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Zebrafish atlastin controls motility and spinal motor axon architecture via inhibition of the BMP pathway

Nature Neuroscience volume 13, pages 1380–1387 (2010)Cite this article

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Abstract

To better understand hereditary spastic paraplegia (HSP), we characterized the function of atlastin, a protein that is frequently involved in juvenile forms of HSP, by analyzing loss- and gain-of-function phenotypes in the developing zebrafish. We found that knockdown of the gene for atlastin (atl1) caused a severe decrease in larval mobility that was preceded by abnormal architecture of spinal motor axons and was associated with a substantial upregulation of the bone morphogenetic protein (BMP) signaling pathway. Overexpression analyses confirmed that atlastin inhibits BMP signaling. In primary cultures of zebrafish spinal neurons, Atlastin partially colocalized with type I BMP receptors in late endosomes distributed along neurites, which suggests that atlastin may regulate BMP receptor trafficking. Finally, genetic or pharmacological inhibition of BMP signaling was sufficient to rescue the loss of mobility and spinal motor axon defects of atl1 morphants, emphasizing the importance of fine-tuning the balance of BMP signaling for vertebrate motor axon architecture and stability.

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Figure 1: Zebrafish atl1 expression and knockdown.
Figure 2: Knockdown of atl1 causes a strong decrease in larval mobility.
Figure 3: Knockdown of atl1 leads to abnormal architecture of SMN axons.
Figure 4: Effect of transplanted SMNs on larval mobility.
Figure 5: Atlastin inhibits BMP signaling.
Figure 6: Upregulation of BMP signaling in atl1 morphant embryos.
Figure 7: Atlastin and type I BMP receptor (BMPRI) partially co-localize to late endosomes in zebrafish spinal neurons.
Figure 8: Genetic inhibition of BMP signaling rescues atl1 morphant mobility and spinal motor axon architecture.

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Acknowledgements

We thank J. Clarke, M. Salanoubat, J. Weissenbach and the Houart, Schneider-Maunoury and Nothias laboratories for discussions and support, S. Llewellyn-Jones, S. Thomas and G. Rodrigues for fish care at King's College London and IFR83/ UPMC, and R. Schwartzmann and V. Georget for the IFR83 imaging platform. We thank the patients' Association Strümpell-Lorrain (A-SL) for their constant support. J.H., a CNRS research fellow, received a senior research fellowship from King's College Charitable Foundation for 2 years in C.H.'s lab. C.F. was supported by fellowships from the FRM and the AFM. This work was supported by research grants to C.H. from the MRC and from AFM and A-SL to J.H.

Author information

Author notes

  1. Corinne Houart and Jamilé Hazan: These authors contributed equally to this work.

Authors and Affiliations

  1. CNRS UMR 7224, Physiopathologie des Maladies du Système Nerveux Central, Paris, France

    Coralie Fassier, Bruno Giros, Fatiha Nothias & Jamilé Hazan

  2. INSERM U952, Paris, France

    Coralie Fassier, Bruno Giros, Fatiha Nothias & Jamilé Hazan

  3. UPMC, University Paris 06, Paris, France

    Coralie Fassier, Bruno Giros, Fatiha Nothias, Sylvie Schneider-Maunoury & Jamilé Hazan

  4. Medical Research Council Centre for Developmental Neurobiology, King's College London, London, UK

    James A Hutt, Steffen Scholpp, Andrew Lumsden, Corinne Houart & Jamilé Hazan

  5. Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Karlsruhe, Germany

    Steffen Scholpp

  6. Department of Psychiatry, Douglas Hospital, McGill University, Montreal, Canada

    Bruno Giros

  7. CNRS UMR7622, Biologie du Développement, Paris, France

    Sylvie Schneider-Maunoury

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Contributions

J.H. and C.F. performed most experiments and analyzed the data with C.H. J.A.H. and S.S. helped with image acquisition and in situ hybridization and C.H. with transplantation. Half of the study was carried out in the C.H. lab by J.H., S.S.-M. and F.N. A.L. and B.G. welcomed J.H. and C.F. in their labs and gave insightful advice on the project. J.H. and C.H. designed all experiments and wrote the manuscript.

Corresponding authors

Correspondence to Corinne Houart or Jamilé Hazan.

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Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–10, and Tables 1 and 2 (PDF 4995 kb)

Supplementary Video 1

Abnormal touch-evoked motility of atlastin (atl1) morphant larvae. Touch-response mobility of 72-hpf (a) control larvae. (MOV 882 kb)

Supplementary Video 1

Abnormal touch-evoked motility of atlastin (atl1) morphant larvae. Touch-response mobility of 72-hpf (b) atl1 morphant larvae. (MOV 3092 kb)

Supplementary Video 1

Abnormal touch-evoked motility of atlastin (atl1) morphant larvae. Touch-response mobility of 72-hpf (c) rescued larvae co-injected with atl1 MO and human ATL1 transcript. (MOV 1289 kb)

Supplementary Video 2

The motility deficit of atlastin (atl1) The motility deficit of atlastin (atl1) morphant larvae is tightly correlated with abnormal branching of spinal motor axons. Touch-response mobility of 4-dpf (a) control (Hb9:GFP; WT). (MOV 1226 kb)

Supplementary Video 2

The motility deficit of atlastin (atl1) The motility deficit of atlastin (atl1) morphant larvae is tightly correlated with abnormal branching of spinal motor axons. Touch-response mobility of 4-dpf (b) atl1 morphant Hb9:GFP; MOatl). (MOV 1607 kb)

Supplementary Video 2

The motility deficit of atlastin (atl1) The motility deficit of atlastin (atl1) morphant larvae is tightly correlated with abnormal branching of spinal motor axons. Touch-response mobility of 4-dpf (c) transplanted (Hb9:GFP; MOatl>WT) mosaic larvae. (MOV 1194 kb)

Supplementary Video 3

The swimming deficit of atlastin (atl1) morphants is rescued by genetic inhibition of BMP signaling. Touch-response mobility of 72-hpf (a) heatshocked and non-injected Tg(hs:DN-BMPRI) transgenic larvae. (MOV 1743 kb)

Supplementary Video 3

The swimming deficit of atlastin (atl1) morphants is rescued by genetic inhibition of BMP signaling. Touch-response mobility of 72-hpf (b) atl1 morphant Tg(hs:DN-BMPRI) larvae which were not submitted to heat shock. (MOV 1835 kb)

Supplementary Video 3

The swimming deficit of atlastin (atl1) morphants is rescued by genetic inhibition of BMP signaling. Touch-response mobility of 72-hpf (c) MOatl/Tg(hs:DN-BMPRI) that were heat-shocked at 32-36 hpf and therefore expressed a dominant-negative version of type-I BMP receptor. (MOV 1273 kb)

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Fassier, C., Hutt, J., Scholpp, S. et al. Zebrafish atlastin controls motility and spinal motor axon architecture via inhibition of the BMP pathway. Nat Neurosci 13, 1380–1387 (2010). https://doi.org/10.1038/nn.2662

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