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Leucine-rich glioma inactivated 1 (Lgi1), an epilepsy-related secreted protein, has a nuclear localization signal and localizes to both the cytoplasm and the nucleus of the caudal ganglionic eminence neurons

Authors

  • Sayaka Kusuzawa,

    1. Department of Anatomy, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
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  • Takao Honda,

    1. Department of Anatomy, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
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  • Yuko Fukata,

    1. Division of Membrane Physiology, Department of Cell Physiology, National Institute for Physiological Sciences, Aichi 444-8585, Japan
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  • Masaki Fukata,

    1. Division of Membrane Physiology, Department of Cell Physiology, National Institute for Physiological Sciences, Aichi 444-8585, Japan
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  • Shigeaki Kanatani,

    1. Department of Anatomy, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
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  • Daisuke H. Tanaka,

    1. Department of Anatomy, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
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    • Present address: Institut de Recherches en Biologie Humaine et Moléculaire (IRIBHM), Université Libre de Bruxelles (ULB), Brussels, Belgium.

  • Kazunori Nakajima

    1. Department of Anatomy, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan
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Dr K. Nakajima, as above.
E-mail: kazunori@z6.keio.jp

Abstract

Leucine-rich glioma inactivated 1 (Lgi1) is a secreted synaptic protein that organizes a transsynaptic protein complex throughout the brain. Mutations in the Lgi1 gene have been found in patients with autosomal dominant lateral temporal lobe epilepsy (ADLTE). Although a large number of studies have focused on the expression and function of Lgi1 in the postnatal brain, information regarding its functions and distribution during development remains sparse. Here we report that Lgi1 mRNA is preferentially expressed in the caudal ganglionic eminence (CGE) of the early embryonic telencephalon, and LGI1 protein is unexpectedly localized in the nucleus of dissociated CGE neurons. Using bioinformatics analysis, we found that LGI1 contains a putative nuclear localization signal (NLS) in its leucine-rich repeat C-terminal domain. Furthermore, we show that the transient expression of Lgi1 in CGE neurons resulted in nuclear translocation of the LGI1 protein, and a mutation in the NLS led to the retention of LGI1 in the cytoplasm. We also confirmed that the NLS sequence of LGI1 had the ability to mediate the nuclear localization by using the NLS-containing fusion protein. Interestingly, when Lgi1 was expressed in neurons obtained from the medial ganglionic eminence or cerebral cortex, almost no nuclear localization of LGI1 was observed. These results raise the possibility of a novel role of Lgi1 within embryonic neurons through nuclear translocation and may provide insight into its potential effects on the development of the central nervous system and ADLTE pathogenesis.

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