- 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
Molecular Mechanisms of Mammalian Development and Human Birth Defects
Three out of 100 babies in the United States are born with a birth defect, which causes huge medical, economical and social burdens for the patients, their families and the society. Our long-term goal is to understand the molecular details of normal development, how it is affected by mutations leading to birth defects and identify methods of intervention to prevent and correct these defects. Our current focus is on the roles of the Hedgehog (Hh) signaling pathways and the primary cilium in mammalian development and diseases.
The Regulation of Cilia Biogenesis in Mammals
The primary cilia are tiny hair-like structures on the surface of almost all the cells in the body of a mammal, and are essential for the development and physiological activities of many 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. Through conventional genetic approaches, we have identified C2cd3, Inturned (Intu) and Fuzzy (Fuz) as important regulators of cilia biogenesis in mammals (Hoover et al, 2008; Heydeck et al, 2009; Zeng et al, 2010a; Heydeck and Liu, 2011). Our subsequent molecular investigation revealed that C2cd3 regulates the synthesis of centrioles, which serve as anchors for the cilia to the cell membrane (Ye et al, 2014). We are currently investigating the mechanisms by which Intu and Fuz regulate cilia formation.
The Relationship Between the Cilia and Hh Signal Transduction
Our genetic studies firmly connected the primary cilia to the Hh signaling pathway, which regulates the developmental of multiple organs including the central nervous system and skeleton (Huangfu et al, 2003; Liu et al, 2005). Interestingly, the transcription factors Gli1, Gli2 and Gli3, along with their interacting partner, Sufu, are localized to the cilia (Zeng et al, 2010b). We find that a major role of the cilia is to relieve the inhibitory function of Sufu on Gli proteins (Jia et al, 2009). To probe the importance of the ciliary localization of these proteins, we replaced Gli2 with a variant incapable of entering the cilia, and showed that this variant could not support Hh signaling, suggesting the ciliary localization is critical for the activation of Gli2 (Liu et al, 2015).
The Levels of Gli Proteins and Their Impact on Development
The levels of the mammalian Gli proteins are regulated by multiple protein degradation and protection mechanisms. One interesting phenomenon we observed in Sufu mutants was the great decrease in Gli proteins (Jia et al, 2009). We showed that such a loss of Gli proteins led to reduced Hh pathway activation in the absence of Sufu, suggesting that the level of Gli proteins are important (Liu et al, 2012). To further investigate the importance of Gli protein level control in development, we characterized mouse mutants of Spop, a ubiquitin-ligase targeting Gli proteins for degradation (Cai and Liu, 2016). We found that loss of Spop led to specific defects in bone and cartilage development and reduced bone density similar to that seen in osteoporosis patients.
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.