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Masahiko HIBI, M. D., Ph. D. 
During
early vertebrate development, the embryonic dorso-ventral (DV) and anterior-posterior
(AP) axes are established through a series of inductive signals that prefigure
and determine the concerted movements and differentiation of a group of
cells. The dorsal organizer plays a major role in the process of axis
formation. In amphibian and teleost fish embryogenesis, the program for
dorsal organizer formation begins soon after fertilization. In these species,
dorsal determinants are believed to be initially localized to the vegetal
pole and later transported to the dorsal side of the embryo.
Although
the molecular nature of the dorsal determinants has not been elucidated,
they are known to activate the canonical Wnt pathway and thereby lead
to the expression of genes involved in the induction of the dorsal organizer.
The dorsal organizer generates secreted signaling molecules that participate
in the generation of the DV axis in the mesoderm and endoderm, and the
formation of the neuroectoderm. We are working to identify the molecules
that are involved in the formation and function of the dorsal organizer.
This search led us to identify the protein Secreted Frizzled (Sizzled)/Ogon
as a negative feedback regulator of BMP signaling that cooperates with
the dorsal organizer protein Chordin to regulate DV axis formation. We
also remain actively interested in determining the molecular identities
of dorsal determinants.
Neural
patterning and neurogenesis as a model of cell fate determination, a process
that is linked to axis formation, is also a question of interest to our
team. Neuronal tissues are generated in a stepwise manner in vertebrates.
These steps include neural induction, AP patterning and neurogenesis.
In amphibian and teleost embryos, neuroectoderm is initially induced by
BMP inhibitors (such as Chordin), which are generated by the dorsal organizer.
The induced neuroectoderm is characteristically anterior in character
and is only subsequently subjected to posteriorization, which involves
signaling by posteriorizing factors emanating from the non-axial mesendoderm.
After neural induction and patterning, the proneuronal domains, in which
neurogenesis takes place, are established. Within the proneuronal domains,
a subset of cells is selected to become primary neurons by a Notch-mediated
lateral inhibition mechanism. We have recently found that the homeobox
gene pnx is regulated by the posteriorizing non-axial mesendoderm and
Notch signaling, and that Pnx is involved in the development
of posterior neurons. We are trying to determine the mechanism by which
the formation of primary neurons is spatially regulated.
