JCB COMMENT LIS-less neurons don’t even make it to the starting gate.pdf

T H E J O U R N A L O F C E L L B IO L O G Y JCB: COMMENT ? The Rockefeller University Press $8.00 The Journal of Cell Biology, Vol. 170, No. 6, September 12, 2005 867–871 /cgi/doi/10.1083/jcb.200506140 JCB 867 LIS-less neurons don’t even make it to the starting gate Mary E. Hatten Laboratory of Developmental Neurobiology, The Rockefeller University, New York, NY 10021 The manuscript by Tsai et al. (935–945) is a tour de force analysis of a controversial issue in developmental neurobiology, namely the molecular basis of the devastat- ing human brain malformation, type I lissencephaly ( Lis1 ) (Jellinger, K., and A. Rett. 1976. Neuropadiatrie . 7:66– 91). For several decades, defects in neuronal migration have been assumed to underlie all defects in cortical histo- genesis. In the paper by Tsai et al., the authors use a vari- ety of elegant approaches, including the first real-time im- aging of cortical neurons with reduced levels of LIS1, to demonstrate that LIS1 and dynactin act as regulators of dynein during cortical histogenesis. A loss of LIS1 results in both a failure to exit the cortical germinal zone and abnormal neuronal process formation. Thus, the primary action of the mutation is to disrupt the production of neu- rons in the developing brain as well as their migration. Lissencephaly (from the Greek “lissos” for smooth and “enke- falos” for brain) is a developmental malformation characterized by the absence of convolutions (Fig. 1). The classic study of Bielschowsky (1923) defined the architectonic features of ab- normal cerebral cortex in type 1 lissencephaly (Lis1). At birth, although children with LIS1 mutations have “normal” head size, a surrogate for brain weight, the values almost always fall below the 50th percentile. The cerebral cortex of these children contains four layers, rather than the usual six. Layer I, the su- perficial layer, corresponds to the molecular or plexiform layer of normal brain. Layer II is a thin la