最先端研究セミナー

Abstract:

The cerebral cortex is the largest part of the human brain, associated with higher brain functions. Our research has aimed to understand molecular mechanisms underlying development and evolution of the mammalian cerebral cortex. We have focused on two important developmental processes, neuronal wiring (6, 8) and cortical folding (1-5, 7). In this talk, I will mainly present our recent work on cortical folding. Folds in the cerebral cortex in mammals are believed to be key structures for accommodating increased cortical neurons in the cranial cavity. However, the mechanisms underlying cortical folding remain largely unknown, mainly because genetic manipulations for the gyrencephalic brain had been unavailable. By combining in utero electroporation and the CRISPR/Cas9 system, here we succeeded in efficient gene knockout of Cdk5, whose mutation was found in patients with classical lissencephaly, in the gyrencephalic brains of ferrets. We uncovered that Cdk5 knockout in the ferret cerebral cortex markedly impaired cortical folding. Furthermore, the results obtained from the introduction of dominant-negative Cdk5 into specific cortical layers suggest that Cdk5 function in upper-layer neurons is more important for cortical folding than that in lower-layer neurons. Cdk5 inhibition induced severe migration defects in cortical neurons. Taken together, our findings suggest that the appropriate positioning of upper-layer neurons is critical for cortical folding.

References:

1. Matsumoto N., Shinmyo Y., Ichikawa Y. and Kawasaki H., Gyrification of the cerebral cortex requires FGF signaling in the mammalian brain. eLife, in press.
2. Shinmyo Y., Terashita Y., Dinh Duong T. A., Horiike T., Kawasumi M., Hosomichi K., Tajima A. and Kawasaki H. Folding of the cerebral cortex requires Cdk5 in upper-layer neurons in gyrencephalic mammals. Cell Reports, 20(9), 2131-2143, 2017.
3. Shinmyo Y. and Kawasaki H. CRISPR/Cas9-mediated gene knockout in the mouse brain using in utero Current Protocols in Neuroscience, 79, 3.32.1-3.32.11, 2017.
4. Toda T., Shinmyo Y., Dinh Duong T. A., Masuda K., and Kawasaki H. An essential role of SVZ progenitors in cortical folding in gyrencephalic mammals. Scientific Reports, 6, 29578, 2016.
5. Shinmyo Y., Tanaka S., Tsunoda S., Hosomichi K., Tajima A. and Kawasaki H. CRISPR/Cas9-mediated gene knockout in the mouse brain using in utero Scientific Reports, 6, 20611, 2016.
6. Shinmyo Y., Riyadh M. A., Ahmed G., Naser I. B., Hossain M., Takebayashi H., Kawasaki H., Ohta K. and Tanaka H. Draxin from neocortical neurons controls the guidance of thalamocortical projections into the neocortex. Nature Communications, 6, 10232, 2015.
7. ^#Masuda K., ^#Toda T., ^#Shinmyo Y., Ebisu H., Hoshiba Y., Wakimoto M., Ichikawa Y. and Kawasaki H. Pathophysiological analyses of cortical malformation using gyrencephalic mammals. Scientific Reports, 5, 15370, 2015. ^#: These authors contributed equally to this work.
8. ^#Islam S. M., ^#Shinmyo Y., Okafuji T., Su Y., Naser I. B., Ahmed G., Zhang S., Chen S., Ohta K., Kiyonari H., Abe T., Tanaka S., Nishinakamura R., Terashima T., Kitamura T. and Tanaka H. Draxin, a repulsive guidance protein for spinal cord and forebrain commissures. Science, 323, 388-393, 2009. ^#: These authors contributed equally to this work.

担当分野：脳発生分野　嶋村（内線：6585)

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