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Elmo1 function, linked to Rac1 activity, regulates peripheral neuronal numbers and myelination in zebrafish

Abstract

Peripheral nervous system development involves a tight coordination of neuronal birth and death and a substantial remodelling of the myelinating glia cytoskeleton to achieve myelin wrapping of its projecting axons. However, how these processes are coordinated through time is still not understood. We have identified engulfment and cell motility 1, Elmo1, as a novel component that regulates (i) neuronal numbers within the Posterior Lateral Line ganglion and (ii) radial sorting of axons by Schwann cells (SC) and myelination in the PLL system in zebrafish. Our results show that neuronal and myelination defects observed in elmo1 mutant are rescued through small GTPase Rac1 activation. Inhibiting macrophage development leads to a decrease in neuronal numbers, while peripheral myelination is intact. However, elmo1 mutants do not show defective macrophage activity, suggesting a role for Elmo1 in PLLg neuronal development and SC myelination independent of macrophages. Forcing early Elmo1 and Rac1 expression specifically within SCs rescues elmo1−/− myelination defects, highlighting an autonomous role for Elmo1 and Rac1 in radial sorting of axons by SCs and myelination. This uncovers a previously unknown function of Elmo1 that regulates fundamental aspects of PNS development.

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Acknowledgements

We would like to thank Philippe Herbomel, Francesca Peri, Nicolas David, David Lyons, Graham Lieschke, Robert Kelsh and Thomas Look for providing materials, Jon Clarke for his critical reading of the manuscript, Philippe Leclerc and Olivier Trassard for technical assistance in confocal microscopy and imaging, Alain Schmitt for assistance in Transmission Electron Microscopy, Pierre-Henri Commere for help in FACS sorting at Institut Pasteur.

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Figure S1. Elmo1 maternal contribution. (A, left panel) RT-PCR showing an early elmo1 expression (normalized to elfa) at 3 and 6 hpf in WT embryos and the net loss of this expression in MZelmo1 embryos of the same developmental stages. (A, right panel) RT-PCR showing maternal elmo1 mRNA expression in elmo1−/− mutants at 24 hpf (RNA was extracted from heads and trunks of 24 hpf embryos and tails were used for genotyping). TEM of cross sections of sib (B,B’), elmo1−/− (C,C’), and MZelmo1 (D-D’’) embryos at 7 dpf. Blue asterisks highlight some large caliber myelinated axons. Scale bars = 0.5 μm in B,C,D and 0.2 μm in B’,C’,D’ and D’’ (presenting a large caliber non-myelinated axon). (E), Quantification of the number of neurons in the PLLg between sib, elmo1−/− and MZelmo1 embryos at 7 dpf (average of 65 ± 2.19 neurons per PLLg in sib, n = 23, and 65.17 ± 4.8 in elmo1−/−, n = 6; average of 49.88 ± 1.6 neurons in MZelmo1, n = 16). (F), Quantification of the number of myelinated axons per nerve in sib, elmo1−/− and MZelmo1 embryos at 7 dpf. (average of 12.6 ± 0.4 myelinated axon per nerve for sib, n = 7 nerves from 4 different embryos; average of 13 ± 0.7 myelinated axon per nerve for elmo1−/−, n = 7 nerves from 4 different embryos; average of 8.5 ± 0.8 myelinated axon per nerve in MZelmo1, n = 7 nerves from 4 different embryos). –RT for negative control; ns, non significant. 1 (TIFF 2659 kb)

Figure S2. Elmo1 is expressed in the PLLg. (A-C) Whole mount in situ hybridisation showing elmo1 mRNA expression in PLLg (arrows) at 24, 48 and 72 hpf. Scale bar = 200 μm. (D), HuC immunostaining labelling the PLLg differentiated neurons at 48 hpf. (E), Elmo1 immunostaining showing its expression in the cytoplasm. (F) Merge of (D) and (E). Scale bar = 5 μm. 2 (TIFF 1579 kb)

Figure S3. Rescue of elmo1 and rac1 morphants by mRNA injection. Graph showing the number of neurons within the PLLg in controls, rac1 morphants injected with constitutive active form of rac1 and elmo1 morphants injected with elmo1 mRNA at 48 hpf. Average of 52.86 ± 1.2 in controls, n = 8; rac1MO + carac1 mRNA, average of 52.8 ± 1.05, n = 15; elmo1MOs + elmo1mRNA, average of 52.74 ± 1.21, n = 11; ns, non significant. 3 (TIFF 50 kb)

Movie S1. Real-time imaging of mitochondria in an elmo1−/− PLLn at 48 hpf. Forty-eight hours elmo1−/− embryo expressing GFP in mitochondria after mito::GFP mRNA injection; the embryo was imaged every 120 ms for several minutes by confocal microscopy. Lateral view; anterior to the left and dorsal to the top. n > 200 mitochondria from 6 different embryos. 4 (MP4 608 kb)

Movie S2. Real-time imaging of mitochondria in a WT PLLn at 48 hpf. Forty-eight hours WT embryo expressing GFP in mitochondria after mito::GFP mRNA injection; the embryo was imaged every 120 ms for several minutes by confocal microscopy. Lateral view; anterior to the left and dorsal to the top. n > 400 mitochondria from 12 different embryos. 5 (MP4 532 kb)

Movie S3. Real-time imaging of macrophages in an MZelmo1 PLLg at 48 hpf. Fourty-eight hours MZelmo1 embryo expressing GFP in macrophages after mpeg:gfp and pu1:gfp injection; the embryo was imaged every 2 min for 3 h by confocal microscopy. Lateral view; anterior to the left and dorsal to the top. White dashes show the PLLg and yellow ones the ear anterior to it. Arrows point to cytoplasmic remodeling observed in macrophages. n = 6 macrophages from 3 different embryos. 6 (MP4 177 kb)

Movie S4. Real-time imaging of macrophages in a WT PLLg at 48 hpf. Fourty-eight hours WT embryo expressing GFP in macrophages after mpeg:gfp and pu1:gfp injection; the embryo was imaged every 2 min for 3 h by confocal microscopy. Lateral view; anterior to the left and dorsal to the top. White dashes show the PLLg and yellow ones the ear anterior to it. Arrows point to cytoplasmic remodelling observed in macrophages. n = 7 macrophages from 4 different embryos. 7 (MP4 138 kb)

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Mikdache, A., Fontenas, L., Albadri, S. et al. Elmo1 function, linked to Rac1 activity, regulates peripheral neuronal numbers and myelination in zebrafish. Cell. Mol. Life Sci. 77, 161–177 (2020). https://doi.org/10.1007/s00018-019-03167-5

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Keywords

  • Elmo1
  • Zebrafish
  • PLLg
  • Schwann cells
  • Myelin
  • Rac1
  • Apoptosis
  • PLLn
  • Dock1