All ETDs from UAB

Advisory Committee Chair

Mary Macdougall

Advisory Committee Members

David D Chaplin

Shuo Chen

John F Kearney

Huw F Thomas

Document Type

Dissertation

Date of Award

2012

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Currently, very little is known regarding tissue-specific gene regulation during the later stages of tooth development, especially those associated with root formation. Re-cent studies have identified nuclear factor I-C (NFI-C) as a critical factor for root for-mation in mammals. NFI-C functions as a cellular transcription factor and adenovirus DNA replication factor. Its role in root formation first became evident when Nfi-c null mice were shown to lack molar roots. A similar phenotype of incomplete or absent root formation is observed in patients with the autosomal dominant disease Radicular Dentin Dysplasia (RDD; MIM125400) also known as Rootless Teeth or Dentin Dysplasia Type I. In humans, the NFI-C gene is alternatively spliced and NFI-C2 was the most abundant transcript of the three isoforms we identified in dental and non-dental cells/tissues. The C-terminus, believed to act as a transcript modulator domain, is unique in the case of the NFI-C2 protein. We mapped the temporal-spatial expression of this isoform during mouse tooth development. NFI-C2 was mainly detected in the mesenchymal tissues dur-ing the earlier stages of tooth formation, at the epithelial-mesenchymal interface. As the tooth organ progresses further, an increased staining is seen within the enamel secreting ameloblasts and dentin forming odontoblasts and later on in the Hertwig's epithelial root sheath, which is important in root development. In human dental cells NFI-C2 is local-ized not only within the nucleus, but is also associated with the Golgi apparatus in the cytoplasm. Finally, our laboratory has identified several consanguineous families with a novel autosomal recessive (AR) form of RDD, leading to premature exfoliation both de-ciduous and permanent dentitions. DNA analysis of these AR RDD families revealed a common 3' untranslated region (UTR) NFI-C mutation. This mutation, contained within an element highly conserved across all available species, results in decreased NFI-C mRNA levels and stability and disruption of normal cellular localization. These studies demonstrate that the NFI-C gene is regulated in part by a conserved element contained within the 3' UTR region of the gene and that a mutation in this regulatory element re-sults in disruption of normal NFI-C expression altering normal signaling cascades for root formation.

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