Research

Current research projects include:

  1. Molecular regulatory mechanisms of cranial neural crest cell fate determination: One of the key features of craniofacial development is the formation of the cranial neural crest (CNC). The specification, migration, proliferation, survival and ultimate fate determination of the CNC play important roles in regulating craniofacial development. Unlike the trunk neural crest, CNC cells give rise to an array of cell types during embryonic development.  For example, CNC cells form most of the hard tissues of the head, such as bone, cartilage and teeth, whereas hard tissues in the rest of the body are formed from mesoderm-derived cells.  Genetic disorders, environmental insults or the combination of both can alter the fate determination of CNC cells and result in craniofacial malformations.  Our research, in conjunction with the work of others, will significantly advance the understanding of how this important population of pluripotent cells is initially established in the early embryo and the molecular mechanisms that mediate neural crest cell lineage segregation, differentiation and final contribution to organogenesis.
  1. Stem cells and craniofacial tissue regeneration: The in vivo identity of mesenchymal stem cells (MSCs) and the niche that regulates MSCs are poorly understood. We have recently identified CNC-derived MSCs in adult jawbones. These MSCs have stem cell properties and can give rise to different cell types in craniofacial tissue regeneration. In parallel, using a mouse incisor model, we discovered that the neurovascular bundle (NVB) acts as an MSC niche and sensory nerves provide Shh protein, activating Gli1 expression in periarterial cells that contribute to all mesenchymal derivatives. These periarterial cells do not express classical MSC markers used to define MSCs in vitro.  NG2+ pericytes represent a MSC subpopulation derived from Gli1+ cells; they contribute little to homeostasis but are actively involved in injury repair (Zhao et al., 2014).  In parallel, we recently discovered that craniosynostosis results from diminished MSCs in cranial sutures and manipulation of MSCs can generate a new biological suture for animal models with craniosynostosis (Zhao et al., 2015; Yu et al., 2021). Collectively, these discoveries position us to translate our basic research into patient care and will provide long lasting benefits for our patients.
  1. Molecular and cellular regulatory mechanism of palatogenesis: Cleft palate is one of the most common congenital birth defects and adversely affects the quality of life. Although many mutant animal models with cleft palate have been generated, many of them do not correlate with palatal defects seen in humans. Significantly, our research program has been focusing on TGF-beta signaling mechanisms in regulating tissue-tissue interactions to control craniofacial development and how abnormal TGF-β signaling causes congenital malformations. We have generated important animal models that closely mimic the cleft palate condition in humans. Our work has provided crucial evidence that mutation in Tgfb causes cleft palate in mice and humans. Most importantly, we have made significant progress in identifying the molecular signaling mechanisms that are responsible for causing cellular defects and cleft palate (Iwata et al., 2012, Han et al., 2021). Furthermore, we have identified a novel TGF-β signaling mechanism that regulates embryonic development. We have applied this information and prevented cleft palate in Tgfb mutant mice. Our study will help to develop important diagnostic biomarkers and drug targets for the prevention and treatment of patients with congenital malformations.
  1. Skull morphogenesis and stem cells in tissue regeneration: Craniofacial bone defects are a major group of congenital birth defects in humans. Members of the TGFβ family mediate a wide range of biological activities, including cell proliferation, differentiation, extracellular matrix formation and induction of homeobox genes, suggesting that TGFβ signaling is important in pattern formation during embryogenesis. Despite this information, we still do not have a comprehensive understanding of the molecular and cellular mechanisms of TGFβ signaling-mediated craniofacial bone formation. Using our Tgfbr mutant animal models, we show that TGFβ regulates Fgf and Dlx5 gene expression to control tissue-tissue interactions in regulating craniofacial bone morphogenesis. Furthermore, we have shown that manipulation of TGFβ downstream target genes can rescue craniofacial malformations in our Tgfb mutant animal models. Our study provides a useful animal model towards a comprehensive understanding of normal craniofacial development, as well as CNC-related congenital malformations.
  1. Regulatory mechanism of tooth morphogenesis and regeneration: The investigation of the regulatory mechanism of tooth development offers an important opportunity to test how tissue-tissue interactions control organogenesis. To date, most studies have focused on early stages of tooth development. We have very limited information on the molecular regulatory mechanism of tooth root development despite the fact that dental roots are crucial for the physiological function of our dentition and oral health. Furthermore, dental root defects resulting from developmental malformations, pathological conditions and dental treatments are common and significantly compromise quality of life. Using different mutant models, we have shown that Bmp/Tgf-β, Shh, Fgf, and Nfic are involved in regulating root development. With our recent publications, we have provided a better understanding of how the Bmp/Tgf-β signaling cascade regulates the interaction between the dental epithelium and mesenchyme during tooth root development and how signaling pathway disruption can lead to craniofacial malformations. The knowledge gained from this study will serve as the foundation for stem cell-mediated tooth regeneration.
  1. FaceBase Consortium: Our group has been  intimately involved in the design and operation of the FaceBase Consortium from its inception, and I served as the Chair of the Steering Committee in FaceBase 1 and 2. We have contributed a total of over 460 datasets to FaceBase to date through our  spoke projects on palate and jaw development in FaceBase 1 and 2, respectively, as well as our ongoing efforts in FaceBase 3. Along with Carl Kesselman of USC’s Information Sciences Institute (ISI), I serve as Co-PI of the FaceBase Hub. Our team works in close concert with ISI scientists to identify, recruit, and curate datasets; develop innovative new features; and conduct outreach and training activities for FaceBase users and contributors. We continue to build FaceBase as an important and comprehensive data resource for the research community.