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      Cytokeratin 18 Is Not Required for Morphogenesis of Developing Prostates but Contributes to Adult Prostate Regeneration

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          Abstract

          Cytokeratin 18 (CK18) is a key component of keratin-containing intermediate filaments and has long been used as a classic luminal cell marker in prostatic tissue. However, the in vivo function of CK18 in prostate is not known so far. We reported in this study, unexpectedly, that deletion of CK18 in a mouse model did not affect the morphological or the histological structures of adult prostate, as the CK18 knockout prostate displayed a normal glandular ductal structure, branching pattern, and composition of both luminal and basal cells. However, CK18 loss compromised the regenerative tubular branching in dorsolateral prostate after castration and androgen replacement. Therefore, in contrast to its importance as luminal cell marker, CK18 is dispensable for the prostate morphogenesis but contributes to adult prostate regeneration.

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          Most cited references30

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          p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development.

          The p63 gene, a homologue of the tumour-suppressor p53, is highly expressed in the basal or progenitor layers of many epithelial tissues. Here we report that mice homozygous for a disrupted p63 gene have major defects in their limb, craniofacial and epithelial development. p63 is expressed in the ectodermal surfaces of the limb buds, branchial arches and epidermal appendages, which are all sites of reciprocal signalling that direct morphogenetic patterning of the underlying mesoderm. The limb truncations are due to a failure to maintain the apical ectodermal ridge, a stratified epithelium, essential for limb development. The embryonic epidermis of p63-/- mice undergoes an unusual process of non-regenerative differentiation, culminating in a striking absence of all squamous epithelia and their derivatives, including mammary, lacrymal and salivary glands. Taken together, our results indicate that p63 is critical for maintaining the progenitor-cell populations that are necessary to sustain epithelial development and morphogenesis.
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            p63 is a p53 homologue required for limb and epidermal morphogenesis.

            The p53 tumour suppressor is a transcription factor that regulates the progression of the cell through its cycle and cell death (apoptosis) in response to environmental stimuli such as DNA damage and hypoxia. Even though p53 modulates these critical cellular processes, mice that lack p53 are developmentally normal, suggesting that p53-related proteins might compensate for the functions of p53 during embryogenesis. Two p53 homologues, p63 and p73, are known and here we describe the function of p63 in vivo. Mice lacking p63 are born alive but have striking developmental defects. Their limbs are absent or truncated, defects that are caused by a failure of the apical ectodermal ridge to differentiate. The skin of p63-deficient mice does not progress past an early developmental stage: it lacks stratification and does not express differentiation markers. Structures dependent upon epidermal-mesenchymal interactions during embryonic development, such as hair follicles, teeth and mammary glands, are absent in p63-deficient mice. Thus, in contrast to p53, p63 is essential for several aspects of ectodermal differentiation during embryogenesis.
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              Hedgehog signalling in prostate regeneration, neoplasia and metastasis.

              Metastatic cancers adopt certain properties of normal cells in developing or regenerating organs, such as the ability to proliferate and alter tissue organization. We find here that activity of the Hedgehog (Hh) signalling pathway, which has essential roles in developmental patterning, is required for regeneration of prostate epithelium, and that continuous pathway activation transforms prostate progenitor cells and renders them tumorigenic. Elevated pathway activity furthermore distinguishes metastatic from localized prostate cancer, and pathway manipulation can modulate invasiveness and metastasis. Pathway activity is triggered in response to endogenous expression of Hh ligands, and is dependent upon the expression of Smoothened, an essential Hh response component that is not expressed in benign prostate epithelial cells. Monitoring and manipulating Hh pathway activity may thus offer significant improvements in diagnosis and treatment of prostate cancers with metastatic potential.
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                Author and article information

                Journal
                Biomed Res Int
                Biomed Res Int
                BMRI
                BioMed Research International
                Hindawi Publishing Corporation
                2314-6133
                2314-6141
                2013
                30 December 2013
                : 2013
                : 576472
                Affiliations
                1State Key Laboratory of Oncogenes and Related Genes, Stem Cell Research Center, Renji Hospital, 160 Pu Jian Road, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
                2Med-X Research Institute, Shanghai Jiao Tong University, Shanghai 200030, China
                Author notes

                Academic Editor: Paul Crispen

                Author information
                http://orcid.org/0000-0002-9810-411X
                Article
                10.1155/2013/576472
                3929997
                e7e5be4d-8a30-4a49-9338-2d5db5e61119
                Copyright © 2013 Chenlu Zhang et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 30 April 2013
                : 17 October 2013
                Funding
                Funded by: http://dx.doi.org/10.13039/501100001809 National Natural Science Foundation of China
                Award ID: 81130038
                Funded by: http://dx.doi.org/10.13039/501100001809 National Natural Science Foundation of China
                Award ID: 81372189
                Funded by: http://dx.doi.org/10.13039/501100001809 National Natural Science Foundation of China
                Award ID: 81270627
                Categories
                Research Article

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