Congenital defects occur in up to
10% of all human pregnancies. A large
percentage of these defects involve
the cardiovascular system. In a broad
sense my lab is interested in defining
the molecular signals guiding the early
patterning of the vertebrate embryo
with emphasis on organogenesis and
cardiovascular development. Through
an understanding of normal development
we hope to better understand how congenital
defects may occur.
The early patterning of the vertebrate
embryo results from a complex milieu
of signals to guide growth,differentiation
and migration of cells to their proper
position and specification. Utilizing
modern genetic techniques, we are attempting
to dissect these signals through loss
and gain of function experiments. As
an example, utilizing the Cre/LoxP
and Flp/Frt recombination systems,
we have targeted the murine Fgf8 gene
locus to perform loss of function studies.
Using this approach we have determined
that Fgf8 is required not only during
gastrulation, limb outgrowth, and CNS
development but is also required as
a left-right axis determinant as well.
From its earliest stages, the cardiovascular
system is patterned in a left-right
asymmetric manner. Loss of Fgf8 function
can result in a phenotype similar to
the human "asplenia" syndrome
where left-sided structures are mispecified
as right. This results in characteristic
complex cardiovascular defects.
We are now primarily interested in
identifying other genes that establish
and pattern the cardiovascular system,
with particular attention paid to those
signals involved in left-right axis
determination. Screening strategies
to identify new candidate genes will
be performed. Studies to determine
downstream targets as well as modifiers
of Fgf8 signaling will also be pursued.
In addition we are generating Cre expressing
transgenic mouse lines to perform tissue
specific elimination of Fgf8 to better
define its role in various organ system
development. Similar strategies will
also be used to examine and target
other candidate genes to study early
patterning of the vertebrate embryo.
These studies will be performed by
pre and post doctoral candidates who
will be trained in state of the art
genetic manipulations to address these
questions in the developing mouse embryo.
