山崎 礼二

Oxysterol-binding protein (OSBP)-related protein (ORP) 6, a member of subfamily III of the ORP family, localizes at endoplasmic reticulum-plasma membrane contact sites and is involved in regulating the turnover of the lipid composition of the plasma membrane through the counter-transport of phosphatidylinositol-4-phosphate and phosphatidylserine in neurons. However, the physiological functions of ORP6-mediated lipid counter-transport remain poorly understood. In the present study, we investigated the developmental expression of ORP6 protein in the mouse cerebellum and the role of ORP6 in neuronal differentiation and migration using Neuro-2A cells and primary cultured cerebellar granule cells (CGCs). The expression of the ORP6 protein increased from P7 to P21, coinciding with a key period of granule cell progenitor proliferation and immature CGC migration. Both ORP6 RNAi knockdown and overexpression of two different types of dominant-negative ORP6 constructs significantly increased the number and length of neurites in retinoic acid-induced differentiated Neuro-2A cells. Similarly, ORP6 knockdown in primary cultured CGCs increased neurite number and length and disrupted their migration in vitro. Furthermore, overexpression of a dominant-negative form of ORP6 in immature CGCs using in vivo electroporation impaired their migration into the granule layer. Taken together, these results suggest the possible involvement of lipid counter-transport by ORP6 in the regulation of neuronal morphology and migration of CGCs.

Neurogenesis and oligodendrogenesis occur throughout life under both physiological and pathophysiological conditions. Brain insults such as ischemia, trauma, epilepsy, or Alzheimer disease result in the promotion of neurogenesis and oligodendrogenesis; however, the mechanisms and the roles of this promotion are not well elucidated. Neurogenesis occurs in two distinct regions in the brain, namely, the subventricular zone (SVZ) of the lateral ventricle and the subgranular zone (SGZ) of the dentate gyrus. Neural stem cells (NSCs) have the potential to self-renew, proliferate, and differentiate into various cell types. NSCs in the SVZ migrate toward the site of injury, and those in the SGZ migrate toward the granule cell layer after ischemic insult. Numerous animal experiments have shown that inhibition of post-ischemic neurogenesis both in the SVZ and the dentate gyrus impairs functional recovery. Oligodendrogenesis regenerates myelin around demyelinated axons after white matter injury, thus promoting functional recovery after ischemia. Oligodendrocyte progenitor cells derived from NSCs and progenitor cells of the SVZ and from intrinsic cells from other brain regions proliferate at the demyelinated lesions. However, deposition of extracellular matrices, including chondroitin sulfate proteoglycans, hyaluronan, fibronectin, and fibrinogen, have been reported to inhibit remyelination. Furthermore, our data showed that type I collagen was deposited in the white matter lesions of stroke patients, and that it may inhibit oligodendrocyte differentiation in these lesions. In this review, we focus on the mechanisms and the roles of post-ischemic neurogenesis and oligodendrogenesis based on recently published data of mainly rodent models.

The activity of oligodendrocyte progenitor cells (OPCs) and oligodendrocytes (OLs) throughout life drives myelination, which is crucial for rapid neuronal communication. OLs in the aging brain demonstrate a reduced capacity for myelin formation and maintenance, but the underlying differentiation of individual OLs and morphological changes of their myelin in aging remain unclear. Here, we utilized Pdgfra-CreERT2:Tau-mGFP double transgenic mice to selectively label and visualize newly generated OLs in aged (78-week-old) mice and compared them with those in young (8-week-old) mice. We revealed a significantly lower percentage of newly generated OLs that differentiated into mature OLs and a decreased rate of myelinating OLs accumulation in aged mice compared with young mice. Additionally, newly generated myelinating mature OLs in aged mice demonstrated significantly greater height compared with those in young mice. Furthermore, myelin internodes were significantly shorter and significantly fewer in aged mice compared with young mice. Our results indicate age-related impairments in the differentiation efficiency of aged OPCs and age-related morphological changes in OLs. These alterations in newly generated OLs may contribute to impaired myelination, reduced myelin turnover, and disrupted myelin maintenance in aged mice.