BBS Faculty Member - Christopher Walsh

Christopher Walsh

Investigator, Howard Hughes Medical Institute
Chief, Division of Genetics, Children's Hospital Boston
Bullard Professor of Neurology and Pediatrics

CLS, Room 15064
300 Longwood Ave.
Boston, MA 02115
Tel: 617-919-2923
Fax: 617-919-2010
Email: christopher.walsh@childrens.harvard.edu
Lab Members: 11 postdoctoral fellows, 8 graduate students
Visit my lab page here.



Our lab is interested in fundamental mechanisms governing development of the human cerebral cortex. The cortex is the largest structure in the brain, essential for the intellectual functions that we humans pride ourselves on. The cerebral cortex has to solve several problems during development: it must be correctly patterned, it must obtain the proper complement of cells of distinct types, and finally all those cells have to get wired up just right in order to work properly. 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 the cortex; instead, they are derived from dividing cells located in specialized proliferative regions far away from the cortex. The dividing “progenitor” cells form postmitotic cortical neurons in a fixed sequence.

2] Postmitotic cortical cells migrate long distances away from the proliferating cells into the cortex before differentiating. Therefore, steps of mitotic and postmitotic neuronal development occur in different places.

3] A surprisingly large number of mutations, affecting humans or mice, disrupt specific steps in cortical development. These mutations affect the size and shape of the cerebral cortex, and often result in the 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 mental retardation, seizures, autism, and/or problems with coordinated movement and language.

We have used positional cloning to identify several genes required for the normal development of the cerebral cortex in humans and mice. An unexpected finding is that many of the genes that are essential for human cortical development were targets of evolutionary selection in the primate lineage leading to humans, suggesting that changes in some of these genes help define our brain as uniquely human. Recent work has mapped and cloned other loci that result in a malformed cortex or that produce subtler defects in language or social interactions (e.g., autism). Using genomic approaches we are also hunting for genes that pattern the cortex or that distinguish our “left” and “right” brain, which have different roles in language and perception. We are also using molecular biological and biochemical means to analyze the functions of the cloned proteins, in order to trace signal transduction cascades from the cell surface to the cytoskeleton.



Last Update: 8/22/2013



Publications

For a complete listing of publications click here.

 


 

Walsh CA, Engle EC. Allelic diversity in human developmental neurogenetics: insights into biology and disease. Neuron. 2010 Oct 21; 68(2):245-53. PMID: PMC3010396

Lehtinen MK, Zappaterra MW, Chen X, Yang YJ, Hill AD, Lun M, Maynard T, Gonzalez D, Kim S, Ye P, D’Ercole AJ, Wong ET, Lamantia AS, Walsh CA. The cerebrospinal fluid provides a proliferative niche for neural progenitor cells. Neuron. 2011 Mar 10;69(5):893-905.

Yu TW, Mochida GH, Tischfield DJ, Sgaier SK, Flores-Sarnat L, Sergi CM, Topcu M, McDonald MT, Barry BJ, Felie JM, Sunu C, Dobyns WB, Folkerth RD, Barkovich AJ, Walsh CA. Mutations in WDR62, encoding a centrosome-associated protein, cause microcephaly with simplified gyri and abnormal cortical architecture. Nature Genetics 2010 Nov;42 (11):1015-20. PMID: PMC2969850



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