Biomedical subjects
Publications and source records attributed to Carien M Niessen.
Given the complexity of signaling pathways in the cell, it is a mystery how these pathways communicate with one other. In this issue of Cell, Wildenberg et al. (2006) reveal that the key effector molecule p120-catenin can mediate crosstalk between the Rac and Rho signaling pathways.
The skin water barrier, essential for terrestrial life, is formed by a multilayered stratifying epithelium, which shows a polarized distribution of both differentiation and intercellular junction markers. Recently, several reports showed the crucial importance of tight junctions for the in vivo water barrier function of the skin. In simple epithelial cells, intercellular junction formation is closely coupled to the establishment of polarity. However, if and how polarity proteins contribute to epidermal differentiation and junction formation is not yet known. Here, we have characterized the localization and isoform expression of the polarity protein atypical PKC (aPKC) and its binding partners Par3 and Par6 in epidermis and primary keratinocytes of mice. Their distribution is only partially overlapping in the granular layer, the site of functional tight junctions, suggesting that next to a common Par3/Par6/aPKC function they also may have functions independent of each other. Both aPKCzeta and aPKCiota/lambda, are expressed in the epidermis but only aPKCiota/lambda showed a strong enrichment in the junctions, suggesting that this aPKC isoform is important for epidermal tight junction function. Indeed, inhibition of aPKC function showed that endogenous aPKC is crucial for in vitro barrier function and this required the presence of both the Par3 and Par6 binding sites.
Cadherin adhesion molecules are key determinants of morphogenesis and tissue architecture. Nevertheless, the molecular mechanisms responsible for the morphogenetic contributions of cadherins remain poorly understood in vivo. Besides supporting cell-cell adhesion, cadherins can affect a wide range of cellular functions that include activation of cell signalling pathways, regulation of the cytoskeleton and control of cell polarity. To determine the role of E-cadherin in stratified epithelium of the epidermis, we have conditionally inactivated its gene in mice. Here we show that loss of E-cadherin in the epidermis in vivo results in perinatal death of mice due to the inability to retain a functional epidermal water barrier. Absence of E-cadherin leads to improper localization of key tight junctional proteins, resulting in permeable tight junctions and thus altered epidermal resistance. In addition, both Rac and activated atypical PKC, crucial for tight junction formation, are mislocalized. Surprisingly, our results indicate that E-cadherin is specifically required for tight junction, but not desmosome, formation and this appears to involve signalling rather than cell contact formation.
Cadherin adhesion molecules play important roles in the establishment of tissue boundaries. Cells expressing different cadherins sort out from each other in cell aggregation assays. To determine the contribution of cadherin binding and adhesion specificity to the sorting process, we examined the adhesion of cells to different purified cadherin proteins. Chinese hamster ovary cell lines expressing one of four different cadherins were allowed to bind to the purified cadherin extracellular domains of either human E-cadherin or Xenopus C-cadherin, and the specificity of adhesion was compared with cell-sorting assays. None of the different cadherin-expressing cells exhibited any adhesive specificity toward either of the two purified cadherin substrates, even though these cadherins differ considerably in their primary sequence. In addition, all cells exhibited similar strengthening of adhesion on both substrates. However, this lack of adhesive specificity did not determine whether different cadherin-expressing cells would sort from each other, and the tendency to sort was not predictable by the extent of sequence diversity in their extracellular domains. These results show that cadherins are far more promiscuous in their adhesive-binding capacity than had been expected and that the ability to sort out must be determined by mechanisms other than simple adhesive-binding specificity.