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Glypican-2 levels in cerebrospinal fluid predict the status of adult hippocampal neurogenesis.

ABSTRACT: Adult hippocampal neurogenesis is a remarkable form of brain plasticity through which new neurons are generated throughout life. Despite its important roles in cognition and emotion and its modulation in various preclinical disease models, the functional importance of adult hippocampal neurogenesis in human health has not been revealed because of a lack of tools for monitoring adult neurogenesis in vivo. Therefore, we performed an unbiased proteomics screen to identify novel proteins expressed during neuronal differentiation using a human neural stem cell model, and we identified the proteoglycan Glypican-2 (Gpc2) as a putative secreted marker of immature neurons. Exogenous Gpc2 binds to FGF2 and inhibits FGF2-induced neural progenitor cell proliferation. Gpc2 is enriched in neurogenic regions of the adult brain. Its expression is increased by physiological stimuli that increase hippocampal neurogenesis and decreased in transgenic models in which neurogenesis is selectively ablated. Changes in neurogenesis also result in changes in Gpc2 protein level in cerebrospinal fluid (CSF). Gpc2 is detectable in adult human CSF, and first pilot experiments with a longitudinal cohort indicate a decrease over time. Thus, Gpc2 may serve as a potential marker to monitor adult neurogenesis in both animal and human physiology and disease, warranting future studies.

SUBMITTER: Lugert S

PROVIDER: S-EPMC5404329 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Glypican-2 levels in cerebrospinal fluid predict the status of adult hippocampal neurogenesis.

Lugert S S Kremer T T Jagasia R R Herrmann A A Aigner S S Giachino C C Mendez-David I I Gardier A M AM Carralot J P JP Meistermann H H Augustin A A Saxe M D MD Lamerz J J Duran-Pacheco G G Ducret A A Taylor V V David D J DJ Czech C C

Scientific reports 20170425

Adult hippocampal neurogenesis is a remarkable form of brain plasticity through which new neurons are generated throughout life. Despite its important roles in cognition and emotion and its modulation in various preclinical disease models, the functional importance of adult hippocampal neurogenesis in human health has not been revealed because of a lack of tools for monitoring adult neurogenesis in vivo. Therefore, we performed an unbiased proteomics screen to identify novel proteins expressed d ...[more]

PMID: 28440309

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Project description:Adult neurogenesis is the life-long process of neural stem cell proliferation, differentiation into neurons, migration, and incorporation into the existing neuronal circuits. After decades of research, it is now widely accepted that mammals and birds retain the capacity to regenerate neurons even after their subadult ontogeny. Cerebrospinal fluid participates in the regulation of the neurogenic niches of the vertebrate brain through signaling pathways not fully elucidated. Proteomic studies of cerebrospinal fluid have the potential to allow the in-depth characterization of its molecular composition. Comparative studies help to delineate those pathways that are universally critical for the regulation of neurogenesis in adulthood. In this review, we performed literature-based data mining in studies using liquid chromatography-tandem mass spectroscopy that analyzed cerebrospinal fluid samples from healthy adult humans (Homo sapiens); mice (Mus musculus); sheep (Ovis aries); chickens (Gallus gallus); and two parrot species, the budgerigar (Melopsittacus undulatus) and cockatiel (Nymphicus hollandicus). We identified up to 911 proteins represented in cerebrospinal fluid, involved in various pathways regulating adult neurogenesis. However, only 196 proteins were common across humans, mice, and birds. Pathway components involved in nervous system development, cell migration, and axonal guidance were commonly evident in all species investigated so far. Extensive bioinformatic analysis revealed that the universally over-represented pathways involved L1 cell adhesion molecule protein interactions, cell-adhesion molecules, signals regulating extracellular matrix remodeling, regulation of insulin growth factor signaling, axonal guidance, programmed cell death, immune signaling, and post-translational modifications. Most of the reported proteins are part of extracellular vesicles enriched in cerebrospinal fluid. However, the information presently available is still highly fragmentary, and far more questions persist than are answered. Technological advances will allow cerebrospinal fluid comparative proteomic research to delve into the fundamental processes of adult neurogenesis and eventually translate this research into any regenerative interventions.

Project description:Comparison of neurodevelopmental sequences between species whose initial period of brain organization may vary from 100 days to 1,000 days, and whose progress is intrinsically non-linear presents large challenges in normalization. Comparing adult timelines when lifespans stretch from 1 year to 75 years, when underlying cellular mechanisms under scrutiny do not scale similarly, presents challenges to simple detection and comparison. The question of adult hippocampal neurogenesis has generated numerous controversies regarding its simple presence or absence in humans versus rodents, whether it is best described as the tail of a distribution centered on early neural development, or is several distinct processes. In addition, adult neurogenesis may have substantially changed in evolutionary time in different taxonomic groups. Here, we extend and adapt a model of the cross-species transformation of early neurodevelopmental events which presently reaches up to the equivalent of the third human postnatal year for 18 mammalian species (www.translatingtime.net) to address questions relevant to hippocampal neurogenesis, which permit extending the database to adolescence or perhaps to the whole lifespan. We acquired quantitative data delimiting the envelope of hippocampal neurogenesis from cell cycle markers (i.e., Ki67 and DCX) and RNA sequencing data for two primates (macaque and humans) and two rodents (rat and mouse). To improve species coverage in primates, we gathered the same data from marmosets (Callithrix jacchus), but additionally gathered data on a number of developmental milestones to find equivalent developmental time points between marmosets and other species. When all species are so modeled, and represented in a common time frame, the envelopes of hippocampal neurogenesis are essentially superimposable. Early developmental events involving the olfactory and limbic system start and conclude possibly slightly early in primates than rodents, and we find a comparable early conclusion of primate hippocampal neurogenesis (as assessed by the relative number of Ki67 cells) suggesting a plateau to low levels at approximately 2 years of age in humans. Marmosets show equivalent patterns within neurodevelopment, but unlike macaque and humans may have wholesale delay in the initiation of neurodevelopment processes previously observed in some precocial mammals such as the guinea pig and multiple large ungulates.

Dataset Information

Glypican-2 levels in cerebrospinal fluid predict the status of adult hippocampal neurogenesis.

Publications

Glypican-2 levels in cerebrospinal fluid predict the status of adult hippocampal neurogenesis.

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