Lissencephaly
Professor Jin-Wu Tsai of the Institute of Brain Science at Yang Ming Chiao Tung University (NYCU), in collaboration with Dr. Meng-Han Tsai, Director of the Epilepsy and Neurology Division at Kaohsiung Chang Gung Memorial Hospital, and Associate Professor Wan-Ching Wang from the Institute of Biochemistry at NYCU. This international research team successfully used next-generation genomic analysis to identify a new gene, CEP85L, which is associated with lissencephaly. The team confirmed and translated the findings through a mouse model that loss of CEP85L function and causes defects in neuronal migration and centrosomal functions. CEP85L is the first centrosomal gene identified to be associated with lissencephaly. This significant research finding was published in April 2020 in the prestigious journal 《Neuron》.
Lissencephaly (LIS), denoting a "smooth brain", is characterized by the absence of normal cerebral convolutions with abnormalities of cortical thickness. Pathogenic variants in over 20 genes are associated with LIS. The majority of posterior predominant LIS is caused by pathogenic variants in LIS1 (also known as PAFAH1B1), although a significant fraction remains without a known genetic etiology. We now implicate CEP85L as an important cause of posterior predominant LIS, identifying 13 individuals with rare, heterozygous CEP85L variants, including 2 families with autosomal dominant inheritance. We show that CEP85L is a centrosome protein localizing to the pericentriolar material, and knockdown of Cep85l causes a neuronal migration defect in mice. LIS1 also localizes to the centrosome, suggesting that this organelle is key to the mechanism of posterior predominant LIS.
「Multiple Roles of the Lissencephaly Gene LIS1 in Embryonic Neurogenesis」
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.
※Related references：
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Tsai MH, Muir AM, Wang WJ, Kang YN, Yang KC, Chao NH, Wu MF, Chang YC, Porter BE, Jansen LA, Sebire G, Deconinck N, Fan WL, Su SC, Chung WH, Almanza Fuerte EP, Mehaffey MG, University of Washington Center for Mendelian Genomics, Ng CC, Chan CK, Lim KS, Leventer RJ, Lockhart PJ, Riney K, Damiano JA, Hildebrand MS, Mirzaa GM, Dobyns WB, Berkovic SF, Scheffer IE, Tsai JW*, Mefford HC* (2020) Pathogenic variants in CEP85L cause sporadic and familial posterior predominant lissencephaly. Neuron, 106(2):237-245.
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Jin-Wu Tsai, Yu Chen, Arnold R. Kriegstein, and Richard B. Vallee. LIS1 RNAi Blocks Neural Stem Cell Division, Morphogenesis, and Motility at Multiple Stages. The Journal of Cell Biology. 2005 Sep 12; 170(6), 935-945.
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Richard B. Vallee and Jin-Wu Tsai. The Cellular Roles of the Lissencephaly Gene LIS1, and What They Tell Us About Brain Development. Genes & Development 20, 1384-1393 (2006).
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Mary E. Hatten. LIS-less neurons don't even make it to the starting gate. The Journal of Cell Biology. 2005 Sep 12;170(6), 867-871.
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Pierre Gressens. Pathogenesis of migration disorders. Current Opinion in Neurology 2006 Apr;19(2), 135-40.
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Tsai MH, Cheng HY, Nian FS, Liu C, Chao NH, Chiang KL, Chen SF, Tsai JW* (2020) Impairment in Dynein-Mediated Nuclear Translocation by BICD2 C-terminal Truncation Leads to Neuronal Migration Defect and Human Brain Malformation. Acta Neuropathol Commun, 8(1):106.
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Tsai MH, Kuo PW, Myers CT, Li SW, Lin WJ, Fu TY, Chang HY, Mefford HC, Chang YC*, Tsai JW* (2016). A novel DCX missense mutation in a family with X-linked lissencephaly and subcortical band heterotopia syndrome inherited from a low-level somatic mosaic mother: Genetic and functional studies. Eur J Paediatr Neurol, 20, 788-94.
Comments from researchers：
"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, 美國洛克斐勒大學 (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; 法國巴黎大學 (Paris 7 University); Robert Debre Hospital
"Recommended...with unusually high enthusiasm." -Don W. Cleveland 教授, 美國加州大學聖地牙哥分校 (UCSD); 細胞生物學期刊主編
"A beautiful paper." -Li-Hui Tsai 教授, 美國哈佛大學 (Harvard Univ.)
"Well done." -M. Elizabeth Ross 教授, 美國康乃爾大學 (Cornell Univ.)
"Very interesting work." -Orly Reiner 教授, 以色列魏茲曼科學研究院 (Weizmann Institute of Science)"Terrific!" -John D. Koester 教授, 美國哥倫比亞大學 (Columbia Univ.)
"Wonderful works!" -林奇宏教授, 國立陽明大學
"Very nice!" -Kevin T. Vaughan 副教授, 美國聖母院大學 (Univ. of Notre Dame)
"Fantastic--the work is so well done and thought of." -Manjari Mazumdar 博士, 美國國家衛生研究院 (National Institute of Health)