Ectodermal Dysplasias and Regulation of Ectodermal Appendage Development

National Institute Of Arthritis And Musculoskeletal And Skin Diseases

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Abstract

Our research efforts have focused on characterizing the regulation and function of the DLX3 homeobox transcription factor, a member of the murine DLX family with essential roles in epidermal development. The DLX3 gene is broadly expressed in the branchial arches and embryonic ectoderm, as well as in the tooth, hair follicle and interfollicular epidermis. To elucidate the functional role of the DLX3 homeodomain protein during early development and during epidermal differentiation, we are currently in the process of determining the target genes and the DLX3 interacting factors necessary to exert the transcription regulatory function. During embryonic development and organ formation, a series of signals between epithelial cells and underlying mesenchymal cells leads to the formation of a variety of appendages/organs. Anomalies in epithelial/mesenchymal-derived organs are characteristics of a group of human heritable pathological disorders defined as ectodermal dysplasias. The importance of Dlx3 in the patterning and development of ectodermal structures derived from epithelial-mesenchymal interactions during embryogenesis (i.e. tooth, hair) is corroborated by the effects of DLX3 mutations in patients with the autosomal dominant Tricho-Dento-Osseous syndrome (TDO). Research on the mechanistic role of Dlx3 in epidermal development and appendage formation has led to the important finding that DLX3 is a direct target of the p63 transcription factor. Besides autosomal mutations in either DLX3 or P63 genes being associated with human ectodermal dysplasias, misregulation of DLX3 function is directly involved in the pathogenesis of ectodermal human syndromes associated with p63 molecular lesions. During development, DLX3 is also expressed in teeth. Thus far, the evidence that DLX3 plays a crucial role in tooth development comes from reports showing that autosomal dominant mutations in DLX3 result in severe enamel and dentin defects leading to abscesses and infections. We have demonstrated that DLX3 is indispensable for the regulation of ion transporters and carbonic anhydrases during the maturation stage of amelogenesis, exerting a crucial regulatory function on pH oscillations during enamel mineralization. We have also shown that DLX3 controls the expression of epithelial hair keratins in tooth and that these keratins are essential organic components of the mineralized tooth enamel. Missense polymorphisms in one of these hair keratins, KRT75, profoundly impact dental caries susceptibility. The impact of two missense polymorphisms on hair keratin 75, KRT75A161T and KRT75E337K, previously identified as causal in two distinct hair disorders, pseudofolliculitis barbae and loose anagen hair syndrome, was tested for the presence of dental caries in a cohort of children and adults who underwent cross-sectional assessment of their teeth to generate dental caries indices. Linear regression analysis showed that the two missense polymorphisms in the KRT75 gene significantly increased susceptibility to caries. We also demonstrated that mutations in hair keratins cause tooth enamel defects leading to altered arrangement of enamel rods and significantly reduced enamel hardness, making the defective enamel more prone to caries. We have expanded our studies to the analysis of KRT6A, KRT6B, KRT6C, KRT16, and KRT17, a set of keratin genes expressed in the nail bed, palmoplantar epidermis, oral mucosal epithelium, hair follicle and sweat gland. Mutations in these keratins is associated with a cutaneous disorder termed Pachyonychia congenita, characterized by nail dystrophy and painful palmoplantar keratoderma. We recently determined that several missense polymorphisms in PC-associated keratins (KRT6A, KRT6B and KRT6C) lead to a higher risk for dental caries.