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A mechanism for inside-out lamination in the neocortex

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We outline a unified model for inside-out layering of the neocortex, hinging on a new interpretation for the effects of Reelin on neuronal migrations. The effects of Reelin on cortical structure have been analyzed in great detail, but it has been unclear how individual migrating cells respond to Reelin. In our opinion, many published results might be explained if Reelin acts on neurons when their leading processes reach the marginal zone. Reelin then stimulates two parallel events: detachment from radial glia and translocation of the cell soma to the top of the developing cortical plate. This ‘detach and go’ model explains many aspects of inside-out lamination, defects in the Reeler mutant and results of recent genetic and in utero experiments.

Introduction

It has been known for over a century that the mammalian neocortex comprises six layers, or laminae, each containing neurons with similar morphology, functional properties, connections, and time and place of origin [1]. A remarkable feature of the neocortex is the inside-out arrangement of projection neurons, with the oldest neurons closest and the youngest neurons farthest from their birthplace near the ventricle 2, 3, 4, 5, 6. Because the layers are conventionally numbered from the top, layers II/III contain the youngest neurons and layer VI the oldest (Figure 1a, left, arrow shows birth order). Inside-out layering means that each neuronal precursor has to migrate outward from the ventricle, pass beyond its predecessors and then stop, undergo terminal differentiation and establish its synaptic connections (Figure 1b). The region where migration stops is defined by a layer of specialized pioneer neurons called Cajal-Retzius (CR) cells, which migrate tangentially into the cortex early in development [7]. Because the CR neurons are continually pushed outward as the cortex grows, they are an exception to the inside-out birth order of the rest of the cortical plate. Below them, the first-migrating (deepest) layer of neurons is called the subplate (SP), whereas the next layers (VI, V, IV, etc. in order from bottom to top) stack up on top of them (Figure 1b). Here we propose a unified model that might explain how inside-out layering is regulated.

Section snippets

Neuron movement requires cell polarity and cytoskeletal motors

A large and growing number of genes have been identified that are implicated in the efficient migration of neuronal precursors 3, 4, 5, 6, 8, 9, 10, 11, 12, 13, 14, 15. The gene products involved include the kinase Cdk5 and its regulatory subunits, various proteins associated with microtubules and the centrosome, including Lis1, and an actin regulator, n-cofilin. In mutants, or in individual cells in which the genes have been inhibited by targeted knockdown or expression of dominant-interfering

Neuron positioning requires the Reelin pathway

Mutations in another group of genes cause the Reeler phenotype, a distinctive defect in which neurons are produced and specified normally but position abnormally 2, 16, 17. Importantly, the Reeler cortex is inverted, with its neurons roughly in outside-in birth order (Figure 1c). The marginal zone contains a ‘superplate’ of SP, layer VI and CR neurons, and younger neurons are found below, somewhat intermixed but approximately in order V, IV, III, II from top to bottom. It is as though the

A ‘detach and stop’ model for Reelin action

Early evidence suggested that Reelin acts as a ‘detach and stop’ signal for neurons (Figure 2) 18, 19, 20, 21. Many neuronal precursors migrate by ‘locomotion’ – crawling along the processes of cells known as radial glia, which span the cortical wall (see Box 1). The radial glia serve a dual purpose as progenitor cells and as guides for locomotion of the neuronal precursors [22]. They have a long process that extends from the cell body near the ventricle to the basement membrane at the pial

Problems with the detach and stop model

More recently, several lines of evidence have undermined the detach and stop model. First, ectopic sources of Reelin along the migratory path do not stop migration prematurely. Curran and colleagues expressed Reelin from a transgene in the ventricular zone of the developing cortex [28]. Although the quantity of Reelin secreted in the ventricular zone was not clear, it seems reasonable to suppose that neuronal precursors were exposed to Reelin at (and before) birth. If Reelin stops cells

Requirements for somal translocation and locomotion

Nadarajah et al.[37] pointed out that the movement of layer VI cells past the subplate – a glia-independent movement – requires Reelin, whereas later migrations – glia-dependent movements – require Cdk5 and Lis1. Thus, Reelin might regulate glia-independent movement and Cdk5 and Lis1 might regulate glia-dependent movement. Indeed, when Cdk5 was inhibited in individual neurons at different times of development, late but not early migrations were inhibited [44]. Cdk5 is required for the

A ‘detach and go’ model for cortical lamination

These observations suggest a ‘detach and go’ model for cortical development (Figure 2e–h). In this model, Reelin regulates two events: detachment from radial glia (as in the detach and stop model) and somal translocation. Early in development of the normal cortex (Figure 2e), future layer VI neurons have an ascending process that reaches the marginal zone. Reelin stimulates these cells to translocate through the subplate. Later in development (Figure 2f), future layer V and subsequent cells

Unanswered questions

There are several aspects of cortical lamination that remain to be explained. First, what regulates the positioning of SP cells? These cells lack a component of the Reelin signaling pathway [55], so their positioning is presumably Reelin independent. However, the mechanism remains to be discovered.

It will also be important to determine which of the genes implicated in locomotion might also play a role in somal translocation. Although the phenotypes of Cdk5 and Lis1 mutants imply that somal

Concluding remarks

We have described a revised model for cortical lamination, inspired by Nadarajah et al.[37]. Our model is a ‘detach and go’ model, in which Reelin stimulates glial detachment and glia-independent somal translocation. Like the ‘detach and stop’ model, this model accounts for many aspects of the architecture of normal and Reeler mutant cortex, but unlike the earlier model it incorporates more recent observations using engineered mice, slice culture and in utero electroporation techniques. The new

Acknowledgements

I thank Robert Hevner, Yves Jossin and Sergi Simo for their thoughtful suggestions, Andre Goffinet for discussions, and grant CA41072 from the U.S. Public Health Service for support.

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