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Over-expression of Plk4 induces centrosome amplification, loss of primary cilia and associated tissue hyperplasia in the mouse

To address the long-known relationship between supernumerary centrosomes and cancer, we have generated a transgenic mouse that permits inducible expression of the master regulator of centriole duplication, Polo-like-kinase-4 (Plk4). Over-expression of Plk4 from this transgene advances the onset of t...

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Autores principales: Coelho, Paula A., Bury, Leah, Shahbazi, Marta N., Liakath-Ali, Kifayathullah, Tate, Peri H., Wormald, Sam, Hindley, Christopher J., Huch, Meritxell, Archer, Joy, Skarnes, William C., Zernicka-Goetz, Magdalena, Glover, David M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Royal Society 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4703062/
https://www.ncbi.nlm.nih.gov/pubmed/26701933
http://dx.doi.org/10.1098/rsob.150209
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author Coelho, Paula A.
Bury, Leah
Shahbazi, Marta N.
Liakath-Ali, Kifayathullah
Tate, Peri H.
Wormald, Sam
Hindley, Christopher J.
Huch, Meritxell
Archer, Joy
Skarnes, William C.
Zernicka-Goetz, Magdalena
Glover, David M.
author_facet Coelho, Paula A.
Bury, Leah
Shahbazi, Marta N.
Liakath-Ali, Kifayathullah
Tate, Peri H.
Wormald, Sam
Hindley, Christopher J.
Huch, Meritxell
Archer, Joy
Skarnes, William C.
Zernicka-Goetz, Magdalena
Glover, David M.
author_sort Coelho, Paula A.
collection PubMed
description To address the long-known relationship between supernumerary centrosomes and cancer, we have generated a transgenic mouse that permits inducible expression of the master regulator of centriole duplication, Polo-like-kinase-4 (Plk4). Over-expression of Plk4 from this transgene advances the onset of tumour formation that occurs in the absence of the tumour suppressor p53. Plk4 over-expression also leads to hyperproliferation of cells in the pancreas and skin that is enhanced in a p53 null background. Pancreatic islets become enlarged following Plk4 over-expression as a result of equal expansion of α- and β-cells, which exhibit centrosome amplification. Mice overexpressing Plk4 develop grey hair due to a loss of differentiated melanocytes and bald patches of skin associated with a thickening of the epidermis. This reflects an increase in proliferating cells expressing keratin 5 in the basal epidermal layer and the expansion of these cells into suprabasal layers. Such cells also express keratin 6, a marker for hyperplasia. This is paralleled by a decreased expression of later differentiation markers, involucrin, filaggrin and loricrin. Proliferating cells showed an increase in centrosome number and a loss of primary cilia, events that were mirrored in primary cultures of keratinocytes established from these animals. We discuss how repeated duplication of centrioles appears to prevent the formation of basal bodies leading to loss of primary cilia, disruption of signalling and thereby aberrant differentiation of cells within the epidermis. The absence of p53 permits cells with increased centrosomes to continue dividing, thus setting up a neoplastic state of error prone mitoses, a prerequisite for cancer development.
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spelling pubmed-47030622016-01-08 Over-expression of Plk4 induces centrosome amplification, loss of primary cilia and associated tissue hyperplasia in the mouse Coelho, Paula A. Bury, Leah Shahbazi, Marta N. Liakath-Ali, Kifayathullah Tate, Peri H. Wormald, Sam Hindley, Christopher J. Huch, Meritxell Archer, Joy Skarnes, William C. Zernicka-Goetz, Magdalena Glover, David M. Open Biol Research To address the long-known relationship between supernumerary centrosomes and cancer, we have generated a transgenic mouse that permits inducible expression of the master regulator of centriole duplication, Polo-like-kinase-4 (Plk4). Over-expression of Plk4 from this transgene advances the onset of tumour formation that occurs in the absence of the tumour suppressor p53. Plk4 over-expression also leads to hyperproliferation of cells in the pancreas and skin that is enhanced in a p53 null background. Pancreatic islets become enlarged following Plk4 over-expression as a result of equal expansion of α- and β-cells, which exhibit centrosome amplification. Mice overexpressing Plk4 develop grey hair due to a loss of differentiated melanocytes and bald patches of skin associated with a thickening of the epidermis. This reflects an increase in proliferating cells expressing keratin 5 in the basal epidermal layer and the expansion of these cells into suprabasal layers. Such cells also express keratin 6, a marker for hyperplasia. This is paralleled by a decreased expression of later differentiation markers, involucrin, filaggrin and loricrin. Proliferating cells showed an increase in centrosome number and a loss of primary cilia, events that were mirrored in primary cultures of keratinocytes established from these animals. We discuss how repeated duplication of centrioles appears to prevent the formation of basal bodies leading to loss of primary cilia, disruption of signalling and thereby aberrant differentiation of cells within the epidermis. The absence of p53 permits cells with increased centrosomes to continue dividing, thus setting up a neoplastic state of error prone mitoses, a prerequisite for cancer development. The Royal Society 2015-12-23 /pmc/articles/PMC4703062/ /pubmed/26701933 http://dx.doi.org/10.1098/rsob.150209 Text en © 2015 The Authors. http://creativecommons.org/licenses/by/4.0/ Published by the Royal Society under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/, which permits unrestricted use, provided the original author and source are credited.
spellingShingle Research
Coelho, Paula A.
Bury, Leah
Shahbazi, Marta N.
Liakath-Ali, Kifayathullah
Tate, Peri H.
Wormald, Sam
Hindley, Christopher J.
Huch, Meritxell
Archer, Joy
Skarnes, William C.
Zernicka-Goetz, Magdalena
Glover, David M.
Over-expression of Plk4 induces centrosome amplification, loss of primary cilia and associated tissue hyperplasia in the mouse
title Over-expression of Plk4 induces centrosome amplification, loss of primary cilia and associated tissue hyperplasia in the mouse
title_full Over-expression of Plk4 induces centrosome amplification, loss of primary cilia and associated tissue hyperplasia in the mouse
title_fullStr Over-expression of Plk4 induces centrosome amplification, loss of primary cilia and associated tissue hyperplasia in the mouse
title_full_unstemmed Over-expression of Plk4 induces centrosome amplification, loss of primary cilia and associated tissue hyperplasia in the mouse
title_short Over-expression of Plk4 induces centrosome amplification, loss of primary cilia and associated tissue hyperplasia in the mouse
title_sort over-expression of plk4 induces centrosome amplification, loss of primary cilia and associated tissue hyperplasia in the mouse
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4703062/
https://www.ncbi.nlm.nih.gov/pubmed/26701933
http://dx.doi.org/10.1098/rsob.150209
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