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Epidermal Development, Growth Control, and Homeostasis in the Face of Centrosome Amplification

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Epidermal Development, Growth Control, and Homeostasis in the Face of Centrosome Amplification Epidermal development, growth control, and PNAS PLUS homeostasis in the face of centrosome amplification Anita Kulukiana, Andrew J. Hollandb,1, Benjamin Vitrec,1, Shruti Naika, Don W. Clevelandd, and Elaine Fuchsa,e,2 aRobin Chemers Neustein Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, NY 10065; bDepartment of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205; cCNRS UMR-5237, Centre de Recherche en Biochimie Macromoleculaire, University of Montpellier, Montpellier 34093, France; dLudwig Institute for Cancer Research and Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093; and eHoward Hughes Medical Institute, The Rockefeller University, New York, NY 10065 Contributed by Elaine Fuchs, September 29, 2015 (sent for review July 2, 2015) As nucleators of the mitotic spindle and primary cilium, centrosomes with mitotic-origin aneuploidy in human embryos, suggestive of a play crucial roles in equal segregation of DNA content to daughter possible link among PLK4, aneuploidy, and pregnancy loss (6). cells, coordination of growth and differentiation, and transduction of Centrosome amplification, or the condition of having more than homeostatic cues. Whereas the majority of mammalian cells carry no acell’s customary pair of such structures, has garnered attention more than two centrosomes per cell, exceptions to this rule apply in for more than a century (11). Given the enhanced apoptosis re- certain specialized tissues and in select disease states, including sulting from centrosome amplification in the brain, it is intriguing cancer. Centrosome amplification, or the condition of having more that centrosome amplification was originally noted for its presence than two centrosomes per cell, has been suggested to contribute to in cancer cells (9). Indeed, increased centrosome number is a instability of chromosomes, imbalance in asymmetric divisions, and hallmark of many cancers, and it correlates with poor clinical reorganization of tissue architecture; however, the degree to which prognoses in some malignancies, including those of epithelial origin these conditions are a direct cause of or simply a consequence of (12, 13). In flies, centrosomal alterations have been found to ex- human disease is poorly understood. Here we addressed this issue by pand the pool of proliferative progenitors in serial neuroblast generating a mouse model inducing centrosome amplification in a transplantation assays, a phenomenon attributed to an imbalance naturally proliferative epithelial tissue by elevating Polo-like kinase in asymmetric divisions (14, 15). In mammals, however, despite the 4 (Plk4) expression in the skin epidermis. By altering centrosome strong correlation with hyperproliferative disorders, whether cen- numbers, we observed multiciliated cells, spindle orientation errors, trosomal abnormalities are the cause, the consequence, or a neu- and chromosome segregation defects within developing epidermis. tral bystander of cancer remains unclear (16, 17). None of these defects was sufficient to impart a proliferative Based on the assumption that centrosome amplification results advantage within the tissue, however. Rather, impaired mitoses in multipolar mitoses, initial research efforts focused on drawing led to p53-mediated cell death and contributed to defective growth mechanistic links to chromosomal instability (18–20). Surprisingly, and stratification. Despite these abnormalities, mice remained viable however, at least in various cancer cell lines examined in vitro, and healthy, although epidermal cells with centrosome amplification multipolar divisions turned out to be rare and typically inviable were still appreciable. Moreover, these abnormalities were insuffi- (21). Instead, these cells seemed to have developed strategies to cient to disrupt homeostasis and initiate or enhance tumorigenesis, cope with extra centrosomes, including clustering them together underscoring the powerful surveillance mechanisms in the skin. such that a bipolar spindle could still form (22–25). That said, even within a bipolar spindle network, chromosome segregation errors centrosome amplification | epidermal development | Plk4 | mitosis involving merotelic attachment have been observed, and these can contribute to chromosomal instability if the mitotic checkpoint is entrosomes play crucial functions within the cell by organizing bypassed (21, 26). Taken together, these studies underscore the microtubules and by participating in the assembly of the pri- C CELL BIOLOGY mary cilium, an antenna-like structure that senses the cellular en- Significance vironment and transmits signaling cues. On a structural basis, each centrosome consists of orthogonally positioned centrioles and its The full extent to which centrosome amplification might directly surrounding protein-rich pericentriolar material (PCM). The ma- contribute to human disease is poorly understood. We gener- jority of mammalian cells contain one centrosome throughout in- ated a mouse model for the induction of centrosome amplifica- terphase (G1), and then replicate during S-phase of the cell cycle in tion in the skin, a tissue that remains proliferative even after its preparation for mitosis (1). Centrosomes generally template their development. We uncover defects in stratification of the epi- own duplication, and they keep their numbers in check through dermis during development, which can be attributed to mitotic tight posttranslational regulation of the duplication process itself. errors. The skin exhibits remarkable resiliency by clearing out Through licensing mechanisms, centrosomal reduplication is pre- these defective cells via a cell death program, however. Despite vented, and by virtue of their role in nucleating a bipolar mitotic sustained centrosome amplification, adult animals are healthy spindle, centrosomes are faithfully partitioned into each daughter and do not develop tumors or skin abnormalities. Our findings cell at the end of mitosis (2, 3). challenge the role for centrosome amplification in the initiation Mutations and misregulation of centrosomal proteins have been of skin tumorigenesis and demonstrate that certain tissues are associated with various human disorders, including ciliopathies, better able to cope with its burden. obesity, neurologic disorders, and miscarriages (4–6). Numerical aberrations in centrosome numbers have been demonstrated to Author contributions: A.K., A.J.H., B.V., D.W.C., and E.F. designed research; A.K. and S.N. performed research; A.K., A.J.H., B.V., D.W.C., and E.F. contributed new reagents/analytic alter ciliary signaling and have been proposed to be the underlying tools; A.K., S.N., and E.F. analyzed data; and A.K. and E.F. wrote the paper. cause for certain defects in tissue organization (7, 8). In addition, The authors declare no conflict of interest. recent genetic studies on the master regulator of centrosome Freely available online through the PNAS open access option. number, polo-like kinase 4 (PLK4), have shown that, whether too 1A.J.H. and B.V. contributed equally to this work. few or too many, perturbations in centrosome numbers can directly 2To whom correspondence should be addressed. Email: [email protected]. impede brain development, leading to microcephaly both in mice This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. and in humans (9, 10). PLK4 mutations also have been associated 1073/pnas.1518376112/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1518376112 PNAS | Published online November 2, 2015 | E6311–E6320 Downloaded by guest on September 27, 2021 importance of delving more deeply into the physiological rele- we generated mice that induce PLK4 overexpression in the basal vance of centrosome amplification in additional mammalian layer. PLK4 is the key to initiating centriole duplication, and at tissues in vivo, and to parse out the centrosomal contribution to elevated levels, this kinase is capable of replicating more than a tissue function. single centriole on the existing one (31–34). After establishing that Mammalian epidermis offers an excellent opportunity to eval- the epidermis acquires an excess of centrosomes, we examined the uate the various proposed cellular mechanisms in which centro- consequences on growth and differentiation, cilia and Notch sig- some amplification affects tissue development, homeostasis, and naling, mitotic spindle formation and orientation, mitotic error- tumorigenesis. During embryogenesis, it begins as a single layer of induced DNA damage response/aneuploidy, and p53-mediated proliferative progenitors, which divide laterally to accommodate apoptosis. Finally, because our mice remained viable, we could embryonic growth, and also perpendicularly to give rise to a evaluate the effects of sustained centrosome amplification on tissue stratified, differentiating tissue (27). Only the innermost basal integrity. Our findings reveal a remarkable resilience of the skin layer retains progenitor status, which relies on integrin-mediated epidermis in coping with abnormalities induced by centrosome attachment to an underlying basement membrane rich in extra- amplification. Moreover, despite the longevity of animals that cellular matrix. Perpendicular divisions are asymmetric, involving overexpress PLK4 in the skin epidermis, this did not lead to an differential Notch and ciliary signaling for proper morphogenesis increased
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