A Developmental and Genetic Classification for Malformations of Cortical Development

Update 2012

A. James Barkovich; Renzo Guerrini; Ruben I. Kuzniecky; Graeme D. Jackson; William B. Dobyns


Brain. 2012;135(5):1348-1369. 

In This Article

Recent Advances in Embryology of Cerebral Cortical Development

The cerebral cortex is a modular structure (Cholfin and Rubenstein, 2007; Cholfin and Rubenstein, 2008; Hoch et al., 2009): modules of neurons are induced in a neuroepithelial sheet and subsequently differentiate, migrate and organize into a functioning cerebral cortex. Neuronal induction results from a combination of graded extracellular signals and transcription factor gradients that operate across several fields of neocortical progenitor cells (Sansom and Livesey, 2009). This process is regulated by interplay between intrinsic genetic mechanisms and extrinsic information relayed to cortex by thalamocortical input and other, largely unknown, factors (O'Leary et al., 2007; Rakic et al., 2009; Supplementary material).

Although details of the neural cell proliferation differ among mammalian species, GABAergic cortical interneurons are produced in the medial and caudal ganglionic eminences, and the subventricular zone of the pallial (dorsal) germinal epithelium (Petanjek et al., 2009; Miyoshi et al., 2010; Lui et al., 2011) and migrate tangentially (from the medial ganglionic eminences) or radially (from the dorsal subventricular zone) to the developing cortex. The precise details in humans are not yet known (Lui et al., 2011). In the dorsal subventricular zone, neuroepithelial cells differentiate into radial glial cells, in part promoted by fibroblast growth factor (Sahara and O'Leary, 2009). Whereas neuroepithelial cells divide symmetrically to expand their numbers, radial glial cells divide asymmetrically to both self-renew and generate restricted intermediate progenitor cells, which divide symmetrically to produce two or more neurons but no progenitors. Both radial glial and intermediate progenitor cells produce glutamatergic neurons (Merkle and Alvarez-Buylla, 2006; Kang et al., 2009). Another class of precursor cells in the dorsal ventricular zone, the short neural precursors, appear to be committed to symmetrical neurogenic divisions (Howard et al., 2006; Stancik et al., 2010).

Based upon interspecies comparisons, the generation of increased numbers of intermediate progenitor cells underlies increased cortical complexity and size (Kriegstein et al., 2006). Thus, the balance between self-renewal and progression to a more restricted state is a critical factor in regulating the number of intermediate progenitor cells, and ultimately, cortical size. The mechanisms that regulate this progression are poorly understood (Elias et al., 2008; Mérot et al., 2009; Subramanian and Tole, 2009; Lui et al., 2011). However, mutations have been found in genes regulating the progenitor cell mitotic cycle in several types of severe congenital microcephaly (Thornton and Woods, 2009; Yu et al., 2010; Castiel et al., 2011; Kalay et al., 2011). Further, human microcephaly syndromes can be classified, to some degree, by the affected cell cycle phase (Supplementary Table 1).

Understanding of cell proliferation has been aided by the discovery that the primate subventricular zone is complex, composed of an outer subventricular zone, a layer of radially oriented neurons that is divided from the underlying subventricular zone by an 'inner fibre layer' that is presumably composed of corticocortical, corticothalamic and thalamocortical axons (Smart et al., 2002; Zecevic et al., 2005). Large numbers of radial glial-like cells and intermediate progenitor cells populate the human outer subventricular zone. The radial glial-like cells are non-epithelial, as they lack contact with the neuroependyma of the ventricular surface (Hansen et al., 2010), but still undergo both symmetric and self-renewing asymmetric divisions that allow further proliferation (Hansen et al., 2010). The expansive proliferation of progenitor cells in the outer subventricular zone helps to explain the evolutionary expansion of the number of radial glial units, surface area and gyrification in the primate cortex, as these later-born cells are presumed to occupy the outer cortical layers (Zecevic et al., 2005; Lui et al., 2011).