The highly complex, layered structure of the cerebral cortex is fundamental to higher brain functions. However, the underlying genetic factors that regulate its development are poorly understood. In this regard, the Hyh mouse represents a potentially useful tool, as it has a remarkably small cerebral cortex. Now, Christopher Walsh and colleagues (Nature Genet. DOI: 10.1038/ng1302) characterize the underlying molecular defect of the hyh mutant mouse to provide some surprising insights into the development of the cerebral cortex.

The authors first made the surprising observation that hyh mice have a mis-sense mutation in the gene encoding α-SNAP, a central component of the SNARE machinery that governs the specificity of vesicle trafficking in a variety of cellular contexts. Levels of α-SNAP protein were markedly reduced in hyh mice, resulting from reduced RNA stability rather than inherent instability within the protein. However, the levels of α-SNAP still translated were still important functionally, as an α-SNAP-null allele was lethal.

Abnormal cell fates in the cerebral cortex of hyh mutants. Layer-specific markers were used to compare the layer phenotype of wild-type and hyh (αSNAP hypomorph) cortexes. Late-born neurons (layers 2–4) are marked in green and early-born neurons (layer 6) are marked in red.

Next, the authors found that the αSnap mutation causes a marked shift in the balance of early- versus late-born neurons — levels of late neurons were decreased, whereas levels of early neurons were increased. The specified programme of early-to-late neuronal differentiation is necessary for the laminar organization of the cortex (see Figure), which is achieved by sequential migration of neurons to each individual layer. Interestingly, loss of late-born neurons seems to be the result of early withdrawal of neural progenitor cells from the cell cycle.

Because asymmetric division of neural precursors is thought to underlie the choice between proliferation and differentiation, the authors hypothesized that α-SNAP would contribute to this decision through the control of polarized vesicular transport. A number of apical markers implicated in neural cell-fate decisions were indeed found to be mis-localized in hyh mutant cells. Also, VAMP7, a v-SNARE involved in vesicle transport to apical membranes, was mis-localized from apical membranes in the mutant. Interestingly, partial disruption of α-SNAP in the hyh mutant did not seem to affect other more general intracellular transport routes in which α-SNAP is also involved, suggesting that it functions in a dose-dependent manner.

This study is also consistent with earlier observations from the same group (Nature Genet. 36, 69–76 (2004)), showing that disruption of ARF-GEF2 (which blocks transport from the trans-Golgi network to the cell surface) also affects the proliferation and migration of neural progenitor cells in the cerebral cortex.

In conclusion, the observations of Walsh and colleagues demonstrate that the defect in cerebral cortex structure is caused by a disruption of α-SNAP-mediated vesicular transport to apical membranes, which is important for controlling the decision of neural progenitor cells to form proliferative versus post-mitotic cells. Now that the identity of the gene mutated in hyh mice is known, it should serve as a useful tool to examine wider aspects of neural development.