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Gheldof A.,Unit of Molecular and Cellular Oncology | Gheldof A.,Ghent University | Hulpiau P.,Ghent University | Van Roy F.,Ghent University | And 5 more authors.
Cellular and Molecular Life Sciences

ZEB1 and ZEB2, which are members of the ZEB family of transcription factors, play a pivotal role in the development of the vertebrate embryo. However, recent evidence shows that both proteins can also drive the process of epithelial-mesenchymal transition during malignant cancer progression. The understanding of how both ZEBs act as transcription factors opens up new possibilities for future treatment of advanced carcinomas. This review gives insight into the molecular mechanisms that form the basis of the multitude of cellular processes controlled by both ZEB factors. By using an evolutionary approach, we analyzed how the specific organization of the different domains and regulatory sites in ZEB1 and ZEB2 came into existence. On the basis of this analysis, a detailed overview is provided of the different cofactors and post-translational mechanisms that are associated with ZEB protein functionality. © Springer Basel AG 2012. Source

Jackson B.,Copenhagen University | Peyrollier K.,Copenhagen University | Pedersen E.,Copenhagen University | Basse A.,Copenhagen University | And 15 more authors.
Molecular Biology of the Cell

RhoA is a small guanosine-5'-triphosphatase (GTPase) suggested to be essential for cytokinesis, stress fiber formation, and epithelial cell - cell contacts. In skin, loss of RhoA was suggested to underlie pemphigus skin blistering. To analyze RhoA function in vivo, we generated mice with a keratinocyte-restricted deletion of the RhoA gene. Despite a severe reduction of cofilin and myosin light chain (MLC) phosphorylation, these mice showed normal skin development. Primary RhoA-null keratinocytes, however, displayed an increased percentage of multinucleated cells, defective maturation of cell - cell contacts. Furthermore we observed increased cell spreading due to impaired RhoA-ROCK (Rho-associated protein kinase)-MLC phosphatase-MLC - mediated cell contraction, independent of Rac1. Rho-inhibiting toxins further increased multinucleation of RhoA-null cells but had no significant effect on spreading, suggesting that RhoB and RhoC have partially overlapping functions with RhoA. Loss of RhoA decreased directed cell migration in vitro caused by reduced migration speed and directional persistence. These defects were not related to the decreased cell contraction and were independent of ROCK, as ROCK inhibition by Y27632 increased directed migration of both control and RhoA-null keratinocytes. Our data indicate a crucial role for RhoA and contraction in regulating cell spreading and a contraction-independent function of RhoA in keratinocyte migration. In addition, our data show that RhoA is dispensable for skin development. © 2011 Jackson et al. Source

Pieters T.,Ghent University | Pieters T.,Molecular and Cellular Oncology Unit | van Roy F.,Ghent University | van Roy F.,Molecular Cell Biology Unit
Journal of Cell Science

Pluripotent embryonic stem cells (ESCs) can self-renew or differentiate into any cell type within an organism. Here, we focus on the roles of cadherins and catenins - their cytoplasmic scaffold proteins - in the fate, maintenance and differentiation of mammalian ESCs. E-cadherin is a master stem cell regulator that is required for both mouse ESC (mESC) maintenance and differentiation. Ecadherin interacts with key components of the naive stemness pathway and ablating it prevents stem cells from forming welldifferentiated teratomas or contributing to chimeric animals. In addition, depleting E-cadherin converts naive mouse ESCs into primed epiblast-like stem cells (EpiSCs). In line with this, a mesenchymal-to-epithelial transition (MET) occurs during reprogramming of somatic cells towards induced pluripotent stem cells (iPSCs), leading to downregulation of N-cadherin and acquisition of high E-cadherin levels. β-catenin exerts a dual function; it acts in cadherin-based adhesion and in WNT signaling and, although WNT signaling is important for stemness, the adhesive function of β-catenin might be crucial for maintaining the naive state of stem cells. In addition, evidence is rising that other junctional proteins are also important in ESC biology. Thus, precisely regulated levels and activities of several junctional proteins, in particular E-cadherin, safeguard naive pluripotency and are a prerequisite for complete somatic cell reprogramming. © 2014. Published by The Company of Biologists Ltd. Source

Verstraeten B.,Ghent University | Sanders E.,Ghent University | Sanders E.,Molecular Cell Biology Unit | Huysseune A.,Ghent University
Methods in Molecular Biology

Tooth development is increasingly being studied in a variety of vertebrate model organisms, each contributing its own perspective to our understanding of dental diversity. In situ hybridization and immunohistochemistry are well-established and frequently used techniques to study the presence of mRNA and protein. Here, we describe a protocol for whole mount immunohistochemistry and in situ hybridization that can be applied to all stages of zebrafish development and dissected bony parts. The description of these protocols is followed by the outline of a quick decalcification method and the procedure for embedding in epoxy resin to obtain serial sections with high histological quality. © 2012 Springer Science+Business Media, LLC. Source

Verstraeten B.,Ghent University | Sanders E.,Ghent University | Sanders E.,Molecular Cell Biology Unit | Van Hengel J.,Molecular Cell Biology Unit | And 2 more authors.
BMC Developmental Biology

Background. The development of teeth is the result of interactions between competent mesenchyme and epithelium, both of which undergo extensive morphogenesis. The importance of cell adhesion molecules in morphogenesis has long been acknowledged but remarkably few studies have focused on the distribution and function of these molecules in tooth development. Results. We analyzed the expression pattern of an important epithelial cadherin, E-cadherin, during the formation of first-generation teeth as well as replacement teeth in the zebrafish, using in situ hybridization and whole mount immunostaining to reveal mRNA expression and protein distribution. E-cadherin was detected in every layer of the enamel organ during the different stages of tooth development, but there were slight differences between first-generation and replacement teeth in the strength and distribution of the signal. The dental papilla, which is derived from the mesenchyme, did not show any expression. Remarkably, the crypts surrounding the functional teeth showed an uneven distribution of E-cadherin throughout the pharyngeal region. Conclusions. The slight differences between E-cadherin expression in zebrafish teeth and developing mouse and human teeth are discussed in the light of fundamental differences in structural and developmental features of the dentition between zebrafish and mammals. Importantly, the uninterrupted expression of E-cadherin indicates that down-regulation of E-cadherin is not required for formation of an epithelial tooth bud. Further research is needed to understand the role of other cell adhesion systems during the development of teeth and the formation of replacement teeth. © 2010 Verstraeten et al; licensee BioMed Central Ltd. Source

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