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Lissencephaly (Smooth Brain): A Neural Developmental Disorder

"Multiple Roles of the Lissencephaly Gene LIS1 in Embryonic Neurogenesis"

Today, to understand the mechanisms of how neuronal cells are born and how neural stem cells regenerate themselves in the nervous system during embryonic development is a key challenge in neural stem cell research. The pathway by which neuronal cells are born is itself proving to be complex. In human, as well as other mammals, cortical neurons are generated by the neural stem cells lying in the innermost zone of the cerebrum. During proliferation, these neural stem cells exhibit a characteristic yet mysterious pattern of nuclear oscillation within this zone (a). The neuronal cells, consequently, undergo a series of morphological changes (b) and migrate to the outer layer of the cerebrum (c) where most of the neuronal cells reside throughout life and form the highly organized cerebral cortex (d). The complex transformation in morphology and motility involves at least hundreds of genes and dramatic changes in structural organization within the cells at different stages. To date, only a few genes are identified to control and regulate the progression of this neurogenesis pathway. The requirement for this complex morphological changes and how it is controlled by these genes also remains largely unexamined.

My work has emerged from my interest in the human LIS1 gene, mutations in which result in a relatively common (~1 in 100,000 live births) severe congenital cortical disorder, lissencephaly (smooth brain disease), to study neural stem cells under normal and disease conditions through the entire neurogenesis pathway. We are testing the effects of down-regulating this gene on neural stem cell division and neuronal migration. Our results have demonstrated numerous exciting and important effects at each step along the entire neurogenesis pathway. We observed, along with many other novel findings, a complete block in nuclear oscillations within neural stem cells (a'). Surprisingly, the cell division is also abolished, suggesting the nuclear oscillation is necessary for neural stem cell division. This effect sheds important new light on the very long-standing issue of the relationship between nuclear position and cell cycle, and strongly argues that some spatial cues may control neural stem cell division.

Briefly, our observations identified the lissencephaly gene LIS1 as one of the first genes potentially involved in neural stem cell division, morphogenesis (b'), fate determination, and neuronal migration (c'), a phenomenon of considerable interest in understanding normal brain development, and how to control the proliferation and repopulation of the brain by neural stem cells. We are currently searching for other potential genes that involve in embryonic neurogenesis and investigating their functions in this pathway. By understanding the mechanisms of neurogenesis pathway, we may, ultimately, be able to control the proliferation and production of neural stem cells in both embryonic and adult nervous system and apply this knowledge to their possible therapeutic use.

The Journal of Cell Biology features our research on the lissencephaly gene LIS1

Neural stem cells go through a complex process of morphogenesis and migration to produce neurons

Further readings:


Comments from scholars in this field:

"The manuscript by Tsai et al. is a tour de force analysis of a controversial issue in developmental neurobiology... the authors use a variety of elegant approaches... to demonstrate that LIS1 and dynactin act as regulators of dynein during cortical histogenesis." -Prof. Mary E. Hatten, Rockefeller Univ.

"This remarkable original paper combines multiple approaches to demonstrate that Lis1 not only controls neuronal motility but also neuronal precursor cell cycle in the cortical germinative zone, potentially linking cell division with cell migration." -Dr. Pierre Gressens, Inserm; Paris 7 University; Robert Debre Hospital, Paris

"Recommended...with unusually high enthusiasm." -Prof. Don W. Cleveland, Univ. of California, San Diego; Editor, The Journal of Cell Biology

"A beautiful paper." -Prof. Li-Hui Tsai, Harvard Univ.

"Well done." -Prof. M. Elizabeth Ross, Weill Medical College of Cornell Univ.

"Very interesting work." -Prof. Orly Reiner, Weizmann Inst. of Science, Israel

"Terrific!" -Prof. John D. Koester, Columbia Univ.

"Wonderful works!" -Prof. Chi-Hung Lin, Natl. Yang-Ming Univ., Taiwan

"Very nice!" -Assoc. Prof. Kevin T. Vaughan, Univ. of Notre Dame

"Fantastic--the work is so well done and thought of." -Dr. Manjari Mazumdar, Research Fellow, National Institute of Health

Last updated 6/13/2013. Copyright© 2005 Jin-Wu Tsai. All rights reserved.