Aimin Liu

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:

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.

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.

Heydeck, W. and A. Liu. 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: 1938-1948.

Zeng, H., Jia J. and A. Liu. 2010. Coordinated translocation of mammalian Gli proteins and Suppressor of Fused to the primary cilium. PLoS ONE 5(12): e15900.

Zeng, H., A. N. Hoover, and A. Liu. 2010. PCP effector gene Inturned is an important regulator of cilia formation and embryonic development in mammals. Developmental Biology 339: 418-428.

Heydeck, W., H. Zeng, and A. Liu. 2009. PCP effector gene Fuzzy regulates cilia formation and Hh signal transduction in mouse. Developmental Dynamics 238: 3035-3042.

Ko, H. W., A. Liu, and J. Eggenschwiler. 2009. Analysis of Hedgehog signaling in mouse intraflagellar transport mutants. Methods in Cell Biology 93: 347-369.

Jia, J., Å. Kolterud, H. Zeng, A. N. Hoover, S. Teglund, R. Toftgård, and A. Liu. 2009. Suppressor of Fused inhibits mammalian Hedgehog signaling in the absence of cilia. Developmental Biology 330: 452-460.

Hoover, A. N., A. Wynkoop, H. Zeng, J. Jia, L. A. Niswander, and A. Liu, A. 2008. C2cd3 is required for cilia formation and Hedgehog signaling in the mouse. Development 135: 4049-4058.

Liu, A. and L. A. Niswander. 2005. Bone morphogenetic protein signaling and vertebrate nervous system development. Nature Reviews Neuroscience 6: 945-954.

Liu, A., B. Wang, and L. A. Niswander. 2005. Intraflagellar Transport proteins regulate both the activator and repressor functions of Gli transcription factors. Development 132: 3103-3111.

Huangfu, D., A. Liu, A. Rakeman, N. Murcia, L. A. Niswander, and K. V. Anderson. 2003. Hedgehog signalling in the mouse requires intraflagellar transport proteins. Nature 426(6962): 83-87, (a Faculty of 1000 Exceptional Paper).