This proposal addresses the regulation of tangential migration during development of the mammalian forebrain. Many neurons that are born in the ganglionic eminences emigrate to the olfactory bulb, the cerebral cortex, the piriform cortex, the amygdala or the thalamus. The mechanisms that determine when, where and how these diverse migratory streams occur are not well understood. To gain insight into these events we have carried out a genetic screen in mice. The work proposed here is based on three mutants, Spotty-brain, Cross-walk and Polka-dot, that were identified in this screen. Although it is clear that at least some tangential migrations are defective in each of these mutants, it will be important to determine which migratory events are affected by each mutation. This will be pursued using several different approaches. We will label small groups of neurons and follow their migratory paths in tissue slices. This will reveal population-level defects in migration and allow us to determine which migratory streams are affected. At the same time, this approach will provide the opportunity to examine the effects of each mutation on the behavior of individual cells as they migrate. We will also determine which neurons are affected by each mutation, paying particular attention to cells that are known to migrate. The question of which neurons are affected will also be examined using a fate-mapping approach in which many or most cells arising in the ventral telencephalon will be labeled with stable expression of beta-galactosidase, GFP or alkaline phosphatase. Finally, we will determine the chromosomal location of each mutation. This will allow us to search for the molecular lesions that produce migratory defects. We anticipate that we will identify genes for at least one and potentially all three of the available mutants during the course of these studies. This proposal utilizes the R21 grant mechanism because the goal of the work, to develop a body of data upon which significant future research will be based, is in accord with the purpose of that mechanism. Determination of the extent and nature of migratory defects and the molecular basis for those defects will set the stage for pursuing a more detailed and hypothesis driven exploration of molecular mechanisms that regulate tangential migration.
| Zarbalis, Konstantinos; May, Scott R; Shen, Yiguo et al. (2004) A focused and efficient genetic screening strategy in the mouse: identification of mutations that disrupt cortical development. PLoS Biol 2:E219 |
