FIGURE 6.

Proposed pathogenesis of cobblestone malformation. These schematics represent the normal interface of astrocytes with brain basement membranes and the developmental pathophysiology underlying cobblestone malformation. (A) Location of astrocytes within the mature brain parenchyma relative to the meninges (pia in blue and arachnoid [A] in black). The astrocyte foot processes abut the BM at the pial surface, forming the glia limitans. A glia limitans surround blood vessels as they enter the brain parenchyma (not shown here), maintaining the same astrocyte-basement interface as is present at the brain surface. (B) At the level of intraparenchymal capillaries, astrocyte foot processes directly abut the cerebral endothelial basement membranes. (C) In normal brain development, laminin α2 is expressed in the surface BM where radial glia (cerebrum; blue cells) or Bergmann glia (cerebellum; blue cells) anchor their foot processes and form a scaffold for immature neurons (green) to migrate to their respective destinations within the brain parenchyma. In the cerebrum, the predominant neuronal migration is inside-out. In the cerebellar cortex, granule cell neurons migrate outside-in. (D) In MDC1A, the loss of laminin α2 leads to loss of integrity of the glia limitans BM and over-migration of neurons through glia limitans defects in the cerebral cortex or failed migration of granule cell neurons in the cerebellum. The abnormal migration in either site results in heterotopia. BM, basement membrane; CP, cortical plate; EGL, external granule layer; IGL, internal granule layer; IZ, intermediate zone; ML, molecular layer; MZ, marginal zone; SP, subplate; SVZ, subventricular zone; VZ, ventricular zone.