Development and degeneration of spinal motor neurons

Our research programme aims at deciphering the cellular and molecular mechanisms underlying the guidance of spinal motor axons towards their specific muscle targets during development of the zebrafish.

We address the embryonic wiring of the zebrafish motor system via functional analyses of proteins altered in human motor neurodegeneration, such as spastin and atlastin for hereditary spastic paraplegia (HSP). Our preliminary findings on these two HSP proteins have progressively focused our research interests into two main themes aiming at unravelling the role of (i) proteins involved in membrane trafficking, and particularly in BMP receptor trafficking, and (ii) regulators of microtubule dynamics in spinal motor axon outgrowth and navigation during zebrafish embryogenesis.

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Our research programme aims at deciphering the cellular and molecular mechanisms underlying the axon outgrowth and navigation of spinal motor neurons (SMN) towards their specific muscle targets during development of the zebrafish. We address the embryonic wiring of the zebrafish motor system via functional analyses of proteins altered in human motor neurodegeneration, such as spastin and atlastin for hereditary spastic paraplegia (HSP). HSP is a heterogeneous group of neurodegenerative disorders mainly characterised by progressive spasticity of the lower limbs. Among the numerous genes responsible for HSP, the spastin and atlastin genes turn out to be two major loci for these rare axonopathies.

We have shown that zebrafish Atlastin, but also Spastin main isoforms, differentially control the outgrowth and pathfinding of spinal motor axons, and thereby zebrafish larval motility. These preliminary findings on two HSP proteins incited us to study their binding-partners and highly related proteins, both structurally and functionally, like Fidgetin-like 1 and p60-Katanin for the microtubule-severing Spastin, in this axon targeting process.

Our research interests have thus progressively evolved into dissecting the role of proteins associated with two basic cellular processes, namely:

  • membrane trafficking, with a special emphasis on BMP receptor endosomal trafficking
  • microtubule dynamics in spinal motor axon outgrowth and navigation during zebrafish embryogenesis.

Highlights

Our functional analysis of Atlastin during development of the zebrafish revealed that this membrane-bound GTPase controls spinal motor axon pathfinding and thereby larval mobility by inhibiting the Bone Morphogenetic Protein (BMP) pathway.

Using loss- and gain-of-function experiments, we have also shown that spastin major isoforms differentially regulate zebrafish SMN axon outgrowth and guidance. A collaborative study with the group of Evan Reid (University of Cambridge, UK) established the long suspected role of spastin in endosomal trafficking, and have more precisely revealed its Ist1-associated involvement in endocytic degradation and trafficking.

Finally, our functional characterisation of different spastin-related ATPases allowed us to show that fidgetin-like 1, the closest homologue of spastin in the zebrafish proteome, plays a crucial role in SMN axon targeting via its regulation of microtubule dynamics.

Future directions

To achieve significant progress in the understanding of HSP pathogenic mechanisms, we undertook loss- and gain-of-function analyses of atlastin and spastin, two major proteins involved in HSP, during development of the zebrafish. Our functional analysis revealed that atlastin controls SMN axon outgrowth and zebrafish larval mobility by inhibiting BMP signalling, possibly via the regulation of BMP receptor trafficking. Our projects will thus partly consist in:

  • dissecting the cellular mechanisms by which Atlastin down-regulates BMP signalling
  • characterising the downstream targets and molecular mechanisms underlying the control of SMN axon targeting by the BMP pathway.
  • Moreover, we will also explore whether other HSP proteins, and particularly the atlastin-binding partner spastin, also feed into the BMP pathway. Furthermore, our ongoing analysis of spastin function in microtubule dynamics prompted us to undertake a functional characterisation of other structurally related ATPases, including p60-katanin and fidgetin-like 1, during zebrafish embryogenesis to unravel the potential links between the different members of this particular sub-group of ATPasesand their common involvement in spinal motor axon outgrowth.
  • The last part of our research programme will thus focus on the implication of microtubule-associated proteins in growth cone cytoskeleton remodelling and axon guidance decisions.

Collaborations

  • Fatiha Nothias, Neuroscience Paris Seine/IBPS, UPMC, Paris
  • Catalina Betancur, Neuroscience Paris Seine/IBPS, UPMC, Paris
  • Salah El Mestikawy, Neuroscience Paris Seine/IBPS, UPMC, Paris
  • Sylvie Schneider-Maunoury, Biologie du Développement/IBPS, UPMC, Paris
  • Giovanni Stevanin, CRICM, Hôpital de la Salpêtrière/UPMC, Paris
  • Corinne Houart, MRC Developmental Neurobiology, King’s College London, UK
  • Evan Reid, CIMR, University of Cambridge, UK

Publications

1. Fassier C, Hutt JA, Scholpp S, Lumsden A, Giros B, Nothias F, Schneider-Maunoury S, Houart C & Hazan J. Zebrafish atlastin controls motility and spinal motor axon architecture via inhibition of the BMP pathway. Nat Neurosci. 2010,13:1380-7.

2. Allison R, Lumb JH, Fassier C, Connell JW, Ten Martin D, Seaman MN, Hazan J & Reid E. An ESCRT-spastin interaction promotes fission of recycling tubules from the endosome. J Cell Biol. 2013, 202:527-43.