Ectodermal Dysplasias and Regulation of Ectodermal Appendage Development

National Institute Of Arthritis And Musculoskeletal And Skin Diseases

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Abstract

Our research focuses on characterizing 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. DLX3 plays a crucial role in tooth development, with autosomal dominant mutations in DLX3 resulting in severe enamel and dentin defects which lead to abscesses and infections. We have demonstrated that DLX3 is indispensable 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 the tooth and that these keratins are essential organic components of 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 evaluated for the presence of dental caries in a cohort of children and adults. 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 extended our studies to the analysis of the Krt75tm1Der knock-in mouse (KI) with deletion of Asn159, located two amino acids away from KRT75A161T, and shown that it can be a potential model for studying the role of K75 in enamel and the causes of the higher caries susceptibility associated with KRT75A161T mutation. We have also determined interacting proteins and functional role of KRT75 in keratinocytes.