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.
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.