Article | Published:

Teneurin-3 controls topographic circuit assembly in the hippocampus

Nature volume 554, pages 328333 (15 February 2018) | Download Citation

Abstract

Brain functions rely on specific patterns of connectivity. Teneurins are evolutionarily conserved transmembrane proteins that instruct synaptic partner matching in Drosophila and are required for vertebrate visual system development. The roles of vertebrate teneurins in connectivity beyond the visual system remain largely unknown and their mechanisms of action have not been demonstrated. Here we show that mouse teneurin-3 is expressed in multiple topographically interconnected areas of the hippocampal region, including proximal CA1, distal subiculum, and medial entorhinal cortex. Viral-genetic analyses reveal that teneurin-3 is required in both CA1 and subicular neurons for the precise targeting of proximal CA1 axons to distal subiculum. Furthermore, teneurin-3 promotes homophilic adhesion in vitro in a splicing isoform-dependent manner. These findings demonstrate striking genetic heterogeneity across multiple hippocampal areas and suggest that teneurin-3 may orchestrate the assembly of a complex distributed circuit in the mammalian brain via matching expression and homophilic attraction.

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Acknowledgements

We thank C. Guo and the Howard Hughes Medical Institute/Janelia Research Campus for producing the Ten3cre and Ten3fl alleles, M. Sur for providing the Ten3Δ4 allele, the Neuroscience Gene Vector and Virus Core at Stanford for producing viruses, K. DeLoach for technical assistance, T. Mosca and W. Hong for advice and inspiration, members of the Luo laboratory for discussion and support, P. Thomas for the dual transcription unit vector, T. Südhof for advice and the latrophilin-3 construct, and K. Shen, L. Giocomo, T. Mosca, H. Li, J. Li, J. Lui, E. Richman and A. Shuster for critiques of the manuscript. D.S.B. was supported by a National Institute on Deafness and Other Communication Disorders predoctoral fellowship (F31DC013240), L.A.D. was supported by an National Institute of Neurological Disorders and Stroke postdoctoral fellowship (F32NS087860) and L.L. is an investigator of Howard Hughes Medical Institute. This work was supported by a National Institutes of Health grant (R01-NS050580 to L.L.).

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Affiliations

  1. Howard Hughes Medical Institute, Stanford University, Stanford, California 94305, USA

    • Dominic S. Berns
    • , Laura A. DeNardo
    • , Daniel T. Pederick
    •  & Liqun Luo
  2. Department of Biology, Stanford University, Stanford, California 94305, USA.

    • Dominic S. Berns
    • , Laura A. DeNardo
    • , Daniel T. Pederick
    •  & Liqun Luo
  3. Neurosciences Graduate Program, Stanford University, Stanford, California 94305, USA

    • Dominic S. Berns

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Contributions

D.S.B. performed all the experiments and analysed the data except the electrophysiology experiments. L.A.D. performed the electrophysiology experiments and analysed the data. D.T.P. assisted in aggregation assays. L.L. supervised the project. D.S.B. and L.L. wrote the paper.

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The authors declare no competing financial interests.

Corresponding author

Correspondence to Liqun Luo.

Reviewer Information Nature thanks M. Witter and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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https://doi.org/10.1038/nature25463

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