Heritable Defects of Human Tooth Development

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DESCRIPTION: (provided by applicant) The development of many vertebrate organs depends on reciprocal inductive signaling between epithelium and mesenchyme. One class of genes that play important role during this process are those belonging to the Msx homeobox gene family. Studies in both mouse and humans revealed that MSX along with other genes specify the skull, face, skin and tooth development. The dentition which comprises a major component of the mammalian craniofacial system, also provides a powerful and potentially general model for the study of organ development. This is further demonstrated by the wealth of information on the genetic hierarchies which operate during early tooth development (Kratochwil et al., 1996; Vaahtokari et al., 1996; Neubuser et al. 1997: Bei and Maas, 1998; reviewed in Thesleff et a., 1995; Maas and Bei, 1997; Thesleff and Sharpe, 1997; Peters and flailing, 1999). The applicant has been able to unravel part of the genetic pathway responsible for early tooth development using the genetically engineered Msx1 and/or Msx2 mouse mutants. The applicant has been able to unravel part of the genetic pathway responsible for early tooth development using the genetically engineered Msx1 and/or Msx2 mouse mutants. Despite information about the regulation of Msx gene expression by epistasis analysis, the downstream targets of Msx gene regulation and the molecular mechanisms by which the Msx proteins control transcriptional regulation of organogenesis remain largely unknown. To further expand her research activities in molecular biology and human genetics the applicant will seek a new research direction trying to understand from genome based transcriptional profiling and molecular studies the heritable disorders of human tooth development. As a continuation of her previous work and in order to understand the role of Msx genes in mouse and human craniofacial development, the goal of this proposal is to identify novel genes involved in the patterning of normal tooth development in the mouse and to screen whether their human orthologs contain mutations responsible for heritable disorders of tooth development. The applicant has a long-standing interest to understand the different pathways involved in normal craniofacial development and how mutations in different genes disrupt this process which constitutes her career goal. Functional genomics and human genetics are new research areas that provide extremely attractive opportunities for investigation and will enable the applicant to become an independent investigator in contemporary genomics and molecular genetics. This career award will provide her with scientific maturity and experience required for realizing her career goal.