Faculty / Research
Ken-Ichi Takemaru, Ph.D.Associate Professor
Ph.D., Graduate University for Advanced Studies, Japan
Postdoctoral, University of Washington
Cell Signaling and Ciliogenesis in Mammalian Development, Health and Disease
Wnt Signaling in Development and Disease
Intracellular signaling by the Wnt family of secreted cysteine-rich glycoproteins plays critical roles in embryonic development and adult homeostasis. This pathway is highly conserved among the animal kingdom. Importantly, perturbations of Wnt signaling have been linked to a range of human diseases. For instance, the best understood canonical Wnt/β-catenin pathway is aberrantly activated in greater than 70 % of colorectal cancers and to a lesser extent in other tumor types, promoting cancer cell proliferation, survival and migration. More recently, this signaling cascade has emerged as a crucial regulator of stem cells. Our laboratory investigates the function of Wnt signaling in the context of development and disease.
Chibby Family Members and Ciliogenesis
Cilia are ancient microtubule-based organelles that protrude from the apical cell surface to perform diverse biological functions, ranging from fluid movement to intracellular signaling. Dysfunctional cilia have been linked to various diseases, collectively known as ciliopathy. We previously reported a β-catenin-associated antagonist Chibby (Cby). Cby is a conserved shuttling protein that blocks transcriptional activation by β-catenin, a key coactivator downstream of canonical Wnt signaling. In our efforts to investigate the physiological function of Cby using Cby-knockout (Cby-/-) mice, we found that these mice suffer from chronic respiratory infections due to a complete absence of mucociliary transport activity. Our studies further uncovered that ciliated cells in the nasal and lung epithelia of Cby-/- mice are poorly differentiated characterized by markedly fewer ciliary projections. Consistent with this phenotype, endogenous Cby protein is highly enriched at the base of cilia, suggesting that Cby plays an essential role in proper formation/function of cilia. In mammals, there are three Cby homologues. Our current research is directed at understanding roles of Cby family members and Wnt/b-catenin signaling in ciliogenesis and ciliated cell differentiation.
Chen, J., LacLef, C., Moncayo, A., Snedecor, E.R., Yang, N., Li, L.,
Takemaru, K.-I., Paus, R., Schneider-Maunoury, S., & Clark, R.A.
The ciliopathy gene Rpgrip1L is essential for hair follicle development.
J. Invest. Dermatol., 135, 701-709. PMCID: PMC4340706
Burke, B.C., Li, F.-Q., Cyge, B., Arashiro, T., Brechbuhl, H.M., Chen, X., Siller, S.S., Weiss, M.A., O'Connell, C.B., Love, D., Westlake, C.J., Reynolds, S.D., Kuriyama, R. & Takemaru, K.-I. (2014)
Chibby promotes ciliary vesicle formation and basal body docking during airway cell differentiation.
J. Cell Biol., 207, 123-137. PMCID: PMC4195830
Featured on Journal Cover and highlighted in “In This Issue”.
Lee, Y.L., Sante, J., Comerci, C., Cyge, B., Menezes, L.F., Li, F.-Q., Germino, G.G., Moerner, W.E., Takemaru, K.-I. & Stearns. T. (2014)
Cby1 promotes Ahi1 recruitment to a ring-shaped domain at the centriole-cilium interface and facilitates proper cilium formation and function.
Mol. Biol. Cell, 25, 2919-2933. PMCID: PMC4230582
Rodriguez, J.P., Coulter, M., Motke, J., Meyer, R., Takemaru, K.-I. & Levine, J. (2014)
Abrogation of β-catenin signaling in oligodendrocyte precursor cells reduces glial scarring and promotes axon regeneration after CNS injury.
J. Neurosci., 34, 10285-10297. PMCID: PMC4115138
Mancini, M., Leo, E., Takemaru, K.-I., Campi, V., Borsi, E., Castagnetti, F., Gugliotta, G., Santucci, M.A., & Martinelli, G. (2013)
Chibby drives β-catenin cytoplasmic accumulation leading to activation of the unfolded protein response in BCR-ABL1+ cells. PMID: 23707389
Cell Signal., 25, 1820-1827.
Steere, N., Chae, V., Burke, M.C., Li, F.-Q., Takemaru, K.-I. & Kuriyama, R. (2012)
A Wnt/β-catenin pathway antagonist Chibby binds cenexin at the distal end of mother centrioles and functions in primary cilia formation.
PLoS ONE, 7, e41077. PMCID: PMC3401179
Kumamoto, N., Gu, Y., Wang, J., Janoschka, S., Takemaru, K.-I., Levine, J. & Ge, S. (2012)
A role for primary cilia in glutamatergic synaptic integration of adult-born neurons.
Nat. Neurosci., 15, 399-405. PMCID: PMC3288565
Love, D., Li, F.-Q., Burke, M.C., Cyge, B., Ohmitsu, M., Cabello, M., Larson, J.E., Brody, S.L., Cohen, J.C. & Takemaru, K.-I. (2010)
Altered lung morphogenesis, epithelial cell differentiation and mechanics in mice deficient in the Wnt/-catenin antagonist Chibby.
PLoS ONE, 5, e13600. PMCID: PMC2963606
Li, F.-Q.*, Mofunanya, A., Fischer, V., Hall, J., & Takemaru, K.-I.* (2010)
Nuclear-cytoplasmic shuttling of Chibby controls β-catenin signaling.
Mol. Biol. Cell, 21, 311-322. *Co-correspondence. PMCID: PMC2808236
Mofunanya, A., Li, F.-Q., Hsieh, J.-C., & Takemaru, K.-I. (2009)
Chibby forms a homodimer through a heptad repeat of leucine residues in its C-terminal coiled-coil motif.
BMC Mol. Biol., 10, 41. PMCID: PMC2686680
Voronina, V.A., Takemaru, K.-I.*, Treuting, P., Love, D., Grubb, B.R., Hajjar, A.M., Adams, A., Li, F.-Q. & Moon, R.T.* (2009)
Inactivaton of Chibby affects function of motile airway cilia.
J. Cell Biol., 185, 225-233. *Co-correspondence. PMCID: PMC2700371
Li, F.-Q.*, Mofunanya, A., Harris, K. & Takemaru, K.-I.* (2008)
Chibby cooperates with 14-3-3 to regulate β-catenin subcellular distribution and signaling activity.
J. Cell Biol., 181, 1141-1154. *Co-correspondence. PMCID: PMC2442201
Research Highlight by Kritikou, E. (2008) AKTing in Wnt pathway. Nat. Rev. Mol. Cell Biol., 9:584.
Li, F.-Q., Singh, A.M., Mofunanya, A, Love, D., Terada, N., Moon, R.T. & Takemaru, K.-I. (2007)
Chibby promotes adipocyte differentiation through inhibition of β-catenin signaling.
Mol. Cell. Biol., 27, 4347-4354. PMCID: PMC1900052
Takemaru, K.-I., Yamaguchi, S., Lee, Y.S., Zhang, Y., Carthew, R.W. & Moon, R.T. (2003)
Chibby, a nuclear β-catenin-associated antagonist of the Wnt/Wingless pathway.
Nature, 422, 905-909. PMID: 12712206
News and Views by Greaves, S. (2003) Small changes in Wnt signalling. Nat. Cell Biol., 5: 387.
Takemaru, K.-I. & Moon, R.T. (2000)
The transcriptional coactivator CBP interacts with β-catenin to activate gene expression.
J. Cell. Biol., 149, 249-254. PMCID: PMC2175158
Dept. of Pharmacology BST 7-182
Stony Brook, NY 11794-8651
Phone: (631) 444-7976
Fax: (631) 444-3218