Endocannabinoid signalling in stem cells and cerebral organoids drives differentiation to deep layer projection neurons via CB1 receptors

  1. Paraiso-Luna, Juan 1
  2. Aguareles, Jose 1
  3. Martin, Ricardo 2
  4. Ayo-Martin, Ane C. 3
  5. Garcia-Rincon, Daniel 1
  6. Simon-Sanchez, Samuel 1
  7. De Salas-Quiroga, Adan 1
  8. Diaz-Alonso, Javier 1
  9. Garcia-Taboada, Elena 1
  10. Liste, Isabel 4
  11. Sanchez-Prieto, Jose 2
  12. Cappello, Silvia 3
  13. Guzman, Manuel 1
  14. Galve-Roperh, Ismael 1
  15. Costas-Insua, Carlos 1
  1. 1 Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas
    info

    Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas

    Madrid, España

    ROR https://ror.org/00zca7903

  2. 2 Universidad Complutense de Madrid
    info

    Universidad Complutense de Madrid

    Madrid, España

    ROR 02p0gd045

  3. 3 Max Planck Institute of Psychiatry
    info

    Max Planck Institute of Psychiatry

    Múnich, Alemania

    ROR https://ror.org/04dq56617

  4. 4 Instituto de Salud Carlos III
    info

    Instituto de Salud Carlos III

    Madrid, España

    ROR https://ror.org/00ca2c886

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Editor: Dryad

Ano de publicación: 2020

Tipo: Dataset

CC0 1.0

DOI: 10.5061/DRYAD.H9W0VT4G9 lock_openAcceso aberto editor

Resumo

The endocannabinoid (eCB) system, via cannabinoid CB1 receptor, regulates neurodevelopment by controlling neural progenitor proliferation and neurogenesis. CB1 receptor signalling in vivo drives corticofugal deep layer projection neuron development through the regulation of BCL11B and Satb2 transcription factors. Here, we investigated the role of eCB signalling in mouse pluripotent embryonic stem cell-derived neuronal differentiation. Characterization of the eCB system revealed increased expression of eCB-metabolizing enzymes, eCB ligands and CB1 receptors along neuronal differentiation. CB1 receptor knockdown inhibited neuronal differentiation of deep layer neurons and increased upper layer neuron generation, and this phenotype was rescued by CB1 re-expression. Pharmacological regulation with CB1 receptor agonists or elevation of eCB tone with a monoacylglycerol lipase inhibitor promoted neuronal differentiation of deep layer neurons at the expense of upper layer neurons. Patch-clamp analyses revealed that enhancing cannabinoid signalling facilitated neuronal differentiation and functionality. Noteworthy, incubation with CB1 receptor agonists during human iPSC-derived cerebral organoid formation also promoted the expansion of BCL11B+ neurons. These findings unveil a cell-autonomous role of eCB signalling that, via CB1 receptor, promotes mouse and human deep layer cortical neuron development.