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  • Review Article
  • Published:

Neuronal subtype specification in the cerebral cortex

Nature Reviews Neuroscience volume 8, pages 427–437 (2007)Cite this article

Key Points

  • The mammalian neocortex is an extremely complex, highly organized, six-layered structure that contains hundreds of different neuronal cell types. Within the neocortex, distinct populations of projection neurons are located in different cortical layers and areas, have unique morphological features, express different complements of transcription factors, and ultimately serve different functions.

  • Projection neurons are glutamatergic neurons characterized by a typical pyramidal morphology, and function to transmit information both between different regions of the cortex and to other regions of the brain. During development, they are generated from progenitors of the neocortical germinal zone, which includes the ventricular zone (VZ) and, as neurogenesis proceeds, an additional proliferative zone known as the subventricular zone (SVZ).

  • Different types of progenitors contribute to cortical neurogenesis. These include radial glial progenitors located in the VZ as well as progenitors undergoing division away from the ventricular surface, which have been termed 'intermediate progenitors'. The lineage relationship between different progenitors and the type of projection neuron progeny that they generate are largely not understood.

  • Upon induction of the telencephalon by gradients of extracellular signalling molecules, genes including empty spiracles homologue 2 (Emx2), paired box 6 (Pax6), LIM homeobox 2 (Lhx2) and forkhead box G1 (Foxg1) have crucial roles in specifying the progenitors that give rise to neocortical projection neurons. Together, these genes establish the neocortical progenitor domain by repressing dorsal midline (Lhx2 and Foxg1) and ventral (Emx2 and Pax6) fates.

  • Recently, tremendous advances have been made in the identification of laminar- and subtype-specific markers. In this review we provide a comprehensive list of laminar-specific genes with information regarding their expression domains.

  • For many of the layer-specific genes that have been identified, subtype specificity is starting to be defined, and some have been already described as being expressed in one specific neuronal type within a layer or across layers. It is not clear whether the same markers can be used to identify progenitors of each neuronal subtype, or whether such lineage-committed progenitors even exist.

  • Among the different types of cortical projection neuron, subcerebral projection neurons are an ideal model population for studying subtype-specific fate specification in the neocortex. The most well-studied subtype of subcerebral projection neuron is corticospinal motor neurons (CSMNs). During the last several years the identification of a large number of subcerebral- and CSMN-specific genes has activated and enabled an expanding effort to decipher the programmes controlling CSMN development.

  • Although a comprehensive understanding of the part played by additional subcerebral-specific genes still awaits substantial experimental work in vivo, on the basis of the data available thus far, a possible model for the generation of subcerebral projection neurons can be put forward that requires sequential steps of progressive differentiation.

  • Recent experimental data indicate that cortical progenitors might be more plastic than previously suspected, even late in neurogenesis, if manipulated by the appropriate control molecules.

Abstract

In recent years, tremendous progress has been made in understanding the mechanisms underlying the specification of projection neurons within the mammalian neocortex. New experimental approaches have made it possible to identify progenitors and study the lineage relationships of different neocortical projection neurons. An expanding set of genes with layer and neuronal subtype specificity have been identified within the neocortex, and their function during projection neuron development is starting to be elucidated. Here, we assess recent data regarding the nature of neocortical progenitors, review the roles of individual genes in projection neuron specification and discuss the implications for progenitor plasticity.

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Figure 1: Schematic depicting how progenitors residing in the VZ and SVZ in mice produce projection neurons in an 'inside-out' fashion.
Figure 2: Emx2, Pax6, Lhx2 and Foxg1 have crucial roles in the specification of neocortical progenitors.
Figure 3: Laminar- and subtype-specific genes in the mouse neocortex.
Figure 4: Schematic representation of a potential model for the generation of projection neuron subtypes from progenitors.

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Acknowledgements

This work was partially supported by grants from the National Institutes of Health (NS45523, NS49553, NS41590), the Harvard Stem Cell Institute, the Spastic Paraplegia Foundation and the ALS Association to J.D.M. P.A. was partially supported by a Claflin Distinguished Scholar Award, the Harvard Stem Cell Institute, the Spastic Paraplegia Foundation and a grant from the ALS Association. B.J.M. was supported by the Harvard M.S.T.P. and the United Sydney Association.

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Author notes

  1. Paola Arlotta

    Present address: Current address: Center for Regenerative Medicine, Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.,

  2. Bradley J. Molyneaux and Paola Arlotta: These authors contributed equally to this work.

Authors and Affiliations

  1. Departments of Neurosurgery and Neurology, MGH-HMS Center for Nervous System Repair, Program in Neuroscience, Harvard Medical School, Massachusetts General Hospital; and Harvard Stem Cell Institute, Harvard University,

    Bradley J. Molyneaux, Paola Arlotta, Joao R. L. Menezes & Jeffrey D. Macklis

  2. and Harvard Stem Cell Institute, Harvard University, Boston, 02114, Massachusetts, USA

    Bradley J. Molyneaux, Paola Arlotta & Jeffrey D. Macklis

  3. Departamento de Anatomia, Laboratório de Neuroanatomia Celular, Instituto de Ciências Biomédicas, Programa em Ciências Morfológicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil

    Joao R. L. Menezes

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Supplementary information

Supplementary information S1 (table)

Names and Entrez Gene ID numbers of the genes (PDF 174 kb)

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FURTHER INFORMATION

Jeffrey Macklis's laboratory

Allen Brain Atlas

BGEM at St. Jude Children's Hospital

Functional Genomic Atlas of the Mouse Brain

Gene Paint

GENSAT

International Mouse Strain Resource (IMSR)

Glossary

Subcortical targets

Structures located ventral to the cortex, including the thalamus, brainstem and spinal cord.

Subcerebral targets

Structures located ventral to the cerebrum (telencephalon/diencephalon), including the brainstem and spinal cord.

Cajal–Retzius cells

Early-born neurons of cortical layer I that express reelin.

Competence state

The intrinsic molecular state of a cell that determines its differentiation potential.

Niche

Specific anatomical, cellular and molecular environment of a cell or population of cells.

Symmetric cell division

A mode of cell division that gives rise to two daughter cells of the same type.

Asymmetric cell division

A mode of cell division that gives rise to two different daughter cells.

Associative projection neurons

Neurons that extend axonal projections within a single cerebral hemisphere.

Commissural projection neurons

Neurons that extend axonal projections within the cortex to the opposite hemisphere via the corpus callosum or the anterior commissure.

Corticofugal projection neurons

Neurons that extend axonal projections 'away' from the cortex. These include subcerebral projection neurons and corticothalamic neurons.

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Molyneaux, B., Arlotta, P., Menezes, J. et al. Neuronal subtype specification in the cerebral cortex. Nat Rev Neurosci 8, 427–437 (2007). https://doi.org/10.1038/nrn2151

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