Key Points
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The sophisticated circuitry of the neocortex is assembled from a diverse repertoire of neuronal subtypes generated during development under precise molecular regulation, forming distinct functional areas within the tangential expanse of the neocortex. This collection of specialized neurons is produced by various progenitors with distinct morphological and molecular properties and with distinct patterns of cell division.
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The lineages leading from progenitor cells to specific neuronal subtypes and the molecular mechanisms that determine the fixed order in which neuronal subtypes are generated remain largely unknown. Recent work suggests that some subtypes of neurons are produced by lineage-committed progenitors, although a number of models of lineage commitment can be entertained on the basis of current evidence.
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Area identity acquisition is initiated by diffusible factors released from the periphery of the neocortical domain and subsequent induction of graded expression of arealizing transcription factors in ventricular zone progenitors. These progenitor-based controls establish a coordinate system of positional information that anchors area identity to specific rostrocaudal and mediolateral positions, which must then be transmitted to their neuronal progeny to be interpreted by a second network of transcription factors that direct postmitotic acquisition of area identity.
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Projection neuron subtype identity is progressively established by extensive transcriptional cross-repression between genetic programmes driving the development of one subtype of projection neuron and those driving the development of alternative subtypes. These competing regulators sort newly postmitotic projection neurons into one of three broad subtype identities: corticothalamic, subcerebral and callosal.
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Postmitotic regulators, including Lmo4 (LIM domain only 4) and Bhlhb5 (basic helix–loop–helix domain-containing, class B5), transform continuous gradients of positional information inherited from progenitors into sharp areal boundaries, instruct the formation of sensory maps and direct projection neurons to acquire areally appropriate phenotypic characteristics.
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Over the course of evolution, a growing number of transcription factors were progressively recruited to control cortical development, gradually adding layers of neuronal diversity and areal specialization to a simpler ancestral framework.
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The emerging understanding of the expression and function of key molecular regulators is beginning to illuminate a molecular logic underlying subtype and area identity acquisition. We propose that the order- and dose-dependent nature of projection neuron identity specification can be formalized by analogy to first-order Boolean logic, with decision points represented by 'molecular logic gates'.
Abstract
The sophisticated circuitry of the neocortex is assembled from a diverse repertoire of neuronal subtypes generated during development under precise molecular regulation. In recent years, several key controls over the specification and differentiation of neocortical projection neurons have been identified. This work provides substantial insight into the 'molecular logic' underlying cortical development and increasingly supports a model in which individual progenitor-stage and postmitotic regulators are embedded within highly interconnected networks that gate sequential developmental decisions. Here, we provide an integrative account of the molecular controls that direct the progressive development and delineation of subtype and area identity of neocortical projection neurons.
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Acknowledgements
This work was supported by grants from the US National Institutes of Health (NIH) (NS045523 and NS075672, NS041590, and NS049553), the Harvard Stem Cell Institute and the Massachusetts Spinal Cord Research Program to J.D.M. M.B.W. was partially supported by US NIH individual predoctoral National Research Service Award NS064730 and the DEARS Foundation. L.C.G. was partially supported by the Harvard Medical Scientist Training Program and USNIH individual predoctoral National Research Service Award NS080343.
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Glossary
- Hodology
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The path followed by axons to reach their targets.
- Lineages
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The shared ancestries of cells that can be traced back to a common progenitor through sequential cell divisions.
- Neuroepithelial cells
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Neuroectodermal progenitors that are the main proliferative cell type of the early neocortex. They later differentiate into radial glial cells.
- Gyrencephalic
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Having a folded cerebral cortex, with gyri (ridges) and sulci (furrows).
- Competence
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The differentiation potential of a cell, as determined by its intrinsic molecular state.
- Fate-mapping
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Labelling a progenitor cell with a permanent and heritable mark to identify all of its progeny.
- FLP knock-in line
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A mouse line in which expression of FLP recombinase is driven by the promoter of a gene of interest.
- Morphogens
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Secreted factors that can induce at least two different cell fates in a concentration-dependent manner by forming a gradient.
- Fasciculation
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Bundling together of axons that project to a common final or intermediate target through adhesive interactions.
- Cajal–Retzius cells
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Early-born cortical neurons that express the glycoprotein reelin and reside in layer I.
- Enhancer element
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A short region of DNA, typically occupied by multiple transcription factors, which is sufficient to drive expression of a gene with temporal and/or cell-type specificity.
- Chromatin remodelling
-
Changes in the three-dimensional structure of chromatin brought about by epigenetic modifications. These structural changes can result in either transcriptional activation or silencing of genes located in the involved chromatin segment.
- Barrels
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Cylindrical columns of neurons in layer IV of the neocortex that receive and process sensory input from a single whisker. The topographical organization of the barrels in the cortex corresponds precisely to the arrangement of whisker follicles on the snout.
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Greig, L., Woodworth, M., Galazo, M. et al. Molecular logic of neocortical projection neuron specification, development and diversity. Nat Rev Neurosci 14, 755–769 (2013). https://doi.org/10.1038/nrn3586
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DOI: https://doi.org/10.1038/nrn3586
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