What we do
Developmental disorders
Much of our work starts from genetic analyses. Mutations that causes structural brain defects or more subtle abnormalities that alter behavior have led us into several signaling and transcriptional pathways. These include the nuclear receptor Rora, the 30 zinc finger protein Zfp423, and the single zinc finger protein Zfp804a. Each of these genes has mutations associated with human illness. Our work primarily focuses on understanding the biology, which may provide a framework for broader approaches to rare disorders. Our Zfp423 work in particular has led us to investigate ciliopathy disorders that act in a range of tissues.
Brain Disorders
We have a long interest in brain development, especially in the cerebellum. Some aspects of human developmental disorders can be modeled effectively in experimental systems, including mice. Humans with mutations in ZNF423 (JBTS19) have structural abnormalities homologous to Zfp423 mice. We use mice and cell models to understand mechanisms affected by patient mutations and their relative severity. We are also pursuing additional genetic loci that modify the survival or anatomical consequences of Zfp423 mutations.
Modifier genes
Anything interesting in biology is likely to be complex. Even disorders caused by a single gene often appear differently in different people–or flies, or fish, or mice. We use a variety of approaches to identify modifier genes–variations that change the outcome of a "disease" mutation. This has led in some unexpected directions, inlcudiong the discovery that a single amino acid substitution in the mRNA nuclear export factor Nxf1 modifies a whole class of mutations cause by retrovirus insertions in introns of other genes and that the severity of outcomes in Zfp423 mice is a complex trait.
Opportunities
The most exciting thing in science is not "Eureka," but rather, "that's funny." (1) Some projects arise from things we just don't understand and are better positioned to pursue than other labs. We found a novel gene (Nmf9) with an unusual evolutionary history and strong conservation of non-motif sequences. Parallel mutations in mice, fish, and flies show its requirement in balance, locomotion, and other neurological functions, but with different degrees of essentiality in different animals. (1) attributed to Isaac Asimov
Join Us
Scientists interested in postdoctoral or student positions are encouraged to contact the Principal Investigator: Bruce A. Hamilton, Ph.D.