Analysis of Large Phenotypic Variability of EEC and SHFM4 Syndromes Caused by K193E Mutation of the TP63 Gene

EEC (ectrodactyly, ectodermal dysplasia, clefting; OMIM 604292) is an autosomal dominant developmental disorder resulting mainly from pathogenic mutations of the DNA-binding domain (DBD) of the TP63 gene. In this study, we showed that K193E mutation in nine affected individuals of a four-generation kindred with a large degree of phenotypic variability causes four different syndromes or TP63-related disorders: EEC, Ectrodactyly-ectodermal dysplasia (EE), isolated ectodermal dysplasia, and isolated Split Hand/Foot Malformation type 4 (SHFM4). Genotype-phenotype and DBD structural modeling analysis showed that the K193-located loop L2-A is associated with R280 through hydrogen bonding interactions, while R280 mutations also often cause large phenotypic variability of EEC and SHFM4. Thus, we speculate that K193 and several other DBD mutation-associated syndromes may share similar pathogenic mechanisms, particularly in the case of the same mutation with different phenotypes. Our study and others also suggest that the phenotypic variability of EEC is attributed, at least partially, to genetic and/or epigenetic modifiers

Cbx4 maintains the epithelial lineage identity and cell proliferation in the developing stratified epithelium

During development, multipotent progenitor cells establish lineage-specific programmers of gene activation and silencing underlying their differentiation into specialized cell types. We show that the Polycomb component Cbx4 serves as a critical determinant that maintains the epithelial identity in the developing epidermis by repressing nonepidermal gene expression programs. Cbx4 ablation in mice results in a marked decrease of the epidermal thickness and keratinocyte (KC) proliferation associated with activation of numerous neuronal genes and genes encoding cyclin-dependent kinase inhibitors (p16/p19 and p57). Furthermore, the chromodomain- and SUMO E3 ligase–dependent Cbx4 activities differentially regulate proliferation, differentiation, and expression of nonepidermal genes in KCs. Finally, Cbx4 expression in KCs is directly regulated by p63 transcription factor, whereas Cbx4 overexpression is capable of partially rescuing the effects of p63 ablation on epidermal development. These data demonstrate that Cbx4 plays a crucial role in the p63-regulated program of epidermal differentiation, maintaining the epithelial identity and proliferative activity in KCs via repression of the selected nonepidermal lineage and cell cycle inhibitor genes

Stem cells in ectodermal development

Tissue-specific stem cells sustain organs for a lifetime through self-renewal and generating differentiated progeny. Although tissue stem cells are established during organogenesis, the precise origin of most adult stem cells in the developing embryo is unclear. Mammalian skin is one of the best-studied epithelial systems containing stem cells to date, however the origin of most of the stem cell populations found in the adult epidermis is unknown. Here, we try to recapitulate the emergence and genesis of an ectodermal stem cell during development until the formation of an adult skin. We ask whether skin stem cells share key transcriptional regulators with their embryonic counterparts and discuss whether embryonic-like stem cells may persist through to adulthood in vivo

Influence of steam activation on pore structure and acidity of zeolite beta: an Al K-edge XANES study of aluminium coordination

The effect of steam activation on the aluminum coordination in zeolite NH{4}-beta was investigated by means of quantitative analysis of Al K edge XANES spectra. Framework tetrahedral aluminum is converted to octahedral aluminum after calcination and steaming, a process that, at the same time, removes NH{3} and brings about Lewis acidity. After mild activation, this octahedral aluminum can revert to the tetrahedral state by NH{3} treatment while preserving long-range ordering. This implies that structural changes are fully reversible. Intense steaming causes irreversible changes in the structure of the zeolite: some of the tetrahedrally coordinated aluminum is distorted and octahedrally coordinated aluminum is present in the zeolite. NH{3} treatment of intensely steamed zeolite beta results in the reversal of all octahedrally coordinated aluminum to the tetrahedrally coordinated structure, while medium range ordering around some of the tetrahedral aluminum is lost. N{2} physisorption experiments indicate that intense steaming creates clefts or mesopores in the zeolite crystallites, resulting in a decrease in the length of the diffusion pathways of the reactants. This explains, at least in part, the enhanced activity of zeolite beta in the Lewis acid (Al-)-catalyzed Meerwein-Ponndorf-Verley (MPV) reaction after intense steaming