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 the Genetics of Cortical Development

Progress has been made in understanding neuronal migration at the intracellular level (Heng et al., 2008; Nóbrega-Pereira et al., 2008; Stanco et al., 2009; Marin et al., 2010). As the importance of microtubule transport, centrosomal positioning, nuclear transport (associated with LIS1), microtubule stabilization (associated with DCX), vesicle trafficking and fusion (ARFGEF2 and FLNA), and neuroependymal integrity (MEKK4 and FLNA) in neuronal migration are well known (Wynshaw-Boris, 2007; Ferland et al., 2009; Pramparo et al., 2010), it was not surprising that mutations affecting microtubule proteins TUBA1A, TUBA8, TUBB2B and TUBB3 are associated with abnormal neuronal migration (lissencephaly) and postmigrational development (polymicrogyria or polymicrogyria-like dysplasias) (Poirier et al., 2007; Abdollahi et al., 2009; Jaglin and Chelly, 2009; Kumar et al., 2010; Poirier et al., 2010). Many genes linked to several pathways are known to regulate neuronal migration, but the mechanisms are poorly understood. Knockdown of some genes (such as Rnd2) result in migration defects that are identical to those observed with deletions of others (such as Neurog2) (Heng et al., 2008). Proteins that function in anchoring of the radial glial cells to the ventricular epithelium (such as BIG2; Ferland et al., 2009) or to the pial limiting membrane (such as GPR56; Luo et al., 2011) affect migration in a manner similar to those that directly affect migration. Clearly, any classification based upon these genes will require changes as the mechanisms of action of their protein products are elucidated.

The processes that direct postmitotic neurons in the ventricular and subventricular zones are being elucidated. In mice, neurons in the medial ganglionic eminences migrate to the striatum because Nkx2–1 (human NKX2.1 or TITF1) regulates expression of neuropilin-2, a guidance receptor that enables interneurons to enter the developing striatum. When Nkx2–1 is downregulated, interneurons are repulsed by class 3 semaphorins and bypass the striatum, migrating instead to the cortex (Nóbrega-Pereira et al., 2008; Hernández-Miranda et al., 2011). The laminar fate of neurons is determined in progenitor cells prior to their final mitosis. Early cortical progenitors are competent to generate late-born neurons after transplantation into older hosts, indicating that they can respond to later environmental cues, but progenitors become progressively restricted in their ability to populate different lamina as neurogenesis proceeds (Lui et al., 2011). Neuronal genes that correlate with their layer-specific neuronal identity are selectively expressed by cortical progenitors. Many continue to be expressed in their progeny (Chen et al., 2008; Lai et al., 2008), and some exhibit very high laminar specificity in the cortex in both animals and humans. Examples include Ror-beta (in 50% of layer IV neurons), Er81 (in 31% of layer V neurons) and Nurr1 in layer VI (Hevner, 2007; Garbelli et al., 2009).

Newborn projection neurons pause in the subventricular zone for up to 24 h before initiating radial migration, suggesting that the subventricular zone constitutes a unique 'permissive' environment for synchronizing migration by projection neurons and interneurons generated at the same time, thereby giving them their appropriate laminar identity (Mérot et al., 2009; Lui et al., 2011). In contrast, late cortical progenitors generate only upper layer neurons, even when transplanted into the more permissive environment of younger embryos (Lui et al., 2011). Thus, the expression of many early neural genes appears to be 'turned off' as neurogenesis proceeds. These factors may provide clues to genes and pathways underlying malformations of abnormal postmigrational development (formerly malformations of cortical organization) such as polymicrogyria. Misspecification of projection, commissural and association neurons could potentially underlie disorders of sensorimotor or visual function, commissuration or cognition, respectively.

The developing leptomeninges affect multiple stages of cortical development. For example, retinoic acid produced in the leptomeninges regulates the generation of cortical neurons (Siegenthaler et al., 2009). Tangential migration of cortical hem-derived Cajal–Retzius cells, which play an important role in termination of neuronal migration to the cortex, is controlled by the leptomeninges via CXCL12/CXCR4 signalling (Borrell and Marin, 2006). The leptomeninges are also essential for the survival of radial glial cells, which undergo apoptotic cell death if the meninges are removed (Radokovits et al., 2009). Finally, the leptomeninges play an important role in maintaining the cerebral basement membrane. Loss of Zic activity reduces proliferation of meningeal cells, resulting in a thin and disrupted pial basement membrane in mouse models (Inoue et al., 2008). Reduction of Foxc1 activity in the leptomeninges impairs the ability of the basement membrane to expand in conjunction with brain growth, resulting in lamination defects, neuronal overmigration and subpial heterotopia formation (Hecht et al., 2010). Thus, abnormal leptomeningeal development may result in cortical dysgenesis via multiple mechanisms.