Cargando…
Nuclear Isoforms of Neurofibromin Are Required for Proper Spindle Organization and Chromosome Segregation
Mitotic spindles are highly organized, microtubule (MT)-based, transient structures that serve the fundamental function of unerring chromosome segregation during cell division and thus of genomic stability during tissue morphogenesis and homeostasis. Hence, a multitude of MT-associated proteins (MAP...
Autores principales: | , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690890/ https://www.ncbi.nlm.nih.gov/pubmed/33114250 http://dx.doi.org/10.3390/cells9112348 |
_version_ | 1783614172039217152 |
---|---|
author | Peta, Charoula Tsirimonaki, Emmanouella Samouil, Dimitris Georgiadou, Kyriaki Mangoura, Dimitra |
author_facet | Peta, Charoula Tsirimonaki, Emmanouella Samouil, Dimitris Georgiadou, Kyriaki Mangoura, Dimitra |
author_sort | Peta, Charoula |
collection | PubMed |
description | Mitotic spindles are highly organized, microtubule (MT)-based, transient structures that serve the fundamental function of unerring chromosome segregation during cell division and thus of genomic stability during tissue morphogenesis and homeostasis. Hence, a multitude of MT-associated proteins (MAPs) regulates the dynamic assembly of MTs in preparation for mitosis. Some tumor suppressors, normally functioning to prevent tumor development, have now emerged as significant MAPs. Among those, neurofibromin, the product of the Neurofibromatosis-1 gene (NF1), a major Ras GTPase activating protein (RasGAP) in neural cells, controls also the critical function of chromosome congression in astrocytic cellular contexts. Cell type- and development-regulated splicings may lead to the inclusion or exclusion of NF1exon51, which bears a nuclear localization sequence (NLS) for nuclear import at G2; yet the functions of the produced NLS and ΔNLS neurofibromin isoforms have not been previously addressed. By using a lentiviral shRNA system, we have generated glioblastoma SF268 cell lines with conditional knockdown of NLS or ΔNLS transcripts. In dissecting the roles of NLS or ΔNLS neurofibromins, we found that NLS-neurofibromin knockdown led to increased density of cytosolic MTs but loss of MT intersections, anastral spindles featuring large hollows and abnormal chromosome positioning, and finally abnormal chromosome segregation and increased micronuclei frequency. Therefore, we propose that NLS neurofibromin isoforms exert prominent mitotic functions. |
format | Online Article Text |
id | pubmed-7690890 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-76908902020-11-27 Nuclear Isoforms of Neurofibromin Are Required for Proper Spindle Organization and Chromosome Segregation Peta, Charoula Tsirimonaki, Emmanouella Samouil, Dimitris Georgiadou, Kyriaki Mangoura, Dimitra Cells Article Mitotic spindles are highly organized, microtubule (MT)-based, transient structures that serve the fundamental function of unerring chromosome segregation during cell division and thus of genomic stability during tissue morphogenesis and homeostasis. Hence, a multitude of MT-associated proteins (MAPs) regulates the dynamic assembly of MTs in preparation for mitosis. Some tumor suppressors, normally functioning to prevent tumor development, have now emerged as significant MAPs. Among those, neurofibromin, the product of the Neurofibromatosis-1 gene (NF1), a major Ras GTPase activating protein (RasGAP) in neural cells, controls also the critical function of chromosome congression in astrocytic cellular contexts. Cell type- and development-regulated splicings may lead to the inclusion or exclusion of NF1exon51, which bears a nuclear localization sequence (NLS) for nuclear import at G2; yet the functions of the produced NLS and ΔNLS neurofibromin isoforms have not been previously addressed. By using a lentiviral shRNA system, we have generated glioblastoma SF268 cell lines with conditional knockdown of NLS or ΔNLS transcripts. In dissecting the roles of NLS or ΔNLS neurofibromins, we found that NLS-neurofibromin knockdown led to increased density of cytosolic MTs but loss of MT intersections, anastral spindles featuring large hollows and abnormal chromosome positioning, and finally abnormal chromosome segregation and increased micronuclei frequency. Therefore, we propose that NLS neurofibromin isoforms exert prominent mitotic functions. MDPI 2020-10-23 /pmc/articles/PMC7690890/ /pubmed/33114250 http://dx.doi.org/10.3390/cells9112348 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Peta, Charoula Tsirimonaki, Emmanouella Samouil, Dimitris Georgiadou, Kyriaki Mangoura, Dimitra Nuclear Isoforms of Neurofibromin Are Required for Proper Spindle Organization and Chromosome Segregation |
title | Nuclear Isoforms of Neurofibromin Are Required for Proper Spindle Organization and Chromosome Segregation |
title_full | Nuclear Isoforms of Neurofibromin Are Required for Proper Spindle Organization and Chromosome Segregation |
title_fullStr | Nuclear Isoforms of Neurofibromin Are Required for Proper Spindle Organization and Chromosome Segregation |
title_full_unstemmed | Nuclear Isoforms of Neurofibromin Are Required for Proper Spindle Organization and Chromosome Segregation |
title_short | Nuclear Isoforms of Neurofibromin Are Required for Proper Spindle Organization and Chromosome Segregation |
title_sort | nuclear isoforms of neurofibromin are required for proper spindle organization and chromosome segregation |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7690890/ https://www.ncbi.nlm.nih.gov/pubmed/33114250 http://dx.doi.org/10.3390/cells9112348 |
work_keys_str_mv | AT petacharoula nuclearisoformsofneurofibrominarerequiredforproperspindleorganizationandchromosomesegregation AT tsirimonakiemmanouella nuclearisoformsofneurofibrominarerequiredforproperspindleorganizationandchromosomesegregation AT samouildimitris nuclearisoformsofneurofibrominarerequiredforproperspindleorganizationandchromosomesegregation AT georgiadoukyriaki nuclearisoformsofneurofibrominarerequiredforproperspindleorganizationandchromosomesegregation AT mangouradimitra nuclearisoformsofneurofibrominarerequiredforproperspindleorganizationandchromosomesegregation |