Periventricular Heterotopia: Shuttling of Proteins through Vesicles and Actin in Cortical Development and Disease

Abstract

During cortical development, proliferating neural progenitors exhibit polarized apical and basolateral membranes that are maintained by tightly controlled and membrane-specific vesicular trafficking pathways. Disruption of polarity through impaired delivery of proteins can alter cell fate decisions and consequent expansion of the progenitor pool, as well as impact the integrity of the neuroependymal lining. Loss of neuroependymal integrity disrupts radial glial scaffolding and alters initial neuronal migration from the ventricular zone. Vesicle trafficking is also required for maintenance of lipid and protein cycling within the leading and trailing edge of migratory neurons, as well as dendrites and synapses of mature neurons. Defects in this transport machinery disrupt neuronal identity, migration, and connectivity and give rise to a malformation of cortical development termed as periventricular heterotopia (PH). PH is characterized by a reduction in brain size, ectopic clusters of neurons localized along the lateral ventricle, and epilepsy and dyslexia. These anatomical anomalies correlate with developmental impairments in neural progenitor proliferation and specification, migration from loss of neuroependymal integrity and neuronal motility, and aberrant neuronal process extension. Genes causal for PH regulate vesicle-mediated endocytosis along an actin cytoskeletal network. This paper explores the role of these dynamic processes in cortical development and disease.

Figure 1

Periventricular heterotopia as a disorder of vesicle trafficking. Schematic figure illustrates the disruption of various developmental processes that give rise to features seen in PH. Disruption of filamin-ARF- (via BIG2) mediated vesicle trafficking can disrupt both caveolin-mediated endocytosis and presumably trafficking from the Golgi to the membrane. Vesicle trafficking dictates the delivery and degradation of various cell cycle proteins and thereby influences cell proliferation. Disruption of the cyclin B proteins leads to microcephaly in PH. Vesicle trafficking also alters the distribution of proteins involved in neuronal migration such as paxillin. Loss of PH impairs neuronal migration and the morphology of migratory neurons. Lastly, the loss of neuroependymal integrity giving rise to heterotopia is due to impairments in the cell adhesion along the ventricular lining. Genes that disrupt vesicle trafficking impair cell-cell adhesion and disrupt the integrity of the epithelium.