Christopher A. Walsh, M.D., Ph.D.

Bullard Professor of Neurology

Beth Israel Deaconess Med Ctr.
Neurology, NRB-266
77 Avenue Louis Pasteur
Boston, MA 02115
Telephone: 617-667-0813
Fax: 617- 667-0815
Email: cwalsh@bidmc.harvard.edu
Webpage: http://www.walshlab.org

We are interested in fundamental mechanisms governing development of the cerebral cortex. The cortex is the largest structure in the brain, essential for the intellectual functions that we humans pride ourselves on. Whereas the cortex is complex, it provides several advantages as a genetic system for studying neuronal development:

1. Neurons of the cortex are not formed in situ; instead, they are derived from dividing progenitor cells restricted to proliferative regions outside the cortex. The progenitor cells form post-mitotic cortical neurons in a fixed sequence.
2. Post mitotic cortical cells migrate long distances away from the proliferating cells into the cortex before differentiating. Therefore, steps of mitotic and post mitotic neuronal development occur in different places.
3. A variety of mutations, affecting humans or mice, disrupt specific steps in cortical development. These mutations often result in accumulation of cortical cells in abnormal locations, reflecting the site of action and the function of the gene involved. In humans, these genetic disorders result in retardation and seizures.

We have recently identified several genes that are required for neuronal migration into the cortex of mice and humans, or for the formation of the normal complement of cerebral cortical neurons. Ongoing work seeks to understand the functional roles of these genes products by identifying interacting proteins and tracing signal transduction pathways from cell surface to cytoskeleton. We are also studying other human genetic syndromes in order to identify additional genes required for cortical development.

References:

• Gleeson JG, Lin PT, Flanagan LA & Walsh CA.(1999) Doublecortin is a microtubule-associated protein and is expressed widely by migrating neurons.Neuron:23:257-271.
• Feng YG, Olson EC, Flanagan L, Stukenberg T, Kirschner MC, & Walsh CA. (2000)Lis1 binding to mNudE, a central component of the centrosome, regulates neuronal migration. Neuron; 28:665-679.
• Hong SE, Shugart YY, Huang DT, Al Shahwan S, Grant PE, Hourihan JOB, Martin NDT & Walsh CA. (2000) Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations. Nature Genetic; 26:93-96
• Monuki ES, Porter FD & Walsh CA. (2001) Patterning of the dorsal telencephalon and cerebral cortex by a roof plate-Lhx2 pathway. Neuron 32:591-604.
• Chenn A & Walsh CA. (2002) Regulation of cerebral cortical size by control of cell cycle exit in neural precursors.Science; 297:365-369.