| dc.description.abstract | Preplacodal ectoderm (PPE) is a contigous horse-shoe shaped domain that enwraps the anterior neural plate towards the end of gastrulation and eventally resolves into a number of focal epithelial thickenings called placodes. These placodes together with Neural Crest (NC), contributes to the peripheral nervous system in vertebrates. PPE and NC arise at the neural-non neural interface by distinct mechanisms during development. However, a general idea in the field was that a Bmp signaling gradient specifies different ectodermal fates: high Bmp levels specify epidermis, intermediate levels PPE and NC and no Bmp signaling is required for neural fate specification. We showed that while NC responds to intermediate levels of Bmp signals, PPE is specified by a distinct mechanism that involves a two step model for PPE specification. In the first step, Bmp is positively required to activate four competence factors, tfap2a, tfap2c, foxi1 and gata3 throughout the ventral ectoderm and renders this domain competent to respond to inductive factors. In the second step, inductive factors Fgf and Bmp antagonists act to completely block all Bmp signaling to specify PPE at neural-non neural interface. These Bmp-activated competence factors do not need Bmp for subsequent maintenance because they positively cross-regulate and autoregulate each other’s expression forming a gene regulatory network. This network is sufficient to rescue both PPE and NC in the complete absence of Bmp.
The subsequent resolution of PPE into discerte placodal thickenings was hypothesized to involve localized migration of placodal progenitors and one of the molecules that could play an important role during cell migration was extracellular matrix binding molecule, integrin alpha 5 (itga5) because it was expressed at the right time and place. Knockdown of itga5 results in disorganised trigeminal, epibranchial ganglia and smaller otic placodes. Tracing the cell trajectories of placodal progenitors revealed that cells failed to migrate directionally. Additionally, we observed elevated levels of cell death in itga5 morphants which could be rescued by overexpression of Fgf ligands suggesting that Itga5 and Fgf pathways cooperate during placodal development. All together, this dissertation reveals novel genetic mechanisms that regulate placodal development from late-blastula to mid-somitogenesis stages. | en |
