Epidermal development, growth control, and homeostasis in the face of centrosome amplification

Abstract

As nucleators of the mitotic spindle and primary cilium, centrosomes play crucial roles in equal segregation of DNA content to daughter cells, coordination of growth and differentiation, and transduction of homeostatic cues. Whereas the majority of mammalian cells carry no more than two centrosomes per cell, exceptions to this rule apply in certain specialized tissues and in select disease states, including cancer. Centrosome amplification, or the condition of having more than two centrosomes per cell, has been suggested to contribute to instability of chromosomes, imbalance in asymmetric divisions, and reorganization of tissue architecture; however, the degree to which these conditions are a direct cause of or simply a consequence of human disease is poorly understood. Here we addressed this issue by generating a mouse model inducing centrosome amplification in a naturally proliferative epithelial tissue by elevating Polo-like kinase 4 (Plk4) expression in the skin epidermis. By altering centrosome numbers, we observed multiciliated cells, spindle orientation errors, and chromosome segregation defects within developing epidermis. None of these defects was sufficient to impart a proliferative advantage within the tissue, however. Rather, impaired mitoses led to p53-mediated cell death and contributed to defective growth and stratification. Despite these abnormalities, mice remained viable and healthy, although epidermal cells with centrosome amplification were still appreciable. Moreover, these abnormalities were insufficient to disrupt homeostasis and initiate or enhance tumorigenesis, underscoring the powerful surveillance mechanisms in the skin.

Chronic centrosome amplification without tumorigenesis

“…3 I and J). Similarly, an increase in Plk4 RNA drove centrosome amplification in 20% of keratinocytes within the skin epidermis (26). However, despite 4-fold and 30-fold elevations, respectively, in the level of Plk4 transcripts in lung and kidney ( Fig.…”

“…Thus, in mice with active p53, Cre-mediated activation of Plk4 overexpression is sufficient to drive centrosome amplification in permissive tissues, including the liver (Fig. 3) and skin (26). Nevertheless, cohorts of Plk4-overexpressing mice showed no difference in overall survival compared with control animals (Fig.…”

Once and only once: mechanisms of centriole duplication and their deregulation in disease

“…While initial studies failed to observe the development of spontaneous tumors in animals with widespread PLK4 overexpression 156,158,159 , a more modest increase in PLK4 levels was shown to promote persistent centrosome amplification that promoted the development spontaneous tumors 147 . Importantly, these tumors exhibited dramatic numerical and structural chromosomal alterations, mirroring the complex karyotype changes frequently observed in human tumors with extra centrosomes 147 .…”

Centrosome amplification: a suspect in breast cancer and racial disparities

“…In another study, the same group found that mice overexpressing PLK4 in the basal layer of the epidermis exhibited a 20% increase in basal and suprabasal epidermal cells with CA; an increase in multiciliated basal cells; an increase in spindle alignment defects in basal cells due primarily to uncoupling of the spindle from cortical cues; an increase in spindle multipolarity, aneuploidy, and DNA damage in embryonic epidermal tissue; and defective stratification and growth of embryonic epidermal tissue, which was minimally rescued by p53 knockdown (Kulukian, et al 2015). Despite these defects, PLK4-overexpressing mice had normal epidermal barrier function and architecture and similar overall and tumor-free survival compared with control mice.…”