Project II: Studying human structural brain defects using mouse models
Structural Brain Defects (SBDs) constitute an immense health problem. Approximately 4-6% of the human population is affected by developmental disorders that affect the structure of the nervous system. A large number of SBD cases are of genetic origin.
Despite major advances in human genetics and genome research, the majority of genes that are linked to SBDs still need to be identified. There is also a pressing need for animal models to study gene function in the developing brain, to define the molecular pathogenesis of SBDs, and to develop therapeutic approaches for their treatment.
Significantly, the brain of humans and mice share many anatomical and molecular features, suggesting that the genetic program controlling CNS development is in large part conserved between the two species. The mouse is also a leading research tool for genetic studies. We therefore hypothesize that we will generate by forward and reverse genetics in mice valuable animal models for studying the genetic program that controls brain development and for defining the molecular pathogenesis of inherited forms of SBDs in humans.
This hypothesis is supported by our preliminary data, which show that we can generate mouse models for SBDs by forward and reverse genetics. Based on these findings, we therefore propose two specific aims:
In Aim 1, we will capitalize on our expertise in forward genetics in mice using ENU as a mutagen, to generate mouse lines afflicted with inherited forms of SBDs, to positionally clone the affected genes, and to study gene function. The other participants of the program project grants will test the extent to which the genes that we identify are associated with SBDs in humans and zebrafish.
In Aim 2, we will use reverse genetics approaches to generate mouse lines carrying mutations associated with SBDs in humans or zebrafish that have been identified by the other participants of this program project proposal. We anticipate that we will identify a wide range of mutations that cause SBDs and generate important mouse models to study disease mechanisms.