Autophagy linked FYVE (Alfy/WDFY3) is required for establishing neuronal connectivity in the mammalian brain

Unlike many other cells in the body, neurons typically survive throughout the life of a mammal. This long life suggests that they may be more vulnerable to damage from cellular debris. Previous research has found that a protein called Alfy, which is abundant in the brain, is involved in cleaning up debris, such as those involved in neurodegenerative diseases, by a pathway known as autophagy. Alfy guides the formation of spherical compartments called autophagosomes, which deliver the debris to another compartment known as the lysosome to permit degradation. In developing embryos, neurons need to migrate to the right location within the central nervous system and extend projections called axons to communicate with other cells. However, it was not clear whether this process requires cell materials to be selectively sent to lysosomes, and whether this involves the Alfy protein. Dragich et al. addressed this question by studying mouse embryos that lack Alfy. The brains of these mice developed abnormally and were missing the corpus callosum (the dense band of fibers that normally connects the two halves of the brain). Without Alfy, the growing axons could not navigate their way to the right places to connect with other neurons. Furthermore, some neurons migrated to the wrong places in the developing brain, which resulted in the abnormal formation of cell-clusters. The findings of Dragich et al. suggest that autophagy also plays an important role in normal brain development. Future studies are now needed to work out exactly how Alfy controls neuron migration and the growth of axons. The human gene WDFY3 is nearly identical to the gene that encodes the Alfy protein, and has been implicated in neurodevelopmental disorders such as autism and microencephaly. Studying Alfy therefore may help us to understand human conditions that affect the developing or aging brain.