Research

While studying actin cytoskeleton in neural crest cell migration, we uncovered that septin filaments interact closely with actin filaments.  They co-align with actin stress fibers, and regulate the stability and contractility of actin stress fibers.  As a more stable type of cytoskeleton, we think that they support the orientation of more dynamic actin stress fibers and therefore promote persistence in cell migration. Ongoing work includes determining the mechanisms of septin - actin interactions and investigating the crosstalk between septins and actin regulators Cdc42 and Cdc42ep1.

Recently, we also started to explore the role of microtubules in neural crest cell migration. In addition to well known roles of microtubules in cell division and transportation, microtubule and its motor proteins (e.g., dynein) can also regulate cell motility. Our preliminary work suggest that microtubule-dynein is dispensible during cell migration without any physical constraints, but plays important roles in vivo or under constraints. Ongoing project studies the activity of microtubule-dynein in different conditions of neural crest cell migration, and how they interact with other cytoskeletal components, including actin and septin. 

During cell migration, cells interact with their neighbors and the local environment dynamically. In terms of cell-cell interaction, neural crest cells start as epithelial tissue where they maintain stable contact (adhesions) with each other. In the early phase of their migration, they start to rearrange among themselves and their interaction become dynamic and transient, yet they still migrate collectively as a group. In the later phase, neural crest cell become fully mesenchymal, and they migrate as individual cells. During this multi-stage epithelial-to-mesenchymal transition (EMT), cell-cell adhesion is tightly regulated. We and others found that, E-cadherin (CDH1) is expressed and functions in neural crest cells during their collective migration, challenging the traditional view of "Cadherin Switch" in EMT. We are currently investigating the role of E-cadherin in collective migration, from both mechanical and signaling prospective. 

Migrating cells also interact actively with its local environment during migration. For example, cells can synthesize and secrete matrix components, including protein and carbohydrates into the pericellular and extracellular space. One project we work on involves the study of hyaluronan which modulates cell adhesion strenghth and therefore cell motility, in collaboration with Curtis Lab in Physics.  

In addition to secreting matrix components, migrating cell can also secrete matrix proteases that remodel the surrounding matrix. For example, one of our published work examined how metalloprotease MMP14 was produced by neural crest cells, which remodels extracellular matrix and cell adhesion molecules to promote neural crest cell migration.  

Recently, we found that changing local environment can also change the migratory behavior of neural crest cells. For example, physical constraints can shift cells from undergoing collective migration to individual migration. How cell migration mode is regulated and the linkage between cell migration mode, extracellular environment, and the cytoskeletal regulation are under investigation. 

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 (HLHS) patient, one of the most severe congenital heart defects in human. With advanced light-field microscopy and imaging analysis provided by Jia lab at BME, we demonstrated that the loss of Ets1 leads to severely impaired heart performance in tadpoles, again resembles that of HLHS patients.  

We have now formed a multidisciplinary team with Grossfeld Lab in UCSD, who first identified the deletion of ETS-1 gene in patients of Jacobson Syndrome and studies HLHS with genetically modified mice, and Ocorr Lab at SBP,  who uses fly and zebrafish to uncover the mechanisms of Ets1 gene in early development.  We have determined that the loss of Ets1 leads to an early development defects of the heart, especially impacted the endothelial/endocardial tissue rather than the cardiomyocytes. We are also beginning to identify interacting factors of Ets1 and working towards generating the first animal model describing this disease.