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Nrarp functions to modulate neural-crest-cell differentiation by regulating LEF1 protein stability

Nature Cell Biology volume 7, pages 1106–1112 (2005)Cite this article

Abstract

Nrarp (Notch-regulated ankyrin repeat protein) is a small protein that has two ankyrin repeats1,2,3,4,5. Although Nrarp is known to be an inhibitory component of the Notch signalling pathway that operates in different developmental processes1,2,4,5, the in vivo roles of Nrarp have not been fully characterized. Here, we show that Nrarp is a positive regulator in the Wnt signalling pathway. In zebrafish, knockdown of Nrarp-a expression by an antisense morpholino oligonucleotide (MO) results in altered Wnt-signalling-dependent neural-crest-cell development. Nrarp stabilizes LEF1 protein, a pivotal transcription factor in the Wnt signalling cascade, by blocking LEF1 ubiquitination. In accordance with this, the knockdown phenotype of lef1 is similar to that of nrarp-a, at least in part, in its effect on the development of multiple tissues in zebrafish. Furthermore, activation of LEF1 does not affect Notch activity or vice versa. These findings reveal that Nrarp independently regulates canonical Wnt and Notch signalling by modulating LEF1 and Notch protein turnover, respectively.

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Figure 1: Both nrarp-a and lef1 are involved in the development of neural-crest-cell derivatives.
Figure 2: Both nrarp-a and lef1 are involved in NCC migration.
Figure 3: nrarp-a and lef1 are required for Wnt signalling activity in NCC development.
Figure 4: Nrarp facilitates the canonical Wnt pathway via stabilizing LEF1.
Figure 5: Nrarp independently regulates Notch signalling and canonical Wnt signalling.

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Acknowledgements

We thank T. Honjo and C. Kintner for providing plasmid vectors; R.T. Moon for providing TOPdGFP fish; R.I. Dorsky for sharing information on lef1 splicing MO; H. Matsuo for maintaining fish; and K. Matsumoto laboratory members for helpful discussions. This research was supported by special grants from CREST and the Advanced Research on Cancer from the Ministry of Education, Culture and Science of Japan (K.M.), and JSPS Research Fellowship for Young Scientists (T.I.).

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Authors and Affiliations

  1. Division of Biological Science, Unit on Nervous System Development, Laboratory of Cell Regulation, Graduate School of Science, Nagoya University, Nagoya, 464-8602, Japan

    Tohru Ishitani & Motoyuki Itoh

  2. Division of Biological Science, Group of Signal Transduction, Laboratory of Cell Regulation, Graduate School of Science, Nagoya University, and CREST, Japan Science and Technology Corporation, Chikusa-ku, Nagoya, 464-8602, Japan

    Kunihiro Matsumoto

  3. Laboratory of Molecular Genetics, NICHD/NIH, Bethesda, 20892, MD, USA

    Ajay B. Chitnis

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  1. Tohru Ishitani
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Correspondence to Motoyuki Itoh.

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Ishitani, T., Matsumoto, K., Chitnis, A. et al. Nrarp functions to modulate neural-crest-cell differentiation by regulating LEF1 protein stability. Nat Cell Biol 7, 1106–1112 (2005). https://doi.org/10.1038/ncb1311

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