Quantification of three-dimensional morphology of craniofacial mineralized tissue defects in Tgfbr2/Osx-Cre mice.

Craniofacial morphology is affected by the growth, development, and three-dimensional (3D) relationship of mineralized structures including the skull, jaws, and teeth. Despite fulfilling different purposes within this region, cranial bones and tooth dentin are derived from mesenchymal cells that are affected by perturbations within the TGF-ß signaling pathway. TGFBR2 encodes a transmembrane receptor that is part of the canonical, SMAD-dependent TGF-ß signaling pathway and mutations within this gene are associated with Loeys-Dietz syndrome, a condition which often presents with craniofacial signs including craniosynostosis and cleft palate. To investigate the role of Tgfbr2 in immature, but committed, mineralized tissue forming cells, we analyzed postnatal craniofacial morphology in mice with conditional Tgfbr2 deletion in Osx-expressing cells. Novel application of a 3D shape-based comparative technique revealed that Tgfbr2 in Osx-expressing cells results in impaired postnatal molar root and anterior cranial growth. These findings support those from studies using similar Tgfbr2 conditional knockout models, highlight the anomalous facial and dental regions/structures using tomographic imaging-based techniques, and provide insight into the role of Tgfbr2 during postnatal craniofacial development.

TGF-ß Family Signaling in Mesenchymal Differentiation.

Mesenchymal stem cells (MSCs) can differentiate into several lineages during development and also contribute to tissue homeostasis and regeneration, although the requirements for both may be distinct. MSC lineage commitment and progression in differentiation are regulated by members of the transforming growth factor-ß (TGF-ß) family. This review focuses on the roles of TGF-ß family signaling in mesenchymal lineage commitment and differentiation into osteoblasts, chondrocytes, myoblasts, adipocytes, and tenocytes. We summarize the reported findings of cell culture studies, animal models, and interactions with other signaling pathways and highlight how aberrations in TGF-ß family signaling can drive human disease by affecting mesenchymal differentiation.

Cranial neural crest cell contribution to craniofacial formation, pathology, and future directions in tissue engineering.

This review provides an overview of the state and future directions of development and pathology in the craniofacial complex in the context of Cranial Neural Crest Cells (CNCC). CNCC are a multipotent cell population that is largely responsible for forming the vertebrate head. We focus on findings that have increased the knowledge of gene regulatory networks and molecular mechanisms governing CNCC migration and the participation of these cells in tissue formation. Pathology due to aberrant migration or cell death of CNCC, termed neurocristopathies, is discussed in addition to craniosynostoses. Finally, we discuss tissue engineering applications that take advantage of recent advancements in genome editing and the multipotent nature of CNCC. These applications have relevance to treating diseases due directly to the failure of CNCC, and also in restoring tissues lost due to a variety of reasons.

Neural crest cell signaling pathways critical to cranial bone development and pathology.

Neural crest cells appear early during embryogenesis and give rise to many structures in the mature adult. In particular, a specific population of neural crest cells migrates to and populates developing cranial tissues. The ensuing differentiation of these cells via individual complex and often intersecting signaling pathways is indispensible to growth and development of the craniofacial complex. Much research has been devoted to this area of development with particular emphasis on cell signaling events required for physiologic development. Understanding such mechanisms will allow researchers to investigate ways in which they can be exploited in order to treat a multitude of diseases affecting the craniofacial complex. Knowing how these multipotent cells are driven towards distinct fates could, in due course, allow patients to receive regenerative therapies for tissues lost to a variety of pathologies. In order to realize this goal, nucleotide sequencing advances allowing snapshots of entire genomes and exomes are being utilized to identify molecular entities associated with disease states. Once identified, these entities can be validated for biological significance with other methods. A crucial next step is the integration of knowledge gleaned from observations in disease states with normal physiology to generate an explanatory model for craniofacial development. This review seeks to provide a current view of the landscape on cell signaling and fate determination of the neural crest and to provide possible avenues of approach for future research.