望月 信弥

Kinesins, which are motor proteins that primarily move along microtubules by hydrolyzing adenosine triphosphate (ATP), constitute a superfamily of proteins known as kinesin superfamily proteins (KIFs). These molecules play crucial roles not only in intracellular transport but also in cell division, cell survival, morphogenesis, and higher brain functions such as memory, learning, and neural network formation. We previously reported that KIF26A plays a key role in the development of the enteric nervous system of the colon. Here, we demonstrate that KIF26A plays a role in olfaction. Analysis of Kif26a-/- mice reveals that Kif26a is critical for the development of the neuronal layer in the main olfactory epithelium (MOE). At postnatal day 7, Kif26a-/- mice exhibit decreased thickness and disorganization of the MOE with disproportionate numbers of mature and immature olfactory sensory neurons (OSNs). Loss of KIF26A leads to increased apoptosis and accelerated precursor cell proliferation of OSNs. Additionally, in vitro experiments using primary cultures of neurons reveal that KIF26A deficiency impaired neurite outgrowth and disrupted nerve bundle formation in OSNs. Furthermore, Kif26a haploinsufficiency results in impaired olfactory responses. These findings suggest that KIF26A plays important roles in both olfactory epithelium development and olfactory function.

Oxysterol-binding protein (OSBP)-related protein (ORP) 6, a member of subfamily III in the ORP family, localizes to membrane contact sites between the endoplasmic reticulum (ER) and other organelles and functions in non-vesicular exchange of lipids including phosphatidylinositol-4-phosphate (PI4P) in neurons. In this study, we searched for the lipid counter-transported in exchange for PI4P by using molecular cell biology techniques. Deconvolution microscopy revealed that knockdown of ORP6 partially shifted localization of a phosphatidylserine (PS) marker but not filipin in primary cultured cerebellar neurons. Overexpression of ORP6 constructs lacking the OSBP-related ligand binding domain (ORD) resulted in the same shift of the PS marker. A PI4KⅢα inhibitor specifically inhibiting the synthesis and plasma membrane (PM) localization of PI4P, suppressed the localization of ORP6 and the PS marker at the PM. Overexpression of mutant PS synthase 1 (PSS1) inhibited transport of the PS marker to the PM and relocated the PI4P marker to the PM in Neuro-2A cells. Introduction of ORP6 but not the dominant negative ORP6 constructs, shifted the localization of PS back to the PM. These data collectively suggest the involvement of ORP6 in the counter-transport of PI4P and PS.