Projects in the lab concern the neurogenesis, migration, differentiation, axon guidance, and molecular properties of cortical neurons. The following are some major themes.

1. How do the layer–specific properties of cortical projection neurons develop?

Previous studies have shown that, with few exceptions, cells in deeper layers of cortex (the subplate and layer 6 are the deepest) are "born" earlier in embryonic development than are cells in superficial layers (layer 1 is most superficial). The "birthdate" of a neuron is defined as the day in development when the cell undergoes its last mitotic division, and makes the shift from proliferating progenitor to postmitotic neuron. In general, the cells in each layer share similar properties such as their connections and molecular expression. Thus, layer-specific properties are highly correlated with cell birthdate in the cortex. This correlation, and other evidence have led to the hypothesis that laminar fate is specified by birthdate.

Is birthdate the only factor that specifies laminar fate, or are other mechanisms at work? The answers to this question are important, because disorders of cortical development may involve errors of laminar fate specification. Moreover, if we can learn to control aspects of laminar fate specification in neurons—for example, specification of axonal projection targets—we might be able to direct the regeneration of the nervous system, perhaps using engineered stem cells. We are addressing this question by studying mice with mutations that disturb laminar fate specification.

2. How does the cerebral cortex establish connections with other brain regions—especially the thalamus and the spinal cord?

One of the major challenges in neuroscience today is to understand how the wiring diagram of the brain develops. For example, as shown in the illustration, how do axons (pink) from the cortex (ctx) "know" to grow into the internal capsule (ic), and from there into the dorsal thalamus (dt)? The initial steps in this process appear to be driven by a genetic program, which sets up the overall organization of connections. In later steps, the connections are further refined by experience– or activity–dependent mechanisms.

We are researching the early (embryonic) steps in cortical axon guidance, using a combination of in vitro studies (explant co–culture of cortex and thalamus) and gene expression analysis by microarray hybridization. We have previously found that mice with certain genetic mutations lack connections between the cortex and the thalamus, or between the cortex and the spinal cord. By studying what goes wrong in these mice, we hope to identify the molecules and understand the mechanisms that integrate the cortical circuitry with that of other processing centers.