Abstract
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.
Highlights
In the mammalian nervous system, kinesin super family proteins (KIFs) play a crucial role in intracellular transport, microtubule (MT) dynamics, and signal transduction and, are key players in brain function, development, and disease (Hirokawa et al, 2010; Hirokawa, 1998)
Studies of Kinesin super family protein 2A (KIF2A) function in humans have primarily focused on cortical development because KIF2A mutations in residues Ser317 and His321 have been identified in patients with malformed cortical development (MCD) (Cavallin et al, 2017; Poirier et al, 2013)
We sought to determine how KIF2A functions in the postnatal hippocampus, especially during the early postnatal weeks when dentate granule cells (DGCs) are establishing a hippocampal network, because hippocampal KIF2A expression is highest in the third postnatal week (Figure 1B)
Summary
In the mammalian nervous system, kinesin super family proteins (KIFs) play a crucial role in intracellular transport, microtubule (MT) dynamics, and signal transduction and, are key players in brain function, development, and disease (Hirokawa et al, 2010; Hirokawa, 1998). In the early stages of the developing murine nervous system, KIF2A controls neurite elongation by regulating MT dynamics at neuronal growth cones and plays a crucial role in neuronal migration, axonal elongation and axon pruning in vivo (Homma et al, 2003; Noda et al, 2012; Ogawa and Hirokawa, 2015; Maor-Nof et al, 2013). Studies of KIF2A function in humans have primarily focused on cortical development because KIF2A mutations in residues Ser317 and His321 have been identified in patients with malformed cortical development (MCD) (Cavallin et al, 2017; Poirier et al, 2013) Both mutants are expected to lose MT destabilizing activity, due to a disruption in ATP binding or hydrolysis, resulting in a classic form of lissencephaly. After reaching its peak in the early postnatal weeks, the expression of postnatal KIF2A throughout the brain is gradually restricted to specific brain regions, including the hippocampus (Lein et al, 2007), in which new neurons are generated throughout an individual’s life in established
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