HB-GAM inhibits proliferation and enhances differentiation of neural stem cells

Neuroscience Center, Department of Biosciences and Institute of Biotechnology, University of Helsinki, Helsinki 00014, Finland.
Molecular and Cellular Neuroscience (Impact Factor: 3.84). 06/2004; 26(1):75-88. DOI: 10.1016/j.mcn.2004.01.018
Source: PubMed


Proliferation of neural stem cells in the embryonic cerebral cortex is regulated by many growth factors and their receptors. Among the key molecules stimulating stem cell proliferation are FGF-2 and the FGF receptor-1. This ligand-receptor system is highly dependent on the surrounding heparan sulfates. We have found that heparin-binding growth-associated molecule (HB-GAM, also designated as pleiotrophin) regulates neural stem cell proliferation in vivo and in vitro. Deficiency of HB-GAM results in a pronounced, up to 50% increase in neuronal density in the adult mouse cerebral cortex. This phenotype arises during cortical neurogenesis, when HB-GAM knockout embryos display an enhanced proliferation rate as compared to wild-type embryos. Further, our in vitro studies show that exogenously added HB-GAM inhibits formation and growth of FGF-2, but not EGF, stimulated neurospheres, restricts the number of nestin-positive neural stem cells, and inhibits FGF receptor phosphorylation. We propose that HB-GAM functions as an endogenous inhibitor of FGF-2 in stem cell proliferation in the developing cortex.

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    • "Approximately 82% of the variance in EC thickness was accounted for by neuronal area and inter-neuronal distance in layers IV and V, suggesting that different but proportional neuronal area and inter-neuronal distance irregularities might exist in other cortical layers or that abnormalities exist exclusively in layers IV and V. Comparable overall EC thickness between KOs and WTs suggests the latter and indicates the presence of subtle, layer-specific neuronal irregularities not detectable via gross measures of overall cortical morphology. Collectively, these data are consistent with the observation of grossly normal brain size [24] but increased neuronal density in the frontal and parietal cortices of PTN KOs [9]. "
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    ABSTRACT: Pleiotrophin (PTN) is an extracellular matrix-associated protein with neurotrophic and neuroprotective effects that is involved in a variety of neurodevelopmental processes. Data regarding the cognitive-behavioral and neuroanatomical phenotype of pleiotrophin knockout (KO) mice is limited. The purpose of this study was to more fully characterize this phenotype, with emphasis on the domains of learning and memory, cognitive-behavioral flexibility, exploratory behavior and anxiety, social behavior, and the neuronal and vascular microstructure of the lateral entorhinal cortex (EC). PTN KOs exhibited cognitive rigidity, heightened anxiety, behavioral reticence in novel contexts and novel social interactions suggestive of neophobia, and lamina-specific decreases in neuronal area and increases in neuronal density in the lateral EC. Initial learning of spatial and other associative tasks, as well as vascular density in the lateral EC, was normal in the KOs. These data suggest that the absence of PTN in vivo is associated with disruption of specific cognitive and affective processes, raising the possibility that further study of PTN KOs might have implications for the study of human disorders with similar features.
    Full-text · Article · Jul 2014 · PLoS ONE
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    • "Overall our data suggests that endogenous PTN expression maintains the epithelial cells in an undifferentiated phenotype and that blocking its activity stimulates the expansion and differentiation of mammary progenitor cells as indicated by the altered CD29, CD49f, SCA-1 and CD10 expression profile. A role for PTN as a stem and progenitor cell regulator has already been described in the brain, bone and bone marrow [29], [31], [68] our data also suggest such a role for MECs. "
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    ABSTRACT: Expression of the heparin-binding growth factor, pleiotrophin (PTN) in the mammary gland has been reported but its function during mammary gland development is not known. We examined the expression of PTN and its receptor ALK (Anaplastic Lymphoma Kinase) at various stages of mouse mammary gland development and found that their expression in epithelial cells is regulated in parallel during pregnancy. A 30-fold downregulation of PTN mRNA expression was observed during mid-pregnancy when the mammary gland undergoes lobular-alveolar differentiation. After weaning of pups, PTN expression was restored although baseline expression of PTN was reduced significantly in mammary glands of mice that had undergone multiple pregnancies. We found PTN expressed in epithelial cells of the mammary gland and thus used a monoclonal anti-PTN blocking antibody to elucidate its function in cultured mammary epithelial cells (MECs) as well as during gland development. Real-time impedance monitoring of MECs growth, migration and invasion during anti-PTN blocking antibody treatment showed that MECs motility and invasion but not proliferation depend on the activity of endogenous PTN. Increased number of mammospheres with laminin deposition after anti-PTN blocking antibody treatment of MECs in 3D culture and expression of progenitor markers suggest that the endogenously expressed PTN inhibits the expansion and differentiation of epithelial progenitor cells by disrupting cell-matrix adhesion. In vivo, PTN activity was found to inhibit ductal outgrowth and branching via the inhibition of phospho ERK1/2 signaling in the mammary epithelial cells. We conclude that PTN delays the maturation of the mammary gland by maintaining mammary epithelial cells in a progenitor phenotype and by inhibiting their differentiation during mammary gland development.
    Full-text · Article · Oct 2012 · PLoS ONE
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    • "In mice, the Ptn gene is detected in a number of tissues and co-localizes with the Mk gene in many cases during embryogenesis [43]. Although PTN has important roles in various biological events such as differentiation of renal tubular epithelial cells and dopaminergic neurons [44], [45], Ptn−/− mice are fertile and exhibit no gross anatomical abnormalities except for abnormal structure and function of components of the nervous system [46], [47]. Recently, Muramatsu and collegues [56] reported that mice deficient in both Ptn and Mk were infertile and had abnormal estrous cycles with long periods of proestrus and diestrus and short periods of estrus [48]. "
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    ABSTRACT: Pleiotrophin (PTN) is a developmentally-regulated growth factor which is widely distributed in various tissues and also detected in many kinds of carcinomas. However, little is known about the PTN gene in chickens. In the present study, we found chicken PTN to be highly conserved with respect to mammalian PTN genes (91-92.6%) and its mRNA was most abundant in brain, heart and oviduct. This study focused on the PTN gene in the oviduct where it was detected in the glandular (GE) and luminal (LE) epithelial cells. Treatment of young chicks with diethylstilbesterol induced PTN mRNA and protein in GE and LE, but not in other cell types of the oviduct. Further, several microRNAs, specifically miR-499 and miR-1709 were discovered to influence PTN expression via its 3'-UTR which suggests that post-transcriptional regulation influences PTN expression in chickens. We also compared expression patterns and CpG methylation status of the PTN gene in normal and cancerous ovaries from chickens. Our results indicated that PTN is most abundant in the GE of adenocarcinoma of cancerous, but not normal ovaries of hens. Bisulfite sequencing revealed that 30- and 40% of -1311 and -1339 CpG sites are demethylated in ovarian cancer cells, respectively. Collectively, these results indicate that chicken PTN is a novel estrogen-induced gene expressed mainly in the oviductal epithelia implicating PTN regulation of oviduct development and egg formation, and also suggest that PTN is a biomarker for epithelial ovarian carcinoma that could be used for diagnosis and monitoring effects of therapies for the disease.
    Full-text · Article · Apr 2012 · PLoS ONE
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