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Nde1-mediated inhibition of ciliogenesis affects cell cycle re-entry

Abstract

The primary cilium is an antenna-like organelle that is dynamically regulated during the cell cycle. Ciliogenesis is initiated as cells enter quiescence, whereas resorption of the cilium precedes mitosis. The mechanisms coordinating ciliogenesis with the cell cycle are unknown. Here we identify the centrosomal protein Nde1 (nuclear distribution gene E homologue 1) as a negative regulator of ciliary length. Nde1 is expressed at high levels in mitosis, low levels in quiescence and localizes at the mother centriole, which nucleates the primary cilium. Cells depleted of Nde1 have longer cilia and a delay in cell cycle re-entry that correlates with ciliary length. Knockdown of Nde1 in zebrafish embryos results in increased ciliary length, suppression of cell division, reduction of the number of cells forming the Kupffer's vesicle and left–right patterning defects. These data suggest that Nde1 is an integral component of a network coordinating ciliary length with cell cycle progression and have implications for understanding the transition from a quiescent to a proliferative state.

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Figure 1: Depletion of Nde1 induces longer cilia.
Figure 2: Expression of Flag-tagged human Nde1 rescues abnormally long cilia in NIH-3T3Nde1–KD2 cells.
Figure 3: Nde1 suppresses ciliogenesis through LC8.
Figure 4: Nde1 expression inversely correlates with ciliogenesis.
Figure 5: Nde1 depletion causes a delay in cell cycle re-entry.
Figure 6: Knockdown of Nde1 causes a cilium-dependent delay in cell cycle re-entry.
Figure 7: Depletion of nde1 in zebrafish leads to longer cilia and a smaller Kupffer's vesicle.

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Acknowledgements

We thank J. Rosenbaum, S. Doxsey, C. Wood, N. Wilson, D. Dawson, S. Plafker and R. Janknecht for comments on the manuscript, S. Munro, B. Yoder, J. Peränen, J. Salisbury, A. S. McCallion and G. Pazour for reagents, and the Yost, Sive, Amack and Zon labs for zebrafish immunostaining protocols. This work was supported by grants R01HD04260 from the National Institute of Child Health and Development (to N.K.), grants R01DK072301, R01DK075972 (to N.K.), R01DK078209 (to T.O.) and R01DK59599 (to L.T.) from the National Institute of Diabetes, Digestive and Kidney disorders, grant P20RR017703 from the National Center for Research Resources (to L.T.), a Visual Neuroscience Training Program grant from the National Eye Institute (to N.A.Z.), grants HR06-175 (to S.R.) and HR07-097 (to L.T.) from the Oklahoma Center for the Advancement of Science and Technology, and the John S. Gammill Endowed Chair for PKD (to L.T.). S.R. is a Pew Scholar in the Biomedical Sciences, supported by The Pew Charitable Trusts.

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S.K., N.A.Z., E.B., E.C.O. and S.R. performed experiments. S.K., N.A.Z., E.B., S.R., N.K., T.O. and L.T. analysed data. S.K. and L.T. planned the project. S.K. and L.T. wrote the manuscript.

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Correspondence to Leonidas Tsiokas.

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Kim, S., Zaghloul, N., Bubenshchikova, E. et al. Nde1-mediated inhibition of ciliogenesis affects cell cycle re-entry. Nat Cell Biol 13, 351–360 (2011). https://doi.org/10.1038/ncb2183

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