Transient Cell-intrinsic Activity Regulates the Migration and Laminar Positioning of Cortical Projection Neurons.
Neocortical microcircuits are built during development and require the coordinated assembly of excitatory glutamatergic projection neurons (PNs) into functional networks. Neuronal migration is an essential step in this process. In addition to cell-intrinsic mechanisms, external cues including neurotransmitters regulate cortical neuron migration, suggesting that early activity could influence this process. Here, we aimed to investigate the role of cell-intrinsic activity in migrating PNs in vivo using a designer receptor exclusively activated by a designer drug (DREADD) chemogenetic approach. In utero electroporation was used to specifically express the human M3 muscarinic cholinergic Gq-coupled receptor (hM3Dq) in PNs and calcium activity, migratory dynamics, gene expression, and laminar positioning of PNs were assessed following embryonic DREADD activation. We found that transient embryonic DREADD activation induced premature branching and transcriptional changes in migrating PNs leading to a persistent laminar mispositioning of superficial layer PNs into deep cortical layers without affecting expression of layer-specific molecular identity markers. In addition, live imaging approaches indicated that embryonic DREADD activation increased calcium transients in migrating PNs and altered their migratory dynamics by increasing their pausing time. Taken together, these results support the idea that increased cell-intrinsic activity during migration acts as a stop signal for migrating cortical PNs.
Department of Psychiatry, University of Geneva Medical School, CH-1211 Geneva 4, Switzerland.|Department of Basic Neurosciences, University of Geneva Medical School, CH-1211 Geneva 4, Switzerland.
Nicolas
N
Hurni
Department of Psychiatry, University of Geneva Medical School, CH-1211 Geneva 4, Switzerland.|Department of Basic Neurosciences, University of Geneva Medical School, CH-1211 Geneva 4, Switzerland.
Marta
M
Kolodziejczak
Department of Psychiatry, University of Geneva Medical School, CH-1211 Geneva 4, Switzerland.|Department of Basic Neurosciences, University of Geneva Medical School, CH-1211 Geneva 4, Switzerland.
Ugo
U
Tomasello
Department of Psychiatry, University of Geneva Medical School, CH-1211 Geneva 4, Switzerland.|Department of Basic Neurosciences, University of Geneva Medical School, CH-1211 Geneva 4, Switzerland.
Joan
J
Badia
Department of Psychiatry, University of Geneva Medical School, CH-1211 Geneva 4, Switzerland.|Department of Basic Neurosciences, University of Geneva Medical School, CH-1211 Geneva 4, Switzerland.
Moritz
M
Jacobshagen
Department of Psychiatry, University of Geneva Medical School, CH-1211 Geneva 4, Switzerland.|Department of Basic Neurosciences, University of Geneva Medical School, CH-1211 Geneva 4, Switzerland.
Julien
J
Prados
Department of Psychiatry, University of Geneva Medical School, CH-1211 Geneva 4, Switzerland.|Department of Basic Neurosciences, University of Geneva Medical School, CH-1211 Geneva 4, Switzerland.
Alexandre
A
Dayer
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D019521:Body Patterning; D002118:Calcium / Q000378:metabolism; D002465:Cell Movement / Q000235:genetics / Q000502:physiology*; D002540:Cerebral Cortex / Q000166:cytology* / Q000378:metabolism; D003024:Clozapine / Q000031:analogs & derivatives / Q000494:pharmacology; D018274:Electroporation; D004622:Embryo, Mammalian; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism; D066298:In Vitro Techniques; D051379:Mice; D009415:Nerve Net / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000145:classification / Q000166:cytology / Q000502:physiology*; D009687:Nuclear Proteins / Q000378:metabolism; D050809:POU Domain Factors / Q000378:metabolism; D011247:Pregnancy; D000072260:RNA Splicing Factors / Q000235:genetics / Q000378:metabolism; D043587:Receptor, Muscarinic M3 / Q000235:genetics / Q000378:metabolism; D017470:Receptors, Glutamate / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction; D020825:T-Box Domain Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
C000624101:Cux1 protein, mouse; C491198:Eomes protein, mouse; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D050809:POU Domain Factors; C408605:PRPF6 protein, human; D000072260:RNA Splicing Factors; D043587:Receptor, Muscarinic M3; D017470:Receptors, Glutamate; D012097:Repressor Proteins; D020825:T-Box Domain Proteins; D014157:Transcription Factors; C074066:Pou3f2 protein, mouse; D049452:Green Fluorescent Proteins; D003024:Clozapine; C079149:clozapine N-oxide; D002118:Calcium
cortex; early activity; migration; projection neurons