Su Weiping, Foster Scott C, Xing Rubing, Feistel Kerstin, Olsen Reid H J, Acevedo Summer F, Raber Jacob, Sherman Larry S
From the Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon 97006.
Institute of Zoology, University of Hohenheim, Garbenstrasse 30, 70593 Stuttgart, Germany, and.
J Biol Chem. 2017 Mar 17;292(11):4434-4445. doi: 10.1074/jbc.M116.774109. Epub 2017 Jan 31.
Adult neurogenesis in the hippocampal subgranular zone (SGZ) is involved in learning and memory throughout life but declines with aging. Mice lacking the CD44 transmembrane receptor for the glycosaminoglycan hyaluronan (HA) demonstrate a number of neurological disturbances including hippocampal memory deficits, implicating CD44 in the processes underlying hippocampal memory encoding, storage, or retrieval. Here, we found that HA and CD44 play important roles in regulating adult neurogenesis, and we provide evidence that HA contributes to age-related reductions in neural stem cell (NSC) expansion and differentiation in the hippocampus. CD44-expressing NSCs isolated from the mouse SGZ are self-renewing and capable of differentiating into neurons, astrocytes, and oligodendrocytes. Mice lacking CD44 demonstrate increases in NSC proliferation in the SGZ. This increased proliferation is also observed in NSCs grown , suggesting that CD44 functions to regulate NSC proliferation in a cell-autonomous manner. HA is synthesized by NSCs and increases in the SGZ with aging. Treating wild type but not CD44-null NSCs with HA inhibits NSC proliferation. HA digestion in wild type NSC cultures or in the SGZ induces increased NSC proliferation, and CD44-null as well as HA-disrupted wild type NSCs demonstrate delayed neuronal differentiation. HA therefore signals through CD44 to regulate NSC quiescence and differentiation, and HA accumulation in the SGZ may contribute to reductions in neurogenesis that are linked to age-related decline in spatial memory.
海马齿状回颗粒下区（SGZ）的成体神经发生在整个生命过程中都参与学习和记忆，但会随着衰老而减少。缺乏糖胺聚糖透明质酸（HA）的跨膜受体CD44的小鼠表现出多种神经功能障碍，包括海马记忆缺陷，这表明CD44参与了海马记忆编码、存储或检索的相关过程。在这里，我们发现HA和CD44在调节成体神经发生中起重要作用，并且我们提供证据表明HA导致海马中神经干细胞（NSC）增殖和分化与年龄相关的减少。从小鼠SGZ分离出的表达CD44的NSC具有自我更新能力，并能够分化为神经元、星形胶质细胞和少突胶质细胞。缺乏CD44的小鼠在SGZ中的NSC增殖增加。在体外培养的NSC中也观察到这种增殖增加，这表明CD44以细胞自主方式调节NSC增殖。HA由NSC合成，并随着衰老在SGZ中增加。用HA处理野生型而非CD44缺失的NSC会抑制NSC增殖。在野生型NSC培养物或SGZ中进行HA消化会诱导NSC增殖增加，并且CD44缺失以及HA破坏的野生型NSC表现出延迟的神经元分化。因此，HA通过CD44发出信号来调节NSC的静止和分化，并且SGZ中HA的积累可能导致神经发生减少，这与空间记忆的年龄相关下降有关。
