CD44 Transmembrane Receptor and Hyaluronan Regulate Adult Hippocampal Neural Stem Cell Quiescence and Differentiation.
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 grownin vitro, 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.
From the Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon 97006.
Weiping
W
Su
From the Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon 97006.
Scott C
SC
Foster
From the Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon 97006.
Rubing
R
Xing
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.
Kerstin
K
Feistel
Departments of Behavioral Neuroscience.
Reid H J
RH
Olsen
Departments of Behavioral Neuroscience.
Summer F
SF
Acevedo
From the Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon 97006.|Departments of Behavioral Neuroscience.|Neurology and Radiation Medicine, and.
Jacob
J
Raber
From the Division of Neuroscience, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, Oregon 97006, shermanl@ohsu.edu.|Cell, Developmental and Cancer Biology, School of Medicine, Oregon Health and Science University, Portland, Oregon 97239.
Larry S
LS
Sherman
D000818:Animals; D002478:Cells, Cultured; D016922:Cellular Senescence; D005260:Female; D017353:Gene Deletion; D006624:Hippocampus / Q000166:cytology* / Q000378:metabolism; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism*; D006820:Hyaluronic Acid / Q000378:metabolism*; D051379:Mice; D058953:Neural Stem Cells / Q000166:cytology* / Q000378:metabolism; D055495:Neurogenesis
C476399:Cd44 protein, mouse; D018960:Hyaluronan Receptors; D006820:Hyaluronic Acid
CD44; hippocampus; hyaluronan; neural stem cell (NSC); neurogenesis