Search

Kinesin super family protein 2A (KIF2A), an ATP-dependent microtubule (MT) destabilizer, regulates cell migration, axon elongation, and pruning in the developing nervous system. KIF2A mutations have recently been identified in patients with malformed cortical development. However, postnatal KIF2A is continuously expressed in the hippocampus, in which new neurons are generated throughout an individual's life in established neuronal circuits. In this study, we investigated KIF2A function in the postnatal hippocampus by using tamoxifen-inducible Kif2a conditional knockout (Kif2a-cKO) mice. Despite exhibiting no significant defects in neuronal proliferation or migration, Kif2a-cKO mice showed signs of an epileptic hippocampus. In addition to mossy fiber sprouting, the Kif2a-cKO dentate granule cells (DGCs) showed dendro-axonal conversion, leading to the growth of many aberrant overextended dendrites that eventually developed axonal properties. These results suggested that postnatal KIF2A is a key length regulator of DGC developing neurites and is involved in the establishment of precise postnatal hippocampal wiring., eLife digest The brain contains billions of neurons that connect together to form ‘circuits’ that control behavior and process information. By the time we are born, most of the neurons in our brain have already formed and connected into these circuits. But there are some brain areas that continue to make new neurons throughout our lives. One such area is the hippocampus, a region of the brain involved in learning and memory. There, neurons called dentate granule cells keep their ability to divide, migrate to new locations, and develop new connections. Like most neurons, at the heart of each dentate granule cell is a cell body that contains the cell's nucleus and protein-making machinery. Attached to this are a set of small branch-like structures called dendrites that receive signals from surrounding neurons. Extending away from the cell body is another, longer branch called an axon, which transmits signals to other neurons. A protein called KIF2A plays several roles in the developing brain of mammals, including helping neurons to migrate to the right place and controlling how their axons form. Before birth, neurons across the brain make KIF2A. After birth this gradually changes until only the dentate granule cells in the hippocampus produce KIF2A. In humans, mutations that prevent KIF2A from working are thought to cause brain malformations. They may also lead to disorders such as schizophrenia, epilepsy and eye defects. To investigate the role of KIF2A in more detail, Homma et al. genetically engineered mice so that giving them a drug called tamoxifen would inactivate the gene that produces KIF2A. Mice that had this gene switched off three weeks after birth – when KIF2A levels in the hippocampus are normally at their highest – lost weight and became hyperactive. They also developed severe temporal lobe epilepsy. To find out why these problems ocurred, Homma et al. used a microscope to study sections of the brains of the mice. The neurons had divided and migrated to the correct location of the brain with no significant problems. However, dentate granule cells that lacked KIF2A looked unusual. They had too many dendrites, the dendrites were longer than they should be and they showed markers usually only found on axons. This suggests that KIF2A helps to control the length of axons and dendrites and the wiring of the hippocampus. At the moment, it's not known whether the same defects also occur in humans. If the results are reproducible in people, future work could help to diagnose and understand conditions linked to KIF2A, like schizophrenia and epilepsy.

The kinesin-8 motor, KIF19A, accumulates at cilia tips and controls cilium length. Defective KIF19A leads to hydrocephalus and female infertility because of abnormally elongated cilia. Uniquely among kinesins, KIF19A possesses the dual functions of motility along ciliary microtubules and depolymerization of microtubules. To elucidate the molecular mechanisms of these functions we solved the crystal structure of its motor domain and determined its cryo-electron microscopy structure complexed with a microtubule. The features of KIF19A that enable its dual function are clustered on its microtubule-binding side. Unexpectedly, a destabilized switch II coordinates with a destabilized L8 to enable KIF19A to adjust to both straight and curved microtubule protofilaments. The basic clusters of L2 and L12 tether the microtubule. The long L2 with a characteristic acidic-hydrophobic-basic sequence effectively stabilizes the curved conformation of microtubule ends. Hence, KIF19A utilizes multiple strategies to accomplish the dual functions of motility and microtubule depolymerization by ATP hydrolysis. DOI: http://dx.doi.org/10.7554/eLife.18101.001, eLife digest The cells that line the airways and other passages in the body have hair-like structures called cilia on their surface. Maintaining the cilia at an appropriate length is key to allowing fluid to flow efficiently in these passages. A protein called tubulin forms scaffolds known as microtubules that give each cilium its shape and allow it to change length. Motor proteins are also found in cilia, and travel along the microtubules to transport substances. One of these microtubule-based motors, referred to as KIF19A, accumulates at the tip of cilia and controls their length. It does so by combining two actions: it moves along the microtubule to the tip of the cilium, and then removes tubulin molecules from the end. Microtubules are straight along their length and curved at the end, and it is thought that kinesin recognizes both of these shapes in order to carry out these roles. A single region of the KIF19A protein appears to be able to accomplish both roles, but the molecular changes that the protein undergoes to do so are not known. Wang et al. have now investigated these changes by determining the structure of the motor domain of KIF19A from mice using two experimental approaches: X-ray crystallography and cryo-electron microscopy. These structures showed that the specific structural features responsible for the protein's dual roles are indeed clustered on the side of the protein that binds to the microtubule. Wang et al. also identified the regions that make KIF19A flexible enough to fit this interface with both straight and curved microtubules. Next, Wang et al. found that other regions of KIF19A stop it detaching from the microtubule and allow it to stabilize the curved shape of microtubule ends; this stimulates the microtubule to disassemble, or “depolymerize”. The findings show that KIF19A uses multiple strategies to enable it to carry out its roles. To understand better how KIF19A depolymerizes the microtubule, a more detailed structure of KIF19A together with tubulin will be needed. Structural studies of KIF19A in cilia will also be useful to understand how the protein controls the length of microtubules. DOI: http://dx.doi.org/10.7554/eLife.18101.002