劉 福清
基礎神經研究團隊
姓名 劉 福清
電子郵件 fuchin@ym.edu.tw
聯絡電話 +886-2-2826-7216
EDUCATION/TRAINING Ph.D., 1991, Massachusetts Institute of Technology
研究專長 Neural development and plasticity of the basal ganglia circuits in the mammalian forebrain
研究概況 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.



基底核實驗室重要突破研究發現

大腦基因如何建構原始說話語言功能的神經迴路

探討解開Foxp2語言基因在大腦神經元分子、神經迴路、行為控制的作用機制

語言溝通是人類社會互動的獨特基本能力。目前對於人類大腦神經系統如何建構控制語言說話能力仍然不甚清楚。反觀其他物種雖不具有複雜豐富說話語言能力，但仍有其它類似簡單能力，例如小鼠有超音波發聲能力，藉以達成溝通目的。

國立陽明大學神經科學研究所劉福清教授研究團隊以小鼠超音波發聲溝通能力為行為模式，研究大腦神經系統如何建構原始語言說話能力。劉福清教授研究團隊發現Foxp2語言基因能夠開啟Mef2c自閉症基因對於「大腦皮質—基底核神經迴路」突觸接點建立的抑制。這項研究除了深入瞭解基本原始說話語言神經迴路的建立外，亦對自閉症語言能力缺陷的病理基礎有所探討。這篇研究論文發表於國際知名頂尖期刊「自然神經科學」(Nature Neuroscience)。

Foxp2基因控制神經元突觸接點的建立

Foxp2基因在分子層次如何控制神經元突觸接點的建立? 研究團隊發現Foxp2基因抑制下游標的Mef2c基因，間接開啟神經迴路突觸接點的建立。Mef2c突變基因己知是個自閉症基因。正常的Mef2c基因會抑制大腦皮質訊息傳送至基底核神經元突觸接點的發育形成。比喻來說，Mef2c基因正常作用就如同一道安全鎖(Safety Lock)，在胚胎發育早期先行鎖住神經突觸接點形成，避免在發育早期尚無大腦皮質訊息輸入下，神經突觸接點不成熟提早建立，因而形成錯誤的神經迴路。那麼正常下何者是一支鑰匙(Key)可以打開這道安全鎖？研究團隊發現Foxp2基因正是可以打開(Unlock) Mef2c基因這道安全鎖的鑰匙。Foxp2基因可以直接解開Mef2c基因對於神經接點的抑制，進而開啟「大腦皮質—基底核神經迴路」正確的神經突觸接點發育形成。倘若Foxp2基因或Mef2c基因突變喪失其正常功能，Mef2c基因這道安全鎖將會壞掉，導致異常錯誤的神經突觸接點形成，因而建構出錯誤的神經迴路。Mef2c基因突變所導致錯誤的「大腦皮質—基底核神經迴路」有可能是自閉症說話語言功能缺失的病理機制。

Foxp2-Mef2c基因交互作用調控神經迴路功能的重要性

本篇論文第一作者郭曉縈博士說，研究團隊接下來探討的問題是，「大腦皮質—基底核神經迴路」的正常功能為何? 郭曉縈博士解釋研究團隊進一步的研究發現，Foxp2-Mef2c基因交互作用所控制的「大腦皮質—基底核神經迴路」突觸接點建立，對於調控初生小鼠超音波發聲溝通行為(Ultrasonic vocal communication) 扮演著關鍵重要角色。當Foxp2基因或Mef2c基因突變喪失功能，會導致「大腦皮質—基底核神經迴路」突觸接點無法正確建立，進而導致初生小鼠超音波發聲溝通行為異常。

基因分子－神經迴路－行為控制的整合性神經科學研究

劉福清教授實驗室這項與德國、日本、美國、中研院研究團隊合作的研究結果：Foxp2與Mef2c兩個基因的交互作用調控「大腦皮質－基底核神經迴路」的建立與初生小鼠超音波發聲溝通能力，在基礎科學與神經疾病研究有重要引申意義：

基礎科學研究方面

Foxp2已知是個與人類語言說話能力相關的基因，如果我們將小鼠超音波發聲溝通能力比喻為人類的原始說話語言功能，Foxp2-Mef2c基因交互作用所控制的「大腦皮質—基底核神經迴路」突觸接點形成，有可能是人類嬰兒出生後學習建立說話語言溝通能力的一個重要大腦神經元分子發育機制。

瞭解自閉症語言功能缺失的病理基礎方面

本篇論文研究除了瞭解語言神經元迴路建立與其相關疾病外，對自閉症的神經迴路與分子機轉的病理基礎亦可能有所助益。根據臨床醫學文獻報導MEF2C是個自閉症基因，因為帶有MEF2C基因突變缺失患者有智力遲緩與自閉徵症，包括說話語言功能的缺陷。文獻報導自閉症小孩患者的說話語言功能病理異常相當複雜— 從說話語言功能嚴重受損、語言能力發展遲緩、乃至高功能說話異常流利皆有。但是自閉症為何會影響到說話語言溝通能力？目前仍然不清楚。劉福清教授團隊的研究結果顯示自閉症基因病變，可能影響到大腦控制說話語言神經迴路的發育建置。後續研究可以提供線索，幫助我們瞭解說話語言相關神經疾病和自閉症的神經迴路與分子機轉的病理基礎，並進而發展治療疾病策略。
年度 論文名稱
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.
獎項名稱 年度
107年科技部傑出研究獎 2019