Morphological and functional aspects of progenitors perturbed in cortical malformations

Abstract

In this review, we discuss molecular and cellular mechanisms important for the function of neuronal progenitors during development, revealed by their perturbation in different cortical malformations. We focus on a class of neuronal progenitors, radial glial cells (RGCs), which are renowned for their unique morphological and behavioral characteristics, constituting a key element during the development of the mammalian cerebral cortex. We describe how the particular morphology of these cells is related to their roles in the orchestration of cortical development and their influence on other progenitor types and post-mitotic neurons. Important for disease mechanisms, we overview what is currently known about RGC cellular components, cytoskeletal mechanisms, signaling pathways and cell cycle characteristics, focusing on how defects lead to abnormal development and cortical malformation phenotypes. The multiple recent entry points from human genetics and animal models are contributing to our understanding of this important cell type. Combining data from phenotypes in the mouse reveals molecules which potentially act in common pathways. Going beyond this, we discuss future directions that may provide new data in this expanding area.

Keywords: epilepsy; intellectual disability; lamination; mouse mutant; neurodevelopment; proliferation; radial glial cells.

Figure 1

MRI schemas of malformations. (A) Control brain, (B) Cobblestone lissencephaly, where neuronal overmigration (represented by gray patches at the surface of the brain) can arise due to breaks of the basement membrane. (C) Periventricular nodular heterotopia, some neurons (represented by gray nodules) remain stuck at the ventricular surface, most probably due to breaks and disorganization of the ventricular lining. (D) Microcephaly, several mechanisms may give rise to this malformation leading to a greatly reduced size of the brain. In pure forms, brain architecture is relatively well-preserved, in other forms (microcephaly with simplified gyral pattern, MSGP, not shown), brain organization and cortical folds are also affected. (E) Globular or ribbon-like heterotopia, represented by gray globular masses. In this case the heterotopia starts at the level of the ventricles and fills up the white matter in some brain areas. The heterotopia can appear to have gyri. Modified from Francis et al. (2006).

Figure 2

RGC mechanisms leading to mouse malformations. (A) Control situation, apical progenitors (containing blue nuclei) divide by interkinetic nuclear migration (INM) in the VZ, neurons (burgundy nuclei) migrate radially on RGC basal processes across the IZ, to settle in the CP. Cajal Retzius cells (ovals) present in the MZ secrete signals to the migrating neurons. End-feet of RGC basal processes receive signals from ECM molecules in the BM close to the pial surface. (B) Cobblestone lissencephaly phenotype, in this case some RGC basal processes are not well attached to the pial surface, possible breaks in the BM potentially cause neurons (burgundy nuclei at the surface of the brain) in some regions to overmigrate into the meningeal space. (C) Periventricular disorganization, some neurons (burgundy nuclei) remain stuck at the ventricular surface, most probably due to breaks in the ventricular lining where apical end-feet of RGCs normally attach. (D) Microcephaly phenotype, two potential mechanisms may give rise to this malformation leading to a greatly reduced size of the brain. Some mouse models suggest that premature differentiation of progenitors into post-mitotic neurons (burgundy nuclei within radially migrating neuron close to VZ) depletes the progenitor pool (represented by red cross over blue nuclei in VZ). Other studies show instead increased cell death of abnormal progenitors (red cross over blue nuclei present in IZ). (E) Globular heterotopia (e.g., HeCo mice), in this case a proportion of apical progenitors detach from the ventricular surface (represented by blue nuclei without apical attachment to the ventricular lining) and retain proliferation capacity, providing a local source of neurons in the IZ (burgundy nuclei). A subcortical heterotopia subsequently arises. VZ, ventricular zone; IZ, intermediate zone; CP, cortical plate; MZ, marginal zone; BM, basement membrane.

Figure 3

Radial glial cell and different genes. Schematic representation of interphase and dividing RGCs (in green) and neurons (in gray) migrating along basal RGC processes. Higher magnifications show RGC structural details such as basal attachment to the pial surface (represented in red), apically located adherens junctions (black), apical attachments and midbody (purple), centrosomes (pink), primary cilia (blue), and a mitotic cell with the MTs organized in the mitotic spindle (light blue) and the DNA aligned at the metaphase plate (black). The ventricular surface is represented as a gray line. The different genes are represented close to the structure in which they have clearly been shown to be involved based on the classification proposed in this review, with a color corresponding to the color of the structure. Genes involved in RGC basal process attachment to the pial surface are represented in red; in black are genes linked with adherens junctions; in purple are genes participating in apical polarity, attachment to the ventricular surface, and in the apically-located midbody; in blue are genes essential for the primary cilium; in pink are represented centrosome-related genes, and in light blue genes participating in the regulation of mitotic spindle function. Genes that are involved in transcriptional regulation are represented in green.