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Life is a journey: a genetic look at neocortical development

Nature Reviews Genetics volume 3, pages 342–355 (2002)Cite this article

Key Points

  • The neocortex is the most recently evolved part of the cerebral cortex. Its development has been well studied for some time, partly because of its striking organization into six distinct neuronal layers and partly because its development is disrupted in several human diseases.

  • Only recently have significant advances been made in our understanding of the molecular mechanisms that determine neocortical development, mainly based on genetic studies of human diseases that affect cortical development, such as lissencephaly, and of mouse mutants with cortical-layering defects. These studies have provided molecular biologists with several key proteins that are required for proper neuronal migration in the cortex.

  • Genetic and cell-biological studies have identified how several key proteins that are required for the proper radial migration of neurons in the cortex, such as reelin, lissencephaly 1 and cyclin-dependent kinase 5, modulate signalling pathways that are involved in neuronal migration and adhesion. Recent work is beginning to identify how these pathways interact and modulate one another.

  • Further advances in our understanding of neuronal migration and how the pathways that regulate cortical layering are integrated will be best addressed by a combination of both genetic and developmental approaches.

Abstract

Although the basic principles of neocortical development have been known for quite some time, it is only recently that our understanding of the molecular mechanisms that are involved has improved. Such understanding has been facilitated by genetic approaches that have identified key proteins involved in neocortical development, which have been placed into signalling pathways by molecular and cell-biological studies. The challenge of current research is to understand the manner in which these various signalling pathways are interconnected to gain a more comprehensive picture of the molecular intricacies that govern neocortical development.

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Figure 1: Neocortical-layer formation.
Figure 2: Neocortical-layer formation in Lis1 mouse mutants.
Figure 3: Cell migration by leading-edge extension and reeling in of the cell soma.
Figure 4: Mouse mutants with preplate and post-preplate defects.
Figure 5: Reelin signalling.
Figure 6: p35–Cdk5 signalling.
Figure 7: Integration of signalling.

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Author information

Authors and Affiliations

  1. Department of Pathology, Harvard Medical School, Howard Hughes Medical Institute, 200 Longwood Avenue, Boston, 02115, Massachusetts, USA

    Amitabh Gupta & Li-Huei Tsai

  2. Departments of Pediatrics and Medicine, University of California at San Diego, School of Medicine, 9500 Gilman Drive, La Jolla, 92093, California, USA

    Anthony Wynshaw-Boris

Authors
  1. Amitabh Gupta
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  2. Li-Huei Tsai
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  3. Anthony Wynshaw-Boris
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Corresponding authors

Correspondence to Amitabh Gupta or Li-Huei Tsai.

Related links

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DATABASES

LocusLink

β-catenin

Abl

Cables

Cdk5

Cdk5r

Cdk5r2

CLIP-170

Cnr family

cytoplasmic dynein heavy chain

Dab1

DCX

Dcx

Dhc64C

Disabled

enabled

Enah

fax

LIS1

Lis1 (fly)

Lis1 (mouse)

Lrp8

Nude (mouse)

Nude (rat)

Nudel

PAFAH1B

prospero

Reln

Vldlr

Mouse Genome Informatics

reeler

scrambler

yotari

OMIM

isolated lissencephaly sequence

lissencephaly

lissencephaly with cerebellar hypoplasia

Miller–Dieker syndrome

FURTHER INFORMATION

Encyclopedia of Life Sciences

Cerebral cortex development

Li Huei Tsai's lab

Anthony Wynshaw-Boris's lab

Glossary

NEOCORTEX

The most recently evolved part of the cerebral cortex. It is believed to orchestrate high-level motor, sensory and cognitive functions.

RADIAL DIRECTION

The movement of neurons from the inner to the outer brain surface. The inner brain surface lines the brain ventricles, and the outer brain surface lines the pia.

TANGENTIAL DIRECTION

The movement of neurons parallel to the inner or outer brain surface.

PIAL SURFACE

The outer brain surface (the pia is a membrane that covers the brain underneath the skull).

LOCOMOTION

A cell movement along glial fibre tracts in which the length of the leading process of a cell is maintained, as the cell soma and the leading edge move in concert.

RADIAL GLIA CELL

Precursor cell of the developing central nervous system (CNS). They give rise to glia cells (specialized connective tissue cells of the CNS) and also differentiate into neurons.

NUCLEAR TRANSLOCATION

A neuronal movement that is independent of glial fibre tracts, in which the cell nucleus moves towards the leading edge, such that the leading process of the cell (the distance between the apex of the cell soma and the leading edge) shortens over time.

AGYRIA

The absence of gyri (folds in the surface of the brain).

PACHYGYRIA

A reduced number of broadened gyri.

HETEROTOPIA

A group of abnormally placed cells. In the context of neuronal-migration defects, it refers to cells that are out of place in the cortex in either the grey or the white matter.

SUBCORTICAL BAND HETEROTOPIA

(SBH). A group of heterotopic neurons that form in the white matter.

WD40 REPEAT

A conserved finger-like structural motif that consists of repeats of tryptophan (W) and aspartic acid (D). In LIS1, there are seven WD40 repeats that are postulated to assume a 'propeller wheel' configuration similar to other WD40 repeat proteins.

DYNEIN

A minus-end-directed microtubule motor protein that can move along microtubules and carry cell cargo along them towards the cell centre, where the minus ends of the microtubules are positioned. When it is tethered in the periphery to the plasma membrane or to the non-microtubule cytoskeleton, it can transport cell cargo towards the cell periphery.

NUCLEOKINESIS

A process in which nuclei migrate towards the tips of the developing hyphae of Aspergillus nidulans under conditions of nutrient deprivation. This migration of the nuclei is an example of nuclear translocation and is disrupted in nuclear distribution (nud) mutants.

LEADING EDGE

The thin margin of a lamellipodium that spans the area of the cell from the plasma membrane to about 1 μm back into the lamellipodium. Lamellipodia are flattened, sheet-like projections from the surface of a cell, which are often associated with cell migration.

CENTROSOME

The main microtubule-organizing centre of animal cells.

RGD MOTIF

A peptide motif that consists of the amino acids arginine (R), glycine (G) and aspartate (D), which is found in many ligands that bind to integrins.

N-CADHERINS

Adhesion molecules that bind to each other in a calcium-dependent manner, and thereby connect nerve cells to each other. N-cadherin is stabilized on the cell surface by β-catenin, which links N-cadherin to the actin cytoskeleton.

ADHERENS JUNCTIONS

Points of cell–cell contact. In adherens junctions, a member of the cadherin family usually binds to β-catenin, which in turn is linked to the cortical actin cytoskeleton through α-catenin.

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Gupta, A., Tsai, LH. & Wynshaw-Boris, A. Life is a journey: a genetic look at neocortical development. Nat Rev Genet 3, 342–355 (2002). https://doi.org/10.1038/nrg799

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