Loss of primary cilia and tissue hyperplasia associated with centrosome amplification


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David Glover1
1University of Cambridge

Abstract

To address the relationship between supernumerary centrosomes and cancer, we generated a transgenic mouse that permits inducible expression of the centriole duplication regulator, Polo-like-kinase-4 (Plk4). Over-expression of Plk4 advances tumour formation onset in the absence of p53 and leads to hyperproliferation of cells in the skin. Mice overexpressing Plk4 develop grey hair due to a loss of melanocytes and bald skin associated with thickening epidermis. This reflects increased proliferating cells in the basal epidermis and their expansion cells into suprabasal layers. Expression of markers for hyperplasia is paralleled by a decreased expression of differentiation markers. The proliferating cells show increased centrosomes and a loss of primary cilia, events mirrored in primary cultures of keratinocytes. Pancreatic islets become enlarged following Plk4 over-expression and the α- and β-cells exhibit centrosome amplification. Multiple centrosomes and loss of primary cilia also disrupt organisation of both undifferentiated and differentiated pancreatic organoids overexpressing Plk4 and this is exacerbated by p53 loss. Thus in two different tissues, repeated centriole duplication prevents formation of basal bodies leading to loss of primary cilia, disruption of signalling and aberrant differentiation. The absence of p53 permits these cells to continue dividing setting up a neoplastic state of error prone mitoses.