During development, progenitor cells produce a large diversity of young neurons that migrate away from their site of origin and establish distinct identities, including the formation of specific connections. The major aim of this research is to understand the cellular and molecular processes by which young neurons in the mammalian visual cortex achieve their adult identities during development, migrate to appropriate positions, and form axonal connections with appropriate target cells.
Aim 1 : What genes are expressed by newly generated neurons destined for different cortical layers? We hypothesize that newly generated neurons show distinct patterns of gene expression that confer distinct fates and laminar choices. We will isolate newly generated neurons that are destined to adopt different laminar fates and identify genes expressed differentially in these cells using microarray technology.
Aim 2 : What are the molecular mechanisms that determine laminar fates? A number of transcription factors show layer-specific patterns of expression in the cortex and are thus candidates for controlling cell fate identity. Using highly efficient """"""""targeted gene trapping"""""""" methods, we are generating mouse lines in which the expression of layer-specific transcription factors is disrupted. We will examine layer formation and the production of layer-specific patterns of axonal connectivity in these mutants.
Aim 3 : How does Otx1 regulate the refinement of layer 5 projections from visual cortex? A key step in the development of visual projections is the elimination of transient axonal connections to inappropriate targets. The homeodomain protein Otxl is required for the refinement of """"""""exuberant"""""""" projections from visual cortex into the spinal cord. Despite the importance of axon pruning to the production of specific connectivity in the brain, virtually nothing is known about its underlying mechanisms. We propose to use Otxl mutant mice to explore the cellular and molecular basis of axon pruning by visual cortical neurons.
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