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

Open Biology - Tập 5 Số 12 - Trang 150209 - 2015
Paula A. Coelho1, Leah Bury1, Marta N. Shahbazi2, Kifayathullah Liakath‐Ali3,1, P Tate4, Samuel Wormald4, Christopher J. Hindley5, Meritxell Huch5, Joy Archer6, William C. Skarnes4, Magdalena Zernicka‐Goetz2, David M. Glover1
1Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, UK
2Department of Physiology, Development and Neuroscience, Physiological Laboratory, University of Cambridge, Downing Street, Cambridge CB2 3EG, UK
3Centre for Stem Cells and Regenerative Medicine, King’s College London, Floor 28, Tower Wing, Guy’s Hospital, Great Maze Pond, London SE1 9RT, UK
4Wellcome Trust Genome Campus, the Wellcome Trust Sanger Institute, Cambridge, Hinxton CB10 1SA, UK
5Henry Wellcome Building of Cancer and Developmental Biology, the Wellcome Trust/Cancer Research UK Gurdon Institute, Tennis Court Road, Cambridge CB2 1QN, UK
6Department of Veterinary Medicine, University of Cambridge, Madingley Road, Cambridge, CB3 0ES, UK

Tóm tắt

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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Open Biology

Tập 5 Số 12

150209

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