Regulation of vertebrate gastrulation by ErbB signaling

by Nie, Shuyi.

ErbB receptor tyrosine kinases have long been implicated in cancer formation and progression by regulating cell division, migration, and survival. ErbBs are also essential in multiple processes during invertebrate development; however, their activities during vertebrate embryogenesis are not well understood. For functional characterization of ErbB signaling during vertebrate development, frog model Xenopus laevis was used in our studies. The expression pattern and the general activities of ErbB receptors during early frog development were first analyzed and results shown that ErbBs regulate gastrulation, somite organization and head patterning. As gastrulation is the first major morphogenetic event in vertebrate development, I focused the following studies on ErbB signaling in frog gastrulation. During Xenopus gastrulation, mesendodermal cells are internalized and display different movements. Head mesoderm migrates along the blastocoel roof, while trunk mesoderm undergoes convergent extension (C & E). Inhibition of ErbB pathway blocks both C & E of trunk mesoderm and migration of head mesoderm. Cell polarization and intercalation, cell-cell and cell-matrix interaction, as well as formation of membrane protrusions are also impaired, demonstrating that modulation of cell adhesive properties and cell morphology may underlie the functions of ErbBs in gastrulation. These results reveal for the first time that vertebrate ErbB signaling modulates gastrulation movements, thus providing a novel pathway, in addition to noncanonical Wnt and FGF signals, that controls gastrulation. To further elucidate mechanisms of ErbB signaling in Xenopus gastrulation, I next examined downstream ii signals employed by ErbBs during this process. From rescue experiments, PI3K and Erk MAPK were shown to mediate ErbB signaling to regulate gastrulation morphogenesis. Both PI3K and MAPK function sequentially in mesoderm specification and movements, and ErbB signaling is important only for the late phase activation of these pathways. While activation of either pathway rescues gastrulation defects induced by translational inhibitory ErbB4 morpholino oligonucleotides, the two signals preferentially regulate different aspects of cell behaviors. PI3K is more efficient in rescuing cell adhesion and cell spreading while MAPK is more effective in stimulating the formation of filopodia. The data reveal that PI3K and Erk MAPK, which previously considered as mesodermal inducing signals, also act downstream of ErbB signaling to regulate gastrulation morphogenesis. iii