Research
Overview
The fundamental question we are trying to answer is how the coordinated cell movements are regulated during animal development. Different groups of cells move to different locations in a growing embryo to give rise to specific tissue and structures. It is a very complex process since the “ground” cells travel on is also undergoing constant rearrangement and growth. We use neural crest as a model to study the mechanisms of cell migration during embryonic development. The neural crest is a vertebrate innovation, comprised of highly migratory stem-like cells that give rise to multiple tissue and structures, including craniofacial bones and cartilages, connective tissue in the heart, enteric nervous system in the gut, and pigment cells all over the skin. Defects in their proliferation, migration, differentiation, or survival lead to numerous diseases and birth defects, including craniofacial and heart malformations as well as different types of cancer. Ongoing studies aim to uncover how neural crest cell migration is regulated from several prospectives: at the level of cytoskeletal machinery, at the interface between cell and extracellular matrix, and at the level of gene transcription. We hope to understand how neural crest cells achieve such extraordinary migratory abilities, and whether such knowledge can be extended to study cancer metastasis.
Actin Cytoskeletal Control
The rearrangement of actin filaments is the primary force-generating mechanism of cell motility. However, little is known about the dynamic regulations of actin cytoskeleton during cell migration in living embryos. Using advanced molecular, cellular, embryological, and imaging technologies, we are investigating the roles of novel actin cytoskeletal regulators (ACRs) during neural crest migration and actin dynamics, as well as the functional and physical interactions between different ACRs. The long-term goal is to integrate the information obtained regarding the activities and interactions of various ACRs to establish a comprehensive and dynamic actin regulatory network during cell migration in vivo. Although this work focuses on neural crest migration, it promises to provide insights and build a foundation for our general understanding of the mechanistic control of cell migration, both during embryogenesis and in adult homeostasis.
Cell-Matrix Interaction
During cell migration, cell and the local environment constantly interact with each other. The matrix provides support and traction to the migrating cell, while the cell secrets both matrix components and matrix proteases to remodel the matrix. We are employing both candidate approach and exploratory approach to study the interactions between extracellular matrix and the migrating neural crest cells. Ongoing projects include studying the function of metalloprotease MMP14 in neural crest EMT and migration, elucidating the roles of hyaluronan in cell adhesion and migration, and determine the effect of protein glycosylation in neural crest EMT and migration.
Transcriptional Control
We focus on the transcription factor Ets-1, which is critical for cranial and cardiac neural crest EMT and migration. Our previous work suggest that Ets-1 is required in both cardiac neural crest cells and heart mesoderm for proper heart development. At the loss of Ets-1, defective frog heart resembles that of the hypoplastic left heart syndrome patient. We are now collaborating with Dr. Grossfeld in UCSD, who first identified the deletion of ETS-1 gene in patients of Jacobson Syndrome, to elucidate the molecular and cellular mechanisms of hypoplasitc left heart syndrome (HLHs) in both frog and mouse embryos.