My research utilizes genetic analysis of the mouse, and especially of
murine mutations, as a means to study fundamental problems in mammalian
biology. This work has been manifest in two general and overlapping
categories: genetic mapping of cDNAs and the analysis of mapped genes as
a candidates for mutations; and characterization, mapping, and
positional cloning of novel murine mutations. We have also used genetic
analysis to characterize complex traits, such as loci affecting the
progression of polycystic kidney disease.br
More recently, my interests in developmental and genetic analysis have
converged in a highly productive ENU mutagenesis project in which we are
studying abnormalities of late embryonic development and organogenesis. Several
of the numerous mutant phenotypes we have discovered are models of congenital
syndromes, and their characterization has potential implications for
understanding human disease. For example, we have determined that a hypomorphic
defect in the transcription factor Fog2 results in congenital diaphragmatic
hernia, and we have recently discovered that children with this life-threatening
anomaly can carry mutations of this locus. Similarly, we have identified a gene
that causes cleft palate in a mouse model, and have collaborated with Dr. Jeff
Murray to show that children with this disorder carry sequence changes in the
same gene. This work has led to advances in fundamental knowledge as well; for
example, we have identified a novel gene required for GLI3 processing that
mediates normal Sonic hedgehog pathway signalling. We have recently initiated our
fourth mutagenesis screen, with a focus on neurodevelopment. This is being
queried by morphological analysis as well as the inclusion of sensitized
strains and mice carrying anatomical tract-specific reporters.
