刘 福清
基础神经研究团队
姓名 刘 福清
电子邮件 fuchin@ym.edu.tw
联络电话 +886-2-2826-7216
EDUCATION/TRAINING Ph.D., 1991, Massachusetts Institute of Technology
研究专长 Neural development and plasticity of the basal ganglia circuits in the mammalian forebrain
研究概况 My laboratory is devoted to study neural development and plasticity of the basal ganglia circuits in the mammalian forebrain. The striatum is the major input component of the basal ganglia circuits. What makes the striatum an attractive and important system for neurobiological study is its involvement in processing multiple dimensions of neurological function ranging from movement, cognition and reinforcement to plasticity of learning and memory. The importance of the striatum is also reflected in a number of neurological disorders including Parkinson's disease, Huntington's disease, schizophrenia and mood disorders whose pathogeneses involve either degeneration or malfunction of the striatal system. The study of development and function of the striatum is thus fundamentally important not only to the understanding of integrative brain function, but also to the development of therapeutic approach to neurological diseases.

The long-term goal of our research is to elucidate how the infrastructure of the basal ganglia circuits is built to function and adapted to neural plastic changes in the brain. Our strategic approach is to identify the genetic programs underlying neurogenesis, neuronal specification and differentiation in the basal ganglia during development. To this end, we have identified striatum-enriched transcription regulators (Nolz-1, RAR/RXR, Isl-1, Six3, Foxp2) and receptor tyrosine kinase signaling molecules (NRG/ErbB4) that may be involved in neural development and plasticity of the basal ganglia system. We are currently analyzing different lines of gene knockout mice by cellular and molecular biology techniques. Our recent work of the gene regulation of Foxp2 in the developing striatum has led us to studying the primitive circuits engaged in speech and language. We are also approaching the neurobiological basis of schizophrenia, a complex neurodevelopmental disorder, based on our study of NRG/ErbB4 signaling in GABAergic interneurons of the forebrain.

We believe by identifying and characterizing the striatum-enriched transcriptional regulators and associated signaling molecules, we may gain insights into the neural mechanisms by which the basal ganglia circuits are built to function and adapted to environmental challenge. Our work also may be of clincal relevance, as identification of growth factor-associated molecules may provide information for treating neurodegenerative diseases.



基底核实验室重要突破研究发现

大脑基因如何建构原始说话语言功能的神经回路

探讨解开Foxp2语言基因在大脑神经元分子、神经回路、行为控制的作用机制

语言沟通是人类社会互动的独特基本能力。目前对于人类大脑神经系统如何建构控制语言说话能力仍然不甚清楚。反观其他物种虽不具有复杂丰富说话语言能力，但仍有其它类似简单能力，例如小鼠有超音波发声能力，借以达成沟通目的。

国立阳明大学神经科学研究所刘福清教授研究团队以小鼠超音波发声沟通能力为行为模式，研究大脑神经系统如何建构原始语言说话能力。刘福清教授研究团队发现Foxp2语言基因能够开启Mef2c自闭症基因对于「大脑皮质—基底核神经回路」突触接点建立的抑制。这项研究除了深入了解基本原始说话语言神经回路的建立外，亦对自闭症语言能力缺陷的病理基础有所探讨。这篇研究论文发表于国际知名顶尖期刊「自然神经科学」(Nature Neuroscience)。

Foxp2基因控制神经元突触接点的建立

Foxp2基因在分子层次如何控制神经元突触接点的建立? 研究团队发现Foxp2基因抑制下光标的Mef2c基因，间接开启神经回路突触接点的建立。Mef2c突变基因己知是个自闭症基因。正常的Mef2c基因会抑制大脑皮质讯息传送至基底核神经元突触接点的发育形成。比喻来说，Mef2c基因正常作用就如同一道安全锁(Safety Lock)，在胚胎发育早期先行锁住神经突触接点形成，避免在发育早期尚无大脑皮质讯息输入下，神经突触接点不成熟提早建立，因而形成错误的神经回路。那么正常下何者是一支钥匙(Key)可以打开这道安全锁？研究团队发现Foxp2基因正是可以打开(Unlock) Mef2c基因这道安全锁的钥匙。Foxp2基因可以直接解开Mef2c基因对于神经接点的抑制，进而开启「大脑皮质—基底核神经回路」正确的神经突触接点发育形成。倘若Foxp2基因或Mef2c基因突变丧失其正常功能，Mef2c基因这道安全锁将会坏掉，导致异常错误的神经突触接点形成，因而建构出错误的神经回路。Mef2c基因突变所导致错误的「大脑皮质—基底核神经回路」有可能是自闭症说话语言功能缺失的病理机制。

Foxp2-Mef2c基因交互作用调控神经回路功能的重要性

本篇论文第一作者郭晓萦博士说，研究团队接下来探讨的问题是，「大脑皮质—基底核神经回路」的正常功能为何? 郭晓萦博士解释研究团队进一步的研究发现，Foxp2-Mef2c基因交互作用所控制的「大脑皮质—基底核神经回路」突触接点建立，对于调控初生小鼠超音波发声沟通行为(Ultrasonic vocal communication) 扮演着关键重要角色。当Foxp2基因或Mef2c基因突变丧失功能，会导致「大脑皮质—基底核神经回路」突触接点无法正确建立，进而导致初生小鼠超音波发声沟通行为异常。

基因分子－神经回路－行为控制的整合性神经科学研究

刘福清教授实验室这项与德国、日本、美国、中研院研究团队合作的研究结果：Foxp2与Mef2c两个基因的交互作用调控「大脑皮质－基底核神经回路」的建立与初生小鼠超音波发声沟通能力，在基础科学与神经疾病研究有重要引申意义：

基础科学研究方面

Foxp2已知是个与人类语言说话能力相关的基因，如果我们将小鼠超音波发声沟通能力比喻为人类的原始说话语言功能，Foxp2-Mef2c基因交互作用所控制的「大脑皮质—基底核神经回路」突触接点形成，有可能是人类婴儿出生后学习建立说话语言沟通能力的一个重要大脑神经元分子发育机制。

了解自闭症语言功能缺失的病理基础方面

本篇论文研究除了了解语言神经元回路建立与其相关疾病外，对自闭症的神经回路与分子机转的病理基础亦可能有所助益。根据临床医学文献报导MEF2C是个自闭症基因，因为带有MEF2C基因突变缺失患者有智力迟缓与自闭征症，包括说话语言功能的缺陷。文献报导自闭症小孩患者的说话语言功能病理异常相当复杂— 从说话语言功能严重受损、语言能力发展迟缓、乃至高功能说话异常流利皆有。但是自闭症为何会影响到说话语言沟通能力？目前仍然不清楚。刘福清教授团队的研究结果显示自闭症基因病变，可能影响到大脑控制说话语言神经回路的发育建置。后续研究可以提供线索，帮助我们了解说话语言相关神经疾病和自闭症的神经回路与分子机转的病理基础，并进而发展治疗疾病策略。
年度 论文名称
2018 Kuo H-Y, Liu F-C (2018) Molecular Pathology and Pharmacological Treatment of Autism Spectrum Disorder-Like Phenotypes using Rodent Models. Front. Cell. Neurosci. 12:422. doi: 10.3389/fncel.2018.00422.
2018 Fong L, Kuo H-Y, Chen S-Y, Liu F-C (2018) Differential and overlapping expression pattern of Foxp1 and Foxp2 in the striatum of adult mouse brain. Neuroscience 388: 214-223.
2018 Chen S-Y, Kuo H-Y, Liu F-C (2018) Stereotaxic surgery for genetic manipulation in striatal cells of neonatal mouse brains. J. Vis. Exp. (137) e57270, doi:10.3791/57270.
2017 Kuo H-Y, Liu F-C (2017) Valproic acid induces aberrant development of striatal compartments and corticostriatal pathways in a mouse model of autism spectrum disorder. FASEB J 31: 4458-4471. doi: 10.1096/fj.201700054R.
2016 Chen Y-C, Kuo H-Y, Bornschein U, Takahashi H, Chen S-Y, Lu K-M, Yang H-Y, Chen G-M, Lin J-R, Lee Y-H, Chou Y-C, Cheng S-J, Chen C-T, Enard W, Hevers W, Pääbo S, Graybiel AM, Liu F-C (2016) Foxp2 controls synaptic wiring of corticostriatal circuits and vocal communication by opposing Mef2c. Nature Neuroscience 19:1513–1522. doi:10.1038/nn.4380.
2014 Lu K-M, Evans, SM, Hirano S, Liu-F-C (2014) Dual role for Islet-1 in promoting striatonigral and repressing striatopallidal genetic programs to specify striatonigral cell identity. Proc Natl Acad Sci USA 111(1):E168-177.
2013 Chang SL-Y, Chen S-Y, Huang H-H, Ko H-A, Liu P-T, Liu Y-C, Chen P-H, Liu F-C (2013) Ectopic Expression of Nolz-1 in Neural Progenitors Promotes Cell Cycle Exit/Premature Neuronal Differentiation Accompanying with Abnormal Apoptosis in the Developing Mouse Telencephalon. PLoS ONE 8(9): e74975. doi:10.1371/journal.pone.0074975.
2013 Chang L-Y, Liu Y-C, Chen S-Y, Huang T-H, Liu P-T, Liu F-C (2013) Identification of two evolutionarily conserved 5' cis-elements involved in regulating spatiotemporal expression of Nolz-1 during mouse embryogenesis. PLoS ONE 8:e54485.
2011 Chang L-Y,Yan Y-T, Shi Y-L, Liu Y-C, Takahashi H, Liu F-C (2011) Region- and cell type-selective expression of Nolz-1/zfp503 mRNA in the developing mouse hindbrain. Gene Expression Patterns 11:525-532.
2010 Chen C-M, Wang H-Y, You L-R, Shang R-L, Liu F-C (2010) Expression analysis of an evolutionary conserved metallophosphodiesterase gene, Mpped1, in the normal and β-catenin-deficient malformed dorsal telencephalon. Dev Dynamics 239:1797-1806.
2010 Kaoru T, Liu F-C, Ishida M, Oishi T, Hayashi M, Kitagawa M, Shimoda K, Takahashi H (2010) Molecular characterization of the intercalated cell masses of the amygdala: implications for the relationship with the striatum. Neuroscience 166:220-230.
2009 Takahashi H, Takahashi K, Liu F-C (2009) FOXP genes, neural development, speech and language disorders In: Forkhead Transcription Factors: Vital Elements in Biology and Medicine, Section II, Chapter 9, pp1-13, Maiese K, editor, Landes Bioscience, Austin, Texas. (Invited book chapter)
2009 Chen Y-F, Kao C-H, Chen Y-T, Wang C-H, Wu C-Y, Tsai C-Y, Liu F-C, Yang C-W, Wei Y-H, Hsu M-T, Tsai S-F, Tsai T-F (2009) Cisd2 deficiency drives premature aging and causes mitochondria-mediated defects in mice. Genes & Development 23:1183-1194.
2009 Sato T, Miura M, Yamada M, Yoshida T, Wood JD, Yazawa I, Masuda M, Suzuki T, Shin R-M, Yau H-J, Liu F-C, Shimohata T, Onodera O, Ross C A, Katsuki M, Takahashi H, Kano M, Aosaki T, Tsuji S (2009) Severe neurological phenotypes of Q129 DRPLA transgenic mice serendipitously created by en masse expansion of CAG repeats in Q76 DRPLA mice. Human Molecular Genetics 18:723-736.
2009 Tsuchiya R, Takahashi K, Liu F-C, Takahashi H (2009) Aberrant axonal projections from mammillary bodies in Pax6 mutant mice: possible roles of Netrin-1 and Slit 2 in mammillary projections. J Neurosci Res 87:1620-1633.
2008 Liao W-L, Tsai H-C, Wang H-F, Chang J, Lu K-M, Wu H-L, Lee Y-C, Tsai T-F, Takahashi T, Wagner M, Ghyselinck NB, Chambon P, Liu F-C (2008) Modular patterning of structure and function of the striatum by retinoid receptor signaling. Proc Natl Acad Sci 105: 6765-6770.
2008 Takahashi K, Liu F-C, Oishi T, Mori T, Higo N, Hayashi M, Takahashi H (2008) Expression of FOXP2 in the developing monkey forebrain: comparison with the expression of the genes FOXP1, PBX3 and MEIS2. J Comp Neurol 509:180-189.
2008 Takahashi K, Liu F-C, Hirokawa K, Takahashi H (2008) Expression of Foxp4 in the developing and adult rat forebrain. J Neuosci Res 86:3106-3116.
2006 Takahashi H, Liu F-C (2006) Genetic patterning of the mammalian telencephalon by morphogenetic molecules and transcription factors. Birth Defects Res C Embryo Today: Reviews 78:256-266. (Invited review)
2005 Wang H-F, Liu F-C (2005) Regulation of multiple dopamine signal transduction molecules by retinoids in the developing striatum. Neuroscience 134:97-105.
2005 Liao W-L, Liu F-C (2005) RAR( isoform-specific regulation of DARPP-32 gene expression: an ectopic expression study in the developing rat telencephalon. Eur J Neurosci 21: 3262-3268.
2005 Liao W-L, Tsai H-C, Wu C-Y, Liu F-C (2005) Differential expression of RARb isoforms in the mouse striatum during development: a gradient of RARb2 expression along the rostrocaudal axis. Dev Dynamics 233:584–594.
2005 Liao W-L, Wang H-F, Tsai H-C, Chambon P, Wagner M, Kakizuka A, Liu F-C (2005) Retinoid signaling competence and RARb-mediated gene regulation in the developing mammalian telencephalon. Dev Dynamics 232:887-900.
2004 Chang C-W, Tsai C-W, Wang H-F, Tsai H-C, Chen H-Y, Tsai T-F, Takahashi H, Li H-Y, Fann M-J, Yang C-W, Hayashizaki Y, Saito T, Liu F-C (2004) Identification of a developmentally regulated striatum-enriched zinc-finger gene Nolz-1 in the mammalian brain. Proc Natl Acad Sci 101:2613-2618.
2003 Yau H-J, Wang H-F, Lai C, Liu F-C (2003) Neural development of the neuregulin receptor ErbB4 in the cerebral cortex and the hippocampus: preferential expression by interneurons tangentially migrating from the ganglionic eminences. Cerebral Cortex 13:252-264.
2003 Liu F-C (2003) Organotypic culture of developing striatum: Pharmacological induction of gene expression. In: Methods in Molecular Medicine, vol. 79: Drugs of Abuse: Neurological Reviews and Protocols, pp.405-412, Humana Press, Totowa, New Jersey . (Invited book chapter)
2003 Takahashi K, Liu F-C, Hirokawa K, Takahashi H (2003) Expression of Foxp2, a gene involved in speech and language, in the developing and adult striatum. J Neuosci Res 73:61-72.
2003 Lee YC, Chien CL, Sun CN, Huang CL, Huang NK, Chiang MC, Lai HL, Lin YS, Chou SY, Wang CK, Tai MH, Liao WL, Lin TN, Liu FC, Chern Y (2003) Characterization of the rat A2A adenosine receptor gene: a 4.8-kb promoter-proximal DNA fragment confers selective expression in the central nervous system. Eur J Neurosci 7:1786-96.
2001 Wang H-F, Liu F-C (2001) Developmental restriction of the LIM homeodomain transcription factor Isl-1 expression to cholinergic neurons in the striatum. Neuroscience 103:999-1016.
1999 Liu F-C, Graybiel AM (1999) Neural development of the striatal dopamine system. In: The Development of Dopaminergic Neurons, (U. di Porzio, R. Pernas-Alonso, C. Perrone-Capano, eds), Landes Biosciences, Texas , pp.87-100.
1998 Liu F-C, Graybiel AM (1998) Phosphorylation of CREB in organotypic cultures of developing striatum: Kinetics of dopamine and calcium signal interactions. In: Advances in Pharmacology, vol. 42, Catecholamines: Bridging Basic Science with Clinical Medicine, (D.S. Goldstein, G. Eisenhofer, R. McCarty, eds), Academic Press, San Diego, California , pp.682-686.
1998 Liu F-C, Wu G-C, Hsieh S-T, Lai H-L, Wang H-F, Wang T-W, Chern Y (1998) Expression of adenylyl cyclase type VI in the central nervous system: Implication for a general coincidence detector in neurons, FEBS letters 436:92-98.
1998 Liu F-C, Graybiel AM (1998) Region-dependent dynamics of cAMP response element-binding protein phosphorylation in the basal ganglia. Proc Natl Acad Sci USA 95: 4708-4713
1998 Liu F-C, Graybiel AM (1998) Activity-regulated phosphorylation of CREB in the developing striatum: Implications for patterning the neurochemical phenotypes of striatal compartments. Dev Neurosci 20:229-236.
1996 Liu F-C, Graybiel AM (1996) Protein phosphatases regulate CREB phosphorylation and Fos expression in the developing striatum: Evidence and a hypothesis. In: Advances in Behavioral Biology, vol. 47, The Basal Ganglia V,(C.Ohye, M. Kimura and J.S. McKenzie, eds), Plenum Press, New York , pp.97-103.
1996 Liu F-C, Graybiel AM (1996) Spatiotemporal dynamics of CREB phosphorylation: Transient versus sustained phosphorylation in the developing striatum. Neuron 17:1133-1144.
1995 Liu F-C, Graybiel AM (1995) Dopamine-mediated signaling in organotypic striatal slice cultures. In: Molecular and Cellular Mechanisms of the Neostriatal Function, (M. A. Ariano and J. Surmeier, eds), R.G. Landes, Georgetown, Texas , pp.311-319.
1995 Graybiel AM, Berretta B, Moratalla R, Liu F-C, Elibol B (1995) Effects of cocaine on signal transduction in striatal neurons. In: Neurobiology of Cocaine, (R. Hammer, ed), CRC Press, Boca Raton, Florida , pp.215-223.
1995 Liu F-C, Dunnett SB, Graybiel AM (1995) Embryonic striatal grafting: Progress and future directions for therapeutic approaches to neurodegenerative diseases of the basal ganglia. In: Age-related dopamine-dependent disorders, ( N. Segawa and Y. Nomura, eds), Karger, Basel , Monogr Neural Sci 14:225-234.
1995 Liu F-C, Takahashi H, McKay RDG, Graybiel AM (1995) Dopaminergic regulation of transcription factor expression in organotypic cultures of developing striatum. J Neurosci 15:2367-2384.
1993 Liu F-C, Dunnett SB, Graybiel AM (1993) Intrastriatal grafts derived from fetal striatal primordia. IV. Host and donor neurons are not intermixed. Neuroscience 55:363-372.
1992 Liu F-C, Dunnett SB, Graybiel AM (1992) Influence of mesostriatal afferents on the development and transmitter regulation of intrastriatal grafts derived from embryonic striatal primordia. J Neurosci 12:4281-4297.
1992 Liu F-C, Graybiel AM (1992) Transient calbindin-D28K-positive systems in the telencephalon: ganglionic eminence, developing striatum and cerebral cortex. J Neurosci 12:674-690.
1992 Liu F-C, Graybiel AM (1992) Heterogeneous development of calbindin-D28K expression in the developing striatum. J Comp Neurol 320:304-322.
1991 Liu F-C, Dunnett SB, Robertson HA, Graybiel AM (1991) Intrastriatal grafts derived from fetal striatal primordia. III. Induction of modular patterns of Fos-like immunoreactivity by cocaine. Exp Brain Res 85:501-506.
1990 Liu F-C, Graybiel AM, Dunnett SB, Baughman RW (1990) Intrastriatal grafts derived from fetal striatal primordia: II. Reconstitution of cholinergic and dopaminergic systems. J Comp Neurol 295:1-14.
1990 Graybiel AM, Liu F-C, Dunnett SB (1990) Cellular reaggregation in vivo: Modular patterns in intrastriatal grafts derived from fetal striatal primordia. Prog Brain Res 82:401-405.
1989 Graybiel, AM, Liu F-C, Dunnett SB (1989) Intrastriatal grafts derived from fetal striatal primordia. I. Phenotypy and modular organization. J Neurosci 9:3250-3271.
奖项名称 年度
107年科技部杰出研究奖 2019