Research Interests

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 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.

To unify these interests, we have combined our mapping studies with an ENU mutagenesis project. Specifically, we are using a screen for recessive ENU-induced mutations of late embryonic development to identify models of human malformation syndromes that affect organogenesis. An attractive aspect of this is that this technology can be applied to a wide variety of systems, and therefore has virtually unlimited potential. In our previous studies we have identified mutations affecting the development of the neural tube and brain, the heart, the liver, the skeletal system, the craniofacial system, and the kidneys. Most recently, we are using a variety of techniques, such as analysis of reporter genes, to focus on brain cortical development. As part of this project, we have pioneered methods of SNP analysis that allow us to rapidly map new mutations using small numbers of affected progeny. With the rapid progress in the sequence analysis of mammalian genomes, which will facilitate the molecular characterization of these novel mutants, we anticipate that this will be a valuable resource for understanding organ development.

Our positional cloning studies thus far have identified novel genes with important and fundamental roles in development. For example, the Nek8 serine-threonine kinase, which we originally discovered as a causal gene in a mouse model of PKD, is a cilial-localized protein that is required for the specification of left-right asymmetry. A different gene, Thm1, which we discovered as causing limb and neural patterning defects in an ENU-induced mutant line, is also a cilial-localized gene, and is required for mediating Hedgehog signaling. The functional characterization of the proteins identified as causing mutations remains one of the most challenging, but ultimately rewarding, aspects of my research program.