Integration of neuronal clones in the radial cortical columns by EphA and ephrin-A signalling

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Abstract
A feature of the development of the cerebral cortex in the embryo is the migration of neocortical excitatory neurons along radial glial fibres. Less studied than this movement along columnar structures is the regulation and outcome of the tangential mixing of clonal populations of neural progenitors migrating from their origin and encountering those travelling from other proliferative units. Rakic and colleagues report evidence that EphA/ephrin-A signalling modulates this mixing of populations during circuit development. In the absence of ephrin-A, tangential migration is disrupted, leading to impaired lateral dispersion and abnormal columnar organization. Aberrant columnar organization is thought to cause functional impairment within circuits. During development of the cerebral cortex, excitatory projection neurons migrate to form a cellular infrastructure of radial columns. However, some of these clonally related neurons undergo a lateral shift to intermix with neurons originating from neighbouring proliferative units. This process is now shown to be dependent on Eph receptor A and ephrin A signalling, a so far unrecognized mechanism for lateral neuronal dispersion that seems to be essential for the proper intermixing of neuronal types in the cortical columns. The cerebral cortex is a laminated sheet of neurons composed of the arrays of intersecting radial columns1,2,3. During development, excitatory projection neurons originating from the proliferative units at the ventricular surface of the embryonic cerebral vesicles migrate along elongated radial glial fibres4 to form a cellular infrastructure of radial (vertical) ontogenetic columns in the overlaying cortical plate5. However, a subpopulation of these clonally related neurons also undergoes a short lateral shift and transfers from their parental to the neighbouring radial glial fibres6, and intermixes with neurons originating from neighbouring proliferative units5,7. This columnar organization acts as the primary information processing unit in the cortex1,8,9. The molecular mechanisms, role and significance of this lateral dispersion for cortical development are not understood. Here we show that an Eph receptor A (EphA) and ephrin A (Efna) signalling-dependent shift in the allocation of clonally related neurons is essential for the proper assembly of cortical columns. In contrast to the relatively uniform labelling of the developing cortical plate by various molecular markers and retrograde tracers in wild-type mice, we found alternating labelling of columnar compartments in Efna knockout mice that are caused by impaired lateral dispersion of migrating neurons rather than by altered cell production or death. Furthermore, in utero electroporation showed that lateral dispersion depends on the expression levels of EphAs and ephrin-As during neuronal migration. This so far unrecognized mechanism for lateral neuronal dispersion seems to be essential for the proper intermixing of neuronal types in the cortical columns, which, when disrupted, might contribute to neuropsychiatric disorders associated with abnormal columnar organization8,10.