- B.Sc., Peking University, Beijing, China, 1989
- Ph.D., New York University Medical Center, NY, 2000
- Memorial Sloan-Kettering Cancer Center, NY, 2001-2004
- University of Colorado Health Sciences Center, CO (same mentor), 2004-2005
Biogenesis and Function of Cilia in Mammalian Embryonic Development
The primary cilia are cell surface organelles essential for vertebrate embryonic development and physiological activities of adult organs. Multiple human diseases, including Polycystic Kidney Diseases (PKD), Bardet-Biedl Syndrome (BBS), and Meckel-Gruber Syndrome (MKS) are associated with the dysfunction of cilia. The long-term goals of our lab are to reach a comprehensive understanding of the mechanisms underlying the regulation of cilia biogenesis, as well as the roles for the cilia in cell-cell communication, cell polarity control, the development of a variety of organs. Our current research focuses on the following topics:The Relationship Between Cilia and Signal Transduction
We have shown that cilia play a significant role in regulating the intracellular signal transduction of the Hedgehog (Hh) pathway in mammals. Multiple components of the Hh pathway, including Patched-1, Smoothened, Gli2, Gli3, and Suppressor of fused (Sufu) are localized to the cilia. However, the importance of such localization remains unclear. We focus on the relationship between cilia and two of the Hh pathway components: Sufu and Gli. Sufu is an important negative regulator of Hh signaling in both fruit flies and mammals, and its activity seems to be regulated in response to Hh signaling. In collaboration with Dr. Rune Toftgard at the Karolinska Institute, we are addressing the roles for cilia in the regulation of Sufu and Gli activities through genetics and molecular biology approaches. We also are searching for proteins directly responsible for Gli transport in the cilia.
The Roles for PCP Effector Genes in Cilia Biogenesis and Cell Polarity Control
Taking a forward genetic approach, we generated Double-thumb (Dtm), a recessive mouse mutant with both morphological and behavioral defects. We discovered that these defects result from a missense mutation in Inturned (Intu), a gene involved in cell polarity control in the fruit flies. We have generated several tissue-specific mutants for this gene through an embryonic stem cell-based approach, and discovered that Intu is an essential regulator of cilia biogenesis in mammals. We currently are addressing the roles for this gene in both embryonic development and disease pathogenesis, such as PKD.Hearty (Hty), a Novel Regulator of Cilia Biogenesis
We identified Hty through the study of another recessive mouse mutant generated in our forward genetic screen. Hty mutants exhibit multiple defects in embryonic development as the result of a partial loss of cilia. The Hty protein is a novel vertebrate-specific protein specifically localized to the primary cilia. We are currently investigating the molecular mechanism underlying the Hty function through multiple approaches.
Cai H and Liu A. (2016) Spop promotes skeletal development and homeostasis by positively regulating Ihh signaling. Proc Natl Acad Sci U S A., 113 (51): 14751-14756, PMID: 27930311 DOI:10.1073/pnas.1612520114
Chang R, Petersen J R, Niswander L, Liu A. (2015) A hypomorphic allele reveals an important role of Inturned in mouse skeletal development. Developmental Dynamics, 244(6): 736-747. DOI 10.1002/dvdy.24272
Liu, J., Zeng, H. and Liu, A. (2015) The loss of HH responsiveness by a non-ciliary Gli2 variant. Development, 142: 1651-1660. doi:10.1242/dev.119669 (Highlighted article, recommended by Faculty of 1000)
Ye, X., Zeng, H., Ning, G., Reiter J. and Liu, A. (2014) C2cd3 regulates centriolar maturation and IFT protein recruitment essential for cilia formation. Proc Natl Acad Sci U S A., 111(6): 2164-2169. DOI:10.1073/pnas.1318737111
Liu, A. and Eggenschwiler, J. (2014) Identifying essential genes in mouse development via an ENU-based forward genetic approach. Methods in Molecular Biology: Mouse Molecular Embryology (chapter 7), 1092: 95-118. Edited by Mark Lewandowski. Springer, New York, NY. ISBN: 978-1-60327-290-2. DOI: 10.1007/978-1-60327-292-6_7.
Liu, J. and Liu, A. (2014) Immunohistochemistry and RNA in situ hybridization in mouse brain development. Methods in Molecular Biology, 1082: 269-283. Edited by Simon Sprecher. DOI: 10.1007/978-1-62703-655-9_18
Wang, C., Low, W-C, Liu, A., and Wang, B (2013) Centrosomal Protein Dzip1 Regulates Hedgehog Signaling by Promoting Cytoplasmic Retention of Transcription Factor Gli3 and Affecting Ciliogenesis J. Biol. Chem., 288: 29518-29. doi: 10.1074/jbc.M113.492066
Dai, D., Li, L., Huebner, A., Zeng, H., Guevara, E., Claypool, D., Liu, A., Chen, J. (2013) Planar cell polarity effector gene Intu regulates cell fate-specific differentiation of keratinocytes through the primary cilia. Cell Death and Differentiation, 20: 130-8. doi: 10.1038/cdd.2012.104
Liu A (2012) The Cilium-Dependent Hedgehog Signaling in Mammals. Cell Dev Biol ,1:e116. doi:10.4172/2168-9296.1000e116
Liu, J., Heydeck, W., Zeng, H. and Liu, A. (2012) Dual Function of Suppressor of Fused in Shh Pathway Activation and Mouse Spinal Cord Patterning. Developmental Biology, 362: 141-153. DOI: 10.1016/j.ydbio.2011.11.022
Ye, X and Liu, A. (2011) Hedgehog signaling: mechanism and evolution. Frontiers in Biology, 6(6): 504-521. DOI: 10.1007/s11515-011-1146-2
Heydeck, W. and Liu, A. (2011) PCP effector proteins Inturned and Fuzzy play non-redundant roles in the patterning but not convergent extension of mammalian neural tube. Developmental Dynamics, 240 (8): 1938-1948. doi: 10.1002/dvdy.22696
Pyrgaki, C., Liu, A. and Niswander LA. (2011) Grainyhead-like 2 regulates neural tube closure by controlling adhesion molecules during neural fold fusion. Developmental Biology, 353 (1): 38-49. doi: 10.1016/j.ydbio.2011.02.027
Zeng, H., Jia J. and Liu, A. (2010) Coordinated translocation of mammalian Gli proteins and Suppressor of Fused to the primary cilium. PLoS ONE 5(12): e15900. DOI: 10.1371/journal.pone.0015900
Zeng, H., Hoover, AN. and Liu, A. (2010) PCP effector gene Inturned is an important regulator of cilia formation and embryonic development in mammals. Developmental Biology, 339: 418-428.
Heydeck, W., Zeng, H. and Liu, A. (2009) PCP effector gene Fuzzy regulates cilia formation and Hh signal transduction in mouse. Developmental Dynamics, 238: 3035-3042.
Ko, HW., Liu, A., and Eggenschwiler, J. (2009) Analysis of Hedgehog signaling in mouse intraflagellar transport mutants. Methods in Cell Biology, 93: 347-369. Edited by Stephen King and Gregory Pazour. DOI: 10.1016/S0091-679X(08)93017-X
Jia, J., Kolterud, Å, Zeng, H., Hoover, AN., Teglund, S., Toftgård, R. and Liu, A. (2009) Suppressor of Fused inhibits mammalian Hedgehog signaling in the absence of cilia. Developmental Biology, 330: 452-460. (a Faculty of 1000 Must Read paper, top-five cited DB paper in May 2011)
Liu, A., Niswander, LA. (2005) Bone morphogenetic protein signaling and vertebrate nervous system development. Nature reviews neuroscience, 6: 945-954.
Liu, A., Wang, B., Niswander, LA. (2005) Intraflagellar Transport proteins regulate both the activator and repressor functions of Gli transcription factors. Development. 132: 3103-3111.
Liu, A., Wang, C., and Niswander, LA. (2005) Fibroblast Growth Factors in Development. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1038/npg.els.0003306]
Huangfu, D., Liu, A., Rakeman, A., Murcia, N Niswander, LA., and Anderson, KV (2003) Hedgehog signalling in the mouse requires intraflagellar transport proteins. Nature, 426(6962): 83-87. (a Faculty of 1000 Exceptional paper)
Liu, A., Li, JY., Bromleigh, C., Lao, Z, Niswander, LA, and Joyner, AL. (2003) FGF17b and FGF18 have different midbrain regulatory properties from FGF8b or activated FGF receptors. Development. 130(25): 6175-6185. (a Faculty of 1000 Exceptional paper)
Liu, A. and Joyner AL. (2001) Patterning of the midbrain and cerebellum. Annual Review of Neuroscience, Vol. 24, 869-896.
Liu, A. and Joyner, AL. (2001) EN and GBX2 play essential roles downstream of FGF8 in patterning the mouse mid/hindbrain region. Development, 128:181-191. (a Faculty of 1000 Must Read paper)
Joyner AL., Liu, A and Millet S. (2000) Otx2, Gbx2 and Fgf8 interact to position and maintain a mid/hindbrain organizer. Current Opinion in Cell Biology, 12: 736-741.
Liu, A., Losos, K. and Joyner, AL. (1999) FGF8 can activate Gbx2 and transform regions of the rostral mouse brain into a hindbrain fate. Development, 126: 4827-4838.
Liu, A., Joyner, AL. and Turnbull, DH. (1998) Alteration of limb and brain patterning by ultrasound-guided injection of Shh-expressing cells into mouse embryo. Mechanism of Development, 75: 107-115.
Tong, Y., Liu, A., Shang K. and Liu, L. (1997) Establishment and Characterization of Rabbit ES-like Cell Lines. Acta Scientiarum Naturalium Universitatis Pekinensis 33(4): 500-507.
Liu, A. (1995) Gene Targeting in ES cells. In Transgenic Animals, Principles, Techniques and Applications. Ed Xiaoli Tian, Lanying Chen and Rongliang Hu. S&T Press of Jilin Province. pp32-35.
Shang, K., Hu, X., Li, Z. Wang, X., Liu, A., Meng G and Tong, Y. (1994) Effect of different feeder layers on the establishment and character maintenance of mouse ES cell lines. Acta Scientarium Naturalium Universitatis Pekinensis 30(4): 500-508.
Liu, A. and Shang, K. (1994) Targeted disruption of the hprt gene in murine embryonic stem cells. Hereditas(Beijing) 16 (5): 1-5.
Shang, K. and Liu, A. (1992). ES cell and gene manipulation in mammals. in Advance and Progress in Agricultural Biotechnology. ed. Shirong Jia. Chinese University of Science and Technology Press. pp236-254.
Liu, A. and Shang, K. (1991) Gene targeting and transgenic animals. Progress in Biotechnology, 11(3): 20-29.