|M.Sc Student||Elkouby Yaniv|
|Subject||Canonical Wnt Signaling Acts through XMeis3 Protein to|
Specify Posterior Cell Fates in the Developing
CNS of X.laevis Embryos
|Department||Department of Medicine||Supervisor||Professor Dale Frank|
|Full Thesis text|
In the vertebrate, Xenopus laevis (frog), the embryonic nervous system is induced early in development by a two-step process. Initially, during gastrulation, antagonism of BMP4 signaling in the ectoderm provides the first activation step of induction. In this step, anterior neural tissue is induced. During the second transformation step, this anterior neural tissue is patterned to more posterior neural fates. Wnt signaling molecule, is well established as a "posteriorizer" that transform anterior neural tissue (forebrain) to more posterior neural fates (midbrain, hindbrain, spinal cord). Two additional cell types are also induced in the posterior nervous system, primary neurons and neural crest. Wnt is also required for these cell type inductions. XMeis3, a member of the Meis family of proteins acts as a posteriorizer during nervous system development. In the developing embryo, XMeis3 activity is also required for the induction of posterior neural tissues, such as hindbrain, primary neurons and neural crest.
XMeis3 and canonical Wnt signaling are necessary and sufficient for the proper inductions of hindbrain, primary neurons and neural crest tissue in the embryo. The loss-of-function and gain-of-function phenotypes, of XMeis3 and canonical Wnt signaling are strikingly similar. The expression of the Wnt3a ligand, which activates canonical Wnt signaling in the nervous system regionally and temporally overlaps with XMeis3 expression. These important similarities have prompted us to ask whether canonical Wnt signaling and XMeis3 protein act through one another in the specification of posterior neural cell fates.
In this study, we show that canonical Wnt signaling is required and sufficient for the activation of XMeis3 expression in embryos. Moreover, we show that XMeis3, HoxD1 and Gbx2 are all direct target genes of canonical Wnt signaling. By over expressing XMeis3 in embryos on the background of canonical Wnt signaling inhibition, we demonstrate that XMeis3 activity can rescue the inductions of hindbrain, primary neuron and neural crest cells when canonical Wnt activity is inhibited. Thus, XMeis3 acts functionally downstream of canonical Wnt signaling to regulate cell fate specification in the developing nervous system.
In preliminary studies, we further show that XMeis3 strongly induces Wnt3a expression in explants. We hypothesize that this potential "Wnt - XMeis3 - Wnt" mode of action may have implications in several crucial developmental processes. These include the long distance propagation of canonical Wnt signaling, the early sequential activities leading to posterior cell fate inductions, interactions between the different posteriorizers, and the further segmentation of the hindbrain to its rhombomeres