Abstract
The migration of cortical interneurons is a fundamental process for the establishment of cortical connectivity and its impairment underlies several neurological disorders. During development, these neurons are born in the ganglionic eminences and they migrate tangentially to populate the cortical layers. This process relies on various morphological changes that are driven by dynamic cytoskeleton remodelings. By coupling time lapse imaging with molecular analyses, we show that the Elongator complex controls cortical interneuron migration in mouse embryos by regulating nucleokinesis and branching dynamics. At the molecular level, Elongator fine-tunes actomyosin forces by regulating the distribution and turnover of actin microfilaments during cell migration. Thus, we demonstrate that Elongator cell-autonomously promotes cortical interneuron migration by controlling actin cytoskeletal dynamics.
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Acknowledgements
We thank Dr Kenneth Campbell for providing the Dlx5, 6:Cre-GFP transgenic mouse line. We thank Drs Creppe and Gladwyn-Ng for critical reading of the manuscript. ST is a PhD fellow supported by the Belgian Fonds pour la Formation à la Recherche dans l'Industrie et dans l'Agriculture (FRIA). JDG is a postdoctoral researcher from the FRS- FNRS; LN is a Research Associate from FRS-FNRS; AC and BM are Research Directors of the FRS-FNRS. JDG has been granted Marie Curie and EMBO LT fellowships. LN is funded by FRS-FNRS, the Fonds Léon Fredericq, the Fondation Médicale Reine Elisabeth, the Fondation Simone et Pierre Clerdent and the Belgian Science Policy (IAP-VII network P7/20). LN and AC are funded by ARC (ARC11/16-01) and partly funded by WELBIO.
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Supplementary information
Supplementary information, Figure S1
Conditional deletion of Elp3 in cortical interneurons (PDF 1767 kb)
Supplementary information, Figure S2
Conditional deletion of Elp3 impairs tubulin polymerisation but not Filamin A expression (PDF 488 kb)
Supplementary information, Figure S3
Acute knockdown of Elp3 in N2A cells migration and actin dynamics (PDF 216 kb)
Supplementary information, Figure S4
Assessment of the molecular pathway acting downstream Elongator in cortical interneurons (PDF 233 kb)
Supplementary information, Data S1
Material and Methods (PDF 122 kb)
Supplementary information, Movie S1
Time lapse images of GPF+ interneurons from Elp3WT E12.5 organotypic slices recorded in dorso-lateral regions of the cortex. Recordings were acquired every 5 minutes and during 5 hours. Movie is shown in 7 frames per second (fps). (AVI 1649 kb)
Supplementary information, Movie S2
Time lapse images of GPF+ interneurons from Elp3cKO E12.5 organotypic slices recorded in dorso-lateral regions of the cortex. Recordings were acquired every 5 minutes and during 5 hours. Movie is shown in 7 frames per second (fps). (AVI 1767 kb)
Supplementary information, Movie S3
Time lapse recording of an Elp3WT LifeAct expressing migrating interneuron of ex vivo electroporated MGE. Images were acquired every 20 sec for 3 to 4 hours with resonant scanning and xyzt acquisition modes. Movie is shown in 7 frames per second (fps). (AVI 280 kb)
Supplementary information, Movie S4
Time lapse recording of an Elp3cKO LifeAct expressing migrating interneuron of ex vivo electroporated MGE. Images were acquired every 20 sec for 3 to 4 hours with resonant scanning and xyzt acquisition modes. Movie is shown in 7 frames per second (fps). (AVI 94 kb)
Supplementary information, Movie S5
shows an Elp3WT interneuron electroporated with a siSCR and treated with DMSO. The film shows LifeAct intensities during tangential migration, with a typical local intensity in the nuclear rear during nucleokinesis. Explants were cultured 24hours before recordings and treated 5 hours before and during the time lapse. Recordings were taken every 20 seconds during 3-4 hours with resonant scanning and xyzt acquisition modes. Movie is shown in 7 frames per second (fps). (MOV 79 kb)
Supplementary information, Movie S6
shows an Elp3cKO interneuron electroporated with a siSCR and treated with DMSO. The film shows LifeAct intensities during tangential migration, with typical cup-like shape intensity during nucleokinesis. Explants were cultured 24hours before recordings and treated 5 hours before and during the time lapse. Recordings were taken every 20 seconds during 3-4 hours with resonant scanning and xyzt acquisition modes. Movie is shown in 7 frames per second (fps). The little LifAct bright spot corresponds to interfering vesicular Life-Act that is not involved in contraction. (MOV 56 kb)
Supplementary information, Movie S7
shows an Elp3cKO interneuron electroporated with a siSSH2 and treated with DMSO. The film shows LifeAct intensities during tangential migration, with both some cup- like shape events but, most are nuclear rear events during nucleokinesis. Explants were cultured 24hours before recordings and treated 5 hours before and during the time lapse. Recordings were taken every 20 seconds during 3-4 hours with resonant scanning and xyzt acquisition modes. Movie is shown in 7 frames per second (fps). (MOV 26 kb)
Supplementary information, Movie S8
shows an Elp3cKO interneuron electroporated with a siSSH2 and treated with ML7. The film shows LifeAct intensities during tangential migration, with a cup-like shape event and nuclear rear events during nucleokinesis. Explants were cultured 24hours before recordings and treated 5 hours before and during the time lapse. Recordings were taken every 20 seconds during 3-4 hours with resonant scanning and xyzt acquisition modes. Movie is shown in 7 frames per second (fps). (MOV 65 kb)
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Tielens, S., Huysseune, S., Godin, J. et al. Elongator controls cortical interneuron migration by regulating actomyosin dynamics. Cell Res 26, 1131–1148 (2016). https://doi.org/10.1038/cr.2016.112
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DOI: https://doi.org/10.1038/cr.2016.112
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