Endocannabinoids modulate cortical development by configuring Slit2/Robo1 signalling

Alán Alpár; Giuseppe Tortoriello; Daniela Calvigioni; Micah J Niphakis; Ivan Milenkovic; Joanne Bakker; Gary A Cameron; János Hanics; Claudia V Morris; János Fuzik; Gabor G Kovacs; Benjamin F Cravatt; John G Parnavelas; William D Andrews; Yasmin L Hurd; Erik Keimpema; Tibor Harkany

doi:10.1038/ncomms5421

Endocannabinoids modulate cortical development by configuring Slit2/Robo1 signalling

Alán Alpár, Giuseppe Tortoriello, Daniela Calvigioni, Micah J Niphakis, Ivan Milenkovic, Joanne Bakker, Gary A Cameron, János Hanics, Claudia V Morris, János Fuzik, Gabor G Kovacs, Benjamin F Cravatt, John G Parnavelas, William D Andrews, Yasmin L Hurd, Erik Keimpema, Tibor Harkany

Research output: Contribution to journal › Article › peer-review

64 Citations (Scopus)

Abstract

Local environmental cues are indispensable for axonal growth and guidance during brain circuit formation. Here, we combine genetic and pharmacological tools, as well as systems neuroanatomy in human fetuses and mouse models, to study the role of endocannabinoid and Slit/Robo signalling in axonal growth. We show that excess 2-arachidonoylglycerol, an endocannabinoid affecting directional axonal growth, triggers corpus callosum enlargement due to the errant CB1 cannabinoid receptor-containing corticofugal axon spreading. This phenotype mechanistically relies on the premature differentiation and end-feet proliferation of CB2R-expressing oligodendrocytes. We further show the dependence of both axonal Robo1 positioning and oligodendroglial Slit2 production on cell-type-specific cannabinoid receptor activation. Accordingly, Robo1 and/or Slit2 manipulation limits endocannabinoid modulation of axon guidance. We conclude that endocannabinoids can configure focal Slit2/Robo1 signalling to modulate directional axonal growth, which may provide a basis for understanding impaired brain wiring associated with metabolic deficits and prenatal drug exposure.

Original language	English
Article number	4421
Pages (from-to)	1-13
Number of pages	13
Journal	Nature Communications
Volume	5
DOIs	https://doi.org/10.1038/ncomms5421
Publication status	Published - 17 Jul 2014

Bibliographical note

This work was supported by the Swedish Medical Research Council (T.H.), Swedish Brain Research Foundation (‘Hjärnfonden’; T.H.), Novo Nordisk Foundation (T.H.), Petrus & Augusta Hedlunds’ Foundation (T.H.), EU-FP7 project DEVELAGE (N278486, G.G.K.), National Brain Research Program of the Hungarian Academy of Sciences (A.A.), National Institutes of Health (DA023214, T.H. and Y.L.H.; DA030359, Y.L.H; F31-DA031559, C.V.M.) and the Wellcome Trust (#089775, J.G.P. and W.D.A.). The content of this report is solely the responsibility of the authors and does not necessarily represent the official views of the US National Institutes of Health. We thank M. Watanabe, K. Mackie and F. Murakami for antibodies, Y.A. Barde for taugfp/+ mice, K. Mackie for MGL−/− tissues, F. Molina-Holgado for the oligodendrocyte isolation protocol, O.K. Penz for technical assistance, M. Tessier-Lavigne, L. Erskine, R.A. Ross and members of the Harkany laboratory for discussions and feedback and the National Institute of Mental Health for the transfer of CB1R−/− colony founders. Laser-scanning microscopy was performed at the Click Imaging Core Facility of the Karolinska Institutet

Keywords

Cell signalling
Development of the nervous system
Neuronal physiology
Receptor, Cannabinoid, CB1
Endocannabinoids

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Alpár, A., Tortoriello, G., Calvigioni, D., Niphakis, M. J., Milenkovic, I., Bakker, J., Cameron, G. A., Hanics, J., Morris, C. V., Fuzik, J., Kovacs, G. G., Cravatt, B. F., Parnavelas, J. G., Andrews, W. D., Hurd, Y. L., Keimpema, E., & Harkany, T. (2014). Endocannabinoids modulate cortical development by configuring Slit2/Robo1 signalling. Nature Communications, 5, 1-13. Article 4421. https://doi.org/10.1038/ncomms5421

Alpár, A, Tortoriello, G, Calvigioni, D, Niphakis, MJ, Milenkovic, I, Bakker, J, Cameron, GA, Hanics, J, Morris, CV, Fuzik, J, Kovacs, GG, Cravatt, BF, Parnavelas, JG, Andrews, WD, Hurd, YL, Keimpema, E & Harkany, T 2014, 'Endocannabinoids modulate cortical development by configuring Slit2/Robo1 signalling', Nature Communications, vol. 5, 4421, pp. 1-13. https://doi.org/10.1038/ncomms5421

@article{25a16d4f5f5444dea4dd6e11ff40e694,

title = "Endocannabinoids modulate cortical development by configuring Slit2/Robo1 signalling",

abstract = "Local environmental cues are indispensable for axonal growth and guidance during brain circuit formation. Here, we combine genetic and pharmacological tools, as well as systems neuroanatomy in human fetuses and mouse models, to study the role of endocannabinoid and Slit/Robo signalling in axonal growth. We show that excess 2-arachidonoylglycerol, an endocannabinoid affecting directional axonal growth, triggers corpus callosum enlargement due to the errant CB1 cannabinoid receptor-containing corticofugal axon spreading. This phenotype mechanistically relies on the premature differentiation and end-feet proliferation of CB2R-expressing oligodendrocytes. We further show the dependence of both axonal Robo1 positioning and oligodendroglial Slit2 production on cell-type-specific cannabinoid receptor activation. Accordingly, Robo1 and/or Slit2 manipulation limits endocannabinoid modulation of axon guidance. We conclude that endocannabinoids can configure focal Slit2/Robo1 signalling to modulate directional axonal growth, which may provide a basis for understanding impaired brain wiring associated with metabolic deficits and prenatal drug exposure.",

keywords = "Cell signalling, Development of the nervous system, Neuronal physiology, Receptor, Cannabinoid, CB1, Endocannabinoids",

author = "Al{\'a}n Alp{\'a}r and Giuseppe Tortoriello and Daniela Calvigioni and Niphakis, {Micah J} and Ivan Milenkovic and Joanne Bakker and Cameron, {Gary A} and J{\'a}nos Hanics and Morris, {Claudia V} and J{\'a}nos Fuzik and Kovacs, {Gabor G} and Cravatt, {Benjamin F} and Parnavelas, {John G} and Andrews, {William D} and Hurd, {Yasmin L} and Erik Keimpema and Tibor Harkany",

note = "This work was supported by the Swedish Medical Research Council (T.H.), Swedish Brain Research Foundation ({\textquoteleft}Hj{\"a}rnfonden{\textquoteright}; T.H.), Novo Nordisk Foundation (T.H.), Petrus & Augusta Hedlunds{\textquoteright} Foundation (T.H.), EU-FP7 project DEVELAGE (N278486, G.G.K.), National Brain Research Program of the Hungarian Academy of Sciences (A.A.), National Institutes of Health (DA023214, T.H. and Y.L.H.; DA030359, Y.L.H; F31-DA031559, C.V.M.) and the Wellcome Trust (#089775, J.G.P. and W.D.A.). The content of this report is solely the responsibility of the authors and does not necessarily represent the official views of the US National Institutes of Health. We thank M. Watanabe, K. Mackie and F. Murakami for antibodies, Y.A. Barde for taugfp/+ mice, K. Mackie for MGL−/− tissues, F. Molina-Holgado for the oligodendrocyte isolation protocol, O.K. Penz for technical assistance, M. Tessier-Lavigne, L. Erskine, R.A. Ross and members of the Harkany laboratory for discussions and feedback and the National Institute of Mental Health for the transfer of CB1R−/− colony founders. Laser-scanning microscopy was performed at the Click Imaging Core Facility of the Karolinska Institutet",

year = "2014",

month = jul,

day = "17",

doi = "10.1038/ncomms5421",

language = "English",

volume = "5",

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journal = "Nature Communications",

issn = "2041-1723",

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TY - JOUR

T1 - Endocannabinoids modulate cortical development by configuring Slit2/Robo1 signalling

AU - Alpár, Alán

AU - Tortoriello, Giuseppe

AU - Calvigioni, Daniela

AU - Niphakis, Micah J

AU - Milenkovic, Ivan

AU - Bakker, Joanne

AU - Cameron, Gary A

AU - Hanics, János

AU - Morris, Claudia V

AU - Fuzik, János

AU - Kovacs, Gabor G

AU - Cravatt, Benjamin F

AU - Parnavelas, John G

AU - Andrews, William D

AU - Hurd, Yasmin L

AU - Keimpema, Erik

AU - Harkany, Tibor

N1 - This work was supported by the Swedish Medical Research Council (T.H.), Swedish Brain Research Foundation (‘Hjärnfonden’; T.H.), Novo Nordisk Foundation (T.H.), Petrus & Augusta Hedlunds’ Foundation (T.H.), EU-FP7 project DEVELAGE (N278486, G.G.K.), National Brain Research Program of the Hungarian Academy of Sciences (A.A.), National Institutes of Health (DA023214, T.H. and Y.L.H.; DA030359, Y.L.H; F31-DA031559, C.V.M.) and the Wellcome Trust (#089775, J.G.P. and W.D.A.). The content of this report is solely the responsibility of the authors and does not necessarily represent the official views of the US National Institutes of Health. We thank M. Watanabe, K. Mackie and F. Murakami for antibodies, Y.A. Barde for taugfp/+ mice, K. Mackie for MGL−/− tissues, F. Molina-Holgado for the oligodendrocyte isolation protocol, O.K. Penz for technical assistance, M. Tessier-Lavigne, L. Erskine, R.A. Ross and members of the Harkany laboratory for discussions and feedback and the National Institute of Mental Health for the transfer of CB1R−/− colony founders. Laser-scanning microscopy was performed at the Click Imaging Core Facility of the Karolinska Institutet

PY - 2014/7/17

Y1 - 2014/7/17

N2 - Local environmental cues are indispensable for axonal growth and guidance during brain circuit formation. Here, we combine genetic and pharmacological tools, as well as systems neuroanatomy in human fetuses and mouse models, to study the role of endocannabinoid and Slit/Robo signalling in axonal growth. We show that excess 2-arachidonoylglycerol, an endocannabinoid affecting directional axonal growth, triggers corpus callosum enlargement due to the errant CB1 cannabinoid receptor-containing corticofugal axon spreading. This phenotype mechanistically relies on the premature differentiation and end-feet proliferation of CB2R-expressing oligodendrocytes. We further show the dependence of both axonal Robo1 positioning and oligodendroglial Slit2 production on cell-type-specific cannabinoid receptor activation. Accordingly, Robo1 and/or Slit2 manipulation limits endocannabinoid modulation of axon guidance. We conclude that endocannabinoids can configure focal Slit2/Robo1 signalling to modulate directional axonal growth, which may provide a basis for understanding impaired brain wiring associated with metabolic deficits and prenatal drug exposure.

AB - Local environmental cues are indispensable for axonal growth and guidance during brain circuit formation. Here, we combine genetic and pharmacological tools, as well as systems neuroanatomy in human fetuses and mouse models, to study the role of endocannabinoid and Slit/Robo signalling in axonal growth. We show that excess 2-arachidonoylglycerol, an endocannabinoid affecting directional axonal growth, triggers corpus callosum enlargement due to the errant CB1 cannabinoid receptor-containing corticofugal axon spreading. This phenotype mechanistically relies on the premature differentiation and end-feet proliferation of CB2R-expressing oligodendrocytes. We further show the dependence of both axonal Robo1 positioning and oligodendroglial Slit2 production on cell-type-specific cannabinoid receptor activation. Accordingly, Robo1 and/or Slit2 manipulation limits endocannabinoid modulation of axon guidance. We conclude that endocannabinoids can configure focal Slit2/Robo1 signalling to modulate directional axonal growth, which may provide a basis for understanding impaired brain wiring associated with metabolic deficits and prenatal drug exposure.

KW - Cell signalling

KW - Development of the nervous system

KW - Neuronal physiology

KW - Receptor, Cannabinoid, CB1

KW - Endocannabinoids

U2 - 10.1038/ncomms5421

DO - 10.1038/ncomms5421

M3 - Article

C2 - 25030704

SN - 2041-1723

VL - 5

SP - 1

EP - 13

JO - Nature Communications

JF - Nature Communications

M1 - 4421

ER -

Endocannabinoids modulate cortical development by configuring Slit2/Robo1 signalling

Abstract

Bibliographical note

Keywords

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