Progenitor Hyperpolarization Regulates the Sequential Generation of Neuronal Subtypes in the Developing Neocortex

• Published in: Cell Vol. 174; no. 5; pp. 1264 - 1276.e15
• Main Authors: Vitali, Ilaria, Fièvre, Sabine, Telley, Ludovic, Oberst, Polina, Bariselli, Sebastiano, Frangeul, Laura, Baumann, Natalia, McMahon, John J., Klingler, Esther, Bocchi, Riccardo, Kiss, Jozsef Z., Bellone, Camilla, Silver, Debra L., Jabaudon, Denis
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 23.08.2018
• Subjects: Animals; beta Catenin - metabolism; Brain - cytology; Brain - embryology; Cell Differentiation; cortical development; Disease Progression; Electroporation; Female; Gene Expression Regulation, Developmental; Male; membrane potential; Membrane Potentials; Mice; Neocortex - cytology; Neocortex - embryology; Nerve Tissue Proteins - metabolism; Neural Stem Cells - cytology; Neurogenesis; neuronal diversity; Neurons - metabolism; Potassium Channels, Inwardly Rectifying - metabolism; progenitors; Sequence Analysis, RNA; Signal Transduction; Stem Cells - cytology; Time Factors; Wnt Proteins - metabolism; neuronal diversity; progenitors; cortical development; membrane potential
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2018.06.036

During corticogenesis, ventricular zone progenitors sequentially generate distinct subtypes of neurons, accounting for the diversity of neocortical cells and the circuits they form. While activity-dependent processes are critical for the differentiation and circuit assembly of postmitotic neurons, how bioelectrical processes affect nonexcitable cells, such as progenitors, remains largely unknown. Here, we reveal that, in the developing mouse neocortex, ventricular zone progenitors become more hyperpolarized as they generate successive subtypes of neurons. Experimental in vivo hyperpolarization shifted the transcriptional programs and division modes of these progenitors to a later developmental status, with precocious generation of intermediate progenitors and a forward shift in the laminar, molecular, morphological, and circuit features of their neuronal progeny. These effects occurred through inhibition of the Wnt-beta-catenin signaling pathway by hyperpolarization. Thus, during corticogenesis, bioelectric membrane properties are permissive for specific molecular pathways to coordinate the temporal progression of progenitor developmental programs and thus neocortical neuron diversity. [Display omitted] •Apical progenitor (AP) resting membrane potential decreases during corticogenesis•AP hyperpolarization allows progression from direct to indirect neurogenesis•AP hyperpolarization drives neuronal diversity via repression of Wnt signaling Progressive changes in the membrane potential of neural progenitors during corticogenesis coordinate the successive generation of distinct neuronal subtypes.