
| title_fullStr | DIAPH3 deficiency links microtubules to mitotic errors, defective neurogenesis, and brain dysfunction |
| title_full_unstemmed | DIAPH3 deficiency links microtubules to mitotic errors, defective neurogenesis, and brain dysfunction |
| title_short | DIAPH3 deficiency links microtubules to mitotic errors, defective neurogenesis, and brain dysfunction |
| title_sort | DIAPH3 deficiency links microtubules to mitotic errors, defective neurogenesis, and brain dysfunction |
| topic | Biological sciences Biochemistry and cell biology Biomedical and clinical sciences Neurosciences Diaphanous DIAPH3 Formin proteins Actin filaments Cytoskeleton remodeling Cytokinesis Contractile ring Centrosome |