Dept Stem Cell Biology and Regenerative Medicine
Director, Program in Development, Stem Cells, and Regenerative Medicine
- Vertebrate Head Skeleton Development
- Neural Crest Specification
- Skeletal Regeneration
Research OverviewVertebrates come in a dazzling array of shapes and sizes, their outward appearances largely determined by their skeletons. In particular, the cartilages and bones of the face develop from a vertebrate-specific population of neural crest cells that form a series of nearly identical pharyngeal arches in every vertebrate. How then do these cells organize into the facial features appropriate for each animal? This question is fundamental for understanding not only how animal diversity is generated but also why development goes awry in human birth defects affecting the face.
My laboratory studies the cellular basis of skeletal shaping in zebrafish because their embryos are transparent and develop rapidly, thus allowing us to directly observe development in living animals. By making high-resolution time-lapse recordings of transgenic zebrafish, in which a green fluorescent protein has been engineered specifically into skeletal precursor cells, we can specifically follow the cells that make cartilage and bone. In addition, we have isolated several mutant strains that have specific defects in the facial skeleton, and these mutants will allow us to understand the molecular basis of skeletal patterning.
During neural crest development, cells must decide whether to make ectodermal derivatives, such as neurons and glia, or mesoderm-like derivatives such as cartilage and bone. In lpy and myx mutants, neural crest cells lose the ability to make skeletal crest derivatives, yet crest-derived neurons and glia develop normally. By studying these mutants, we hope to better understand the molecular signals that allow neural crest cells to form various derivatives.
In mutants for the Alagille Syndrome gene homolog, Jag1b, the upper face is transformed to resemble a duplicate version of the lower face. By characterizing this mutant, we are learning about the molecular signals that specify distinct parts of the head skeleton. In addition, facial patterning involves intricate crosstalk between the endodermal and ectodermal epithelia and the preskeletal mesenchyme. In order to better understand this crosstalk, we are creating libraries of transgenic lines that will allow us to manipulate signaling in both the epithelia and the mesenchyme at specific times of development.
In addition, we are interested in how the facial skeleton can rebuild itself following injury. Zebrafish is an excellent model for regeneration, as it can regenerate most of its organs throughout adulthood. We find that the jaw can also regenerate, and we have identified neural crest cells that persist into the adult. We are currently pursuing several strategies to isolate and characterize the neural-crest-derived stem cells that can regenerate the facial skeleton.