|Abstract or Summary
- BCL11B is a transcriptional regulatory protein that plays essential roles during mouse embryonic development. BCL11B is expressed and functions in the immune and nervous systems as well as within ectodermal organs. Multiple studies have characterized the roles of BCL11B in T cells, brain, and skin. However, very little is known about the mechanistic role of BCL11B during tooth development, and data are not available on the function of BCL11B in the craniofacial skeleton.
BCL11B is expressed widely within the oral cavity during development, and mice lacking BCL11B exhibit a spectrum of tooth developmental defects. The most striking feature of the Bcl11b[superscript -/-] dental phenotype is a defect in development of enamel-secreting cells, known as ameloblasts, in the mouse incisor. Ameloblasts are localized exclusively on the labial aspect of the mouse incisor in wild-type mice. In contrast, Bcl11b[superscript -/-] mice exhibit defective ameloblasts on the labial and develop ectopic, ameloblast-like cells on the lingual aspect of the tooth. BCL11B regulates asymmetric ameloblast formation by regulating the development of epithelial stem cell niches in the posterior part of the incisor. Specifically, BCL11B induces proliferation and differentiation of epithelial stem cells into ameloblasts in the labial cervical loop, whereas BCL11B suppresses these processes within the lingual epithelium. Such bidirectional actions of BCL11B are mediated by spatio-specific regulation of a large gene network comprised of genes that encode members of fibroblast growth factor (FGF) and transforming growth factor β (TGFβ) superfamilies, Sprouty proteins, and sonic hedgehog (SHH). In addition, my data integrate BCL11B into FGF and SHH signaling pathways revealing the molecular mechanisms that suppress development of ectopic ameloblast-like cells in the lingual epithelium. In the second half of this dissertation, I show that BCL11B is expressed in the osteogenic mesenchyme of developing craniofacial skeleton, and loss of BCL11B in these tissues has striking effects on craniofacial development. Bcl11b[superscript -/-] mice exhibit accelerated mineralization of the skull during embryonic development and synostosis of facial and coronal sutures. My results demonstrate that BCL11B normally functions to suppress proliferation and premature differentiation of osteoblasts in the craniofacial complex. I suggest that the principal mechanistic basis of these actions of BCL11B is the repression of Fgfr2c expression within the osteogenic mesenchyme. Taken together, my data demonstrate that BCL11B plays an important role in proliferation and differentiation of ameloblast and osteoblast lineages. In addition, my work implicates BCL11B in regulation of FGF and TGFβ signaling pathways. Therefore, these studies contribute to a better understanding of the molecular and cellular functions of BCL11B in vivo.