MASA TADA GROUP
We are interested in cellular and molecular mechanisms that shape the embryo. During gastrulation, there are several different types of cells, all moving to different directions but in a highly co-ordinated manner. For example, prechordal plate progenitors migrate as a coherent sheet of cells to their destination, whereas notochord progenitors intercalate between one another to elongation the tissue along the forming body axis. These orchestrated movements transform ball-like embryos to fry with head-to-tail structures. Also, there are similarities in collective cell behaviours between gastrulating cells and metastasizing cancer cells. How do cells know where to go? How do cells communicate within the same group or between different groups? To tackle these questions, we use the zebrafish as a fantastic model system for in vivo cell biology based on time-lapse imaging analyses based on genetic approaches. The primary interests are; i) how cells keep themselves from behaving randomly; ii) what mediates the mode of migration of prechordal progenitors, collectively or individually and iii) how normal cells detect transformed cells in a simple epithelium and eliminate them from the epithelium at initiation of carcinogenesis.
The current topics
i) Planar cell polarity and cell adhesion
One genetic pathway that co-ordinates cell movements is planar cell polarity (PCP). This pathway has been originally discovered in simple epithelia in Drosophila but also been shown to be required for convergent extension movement of notochord progenitors in vertebrates. In other words, the PCP pathway plays a pivotal role in suppressing 'random' behaviour within the same cell population regardless of different contexts. The core PCP protein Flamingo, an atypical cadherin with a seven-pass-transmembrane domain, regulates convergent extension and cell adhesion by PCP-dependent and -independent mechanisms (Carreira-Barbosa et al., 2009). We are investigating how Flamingo/Celsr regulates planar cell polarity and cell adhesion separately.
ii) Collective migration of prechordal plate progenitors
Prechordal plate progenitors undergo collective migration as a cohesive sheet of mesenchymal cells, and the cells located at the leading edge produce different types of protrusions, lamellipodia and blebs. We found that prechordal plate progenitors can change the mode of their collective migration into individual migration when PCP and sphingosine-1-phosphate (S1P) signals are both compromised (Kai et al., 2008). We try to understand the mechanism underlying this transition. Moreover, we are investigating the mechanism underlying ethanol-induced alterations in collective migration of prechordal plate progenitors as they are more sensitive to ethanol treatment than notochord progenitors. Understanding the molecular mechanisms for the effects of ethanol on collective migration of prechordal plate progenitors helps us prevent foetal alcohol syndromes, potentially leading to cyclopia.
iii) Cancer cell extrusion from simple epithelia
At early stages of cancer initiation, normal cells detect cancer cells in the epithelium and try to eliminate them from the epithelium or vice versa. We found that Src-transformed cells are apically extruded when surrounded by normal cells in the enveloping layer of the zebrafish embryo (Kajita et al., 2010). We are investigating how normal cells detect transformed cells and what are the signals that are emitted by transformed cells towards neighbouring normal cells. Better understanding of the detection and exclusion mechanisms in vivo will provide us with a clue to cancer therapies as one can prevent cancer cells from spreading over the body through basal invasion. This project is in collaboration with Yasu Fujita (Hokkaido Univ, Japan).
My SLMS page is here