Estrogen-Receptor-Dependent Regulation of Neural Stem Cell Proliferation and Differentiation

Brännvall, Karin; Korhonen, Laura; Lindholm, Dan

doi:10.1006/mcne.2002.1194

Cited by 213 publications

(194 citation statements)

References 34 publications

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“…Our data support this finding, as we observed ESR1-mediated neuronal differentiation of SK-N-BE(2) cells. The importance of estrogen and its receptors during neural development is recapitulated in embryonic neuronal stem cells, which undergo differentiation in response to estradiol exposure (38). Clearly, estrogen signaling plays a pivotal role in neuroendocrine biology, which if impaired, may have detrimental consequences for normal developmental processes, including proper maturation and differentiation of progenitor cells derived from the sympathetic nervous system.…”

Section: Discussionmentioning

confidence: 99%

MYCN-regulated microRNAs repress estrogen receptor-α ( ESR1 ) expression and neuronal differentiation in human neuroblastoma

Lovén

Zinin

Wahlström

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

122

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MYCN, a proto-oncogene normally expressed in the migrating neural crest, is in its amplified state a key factor in the genesis of human neuroblastoma (NB). However, the mechanisms underlying MYCN-mediated NB progression are poorly understood. Here, we present a MYCN-induced miRNA signature in human NB involving the activation and transrepression of several miRNA genes from paralogous clusters. Several family members derived from the miR-17∼92 cluster, including miR-18a and miR-19a, were among the up-regulated miRNAs. Expression analysis of these miRNAs in NB tumors confirmed increased levels in MYCN-amplified samples. Specifically, we show that miR-18a and miR-19a target and repress the expression of estrogen receptor-α (ESR1), a ligand-inducible transcription factor implicated in neuronal differentiation. Immunohistochemical staining demonstrated ESR1 expression in human fetal sympathetic ganglia, suggesting a role for ESR1 during sympathetic nervous system development. Concordantly, lentiviral restoration of ESR1 in NB cells resulted in growth arrest and neuronal differentiation. Moreover, lentiviral-mediated inhibition of miR-18a in NB cells led to severe growth retardation, outgrowth of varicosity-containing neurites, and induction of neuronal sympathetic differentiation markers. Bioinformatic analyses of microarray data from NB tumors revealed that high ESR1 expression correlates with increased event-free survival in NB patients and favorable disease outcome. Thus, MYCN amplification may disrupt estrogen signaling sensitivity in primitive sympathetic cells through deregulation of ESR1, thereby preventing the normal induction of neuroblast differentiation. Collectively, our findings demonstrate the molecular consequences of abnormal miRNA transcription in a MYCN-driven tumor and offer unique insights into the pathology underlying MYCN-amplified NB.oncogene | embryonic development | pediatric tumor | transcription factor | hormone receptor N euroblastoma (NB) represents a remarkably heterogeneous pediatric cancer derived from precursor cells of the sympathetic ganglionic lineage, with clinical behavior ranging from spontaneous regression to rapid progression and death (1, 2). Despite the frequent display of multiple genetic defects, including chromosomal gains and losses, aneuploidy, and amplification of chromosomal material, few established molecular genetic markers associate with disease outcome. Amplification of the MYCN locus, present in ≈20 to 30% of all cases, represents the most important genetic aberration, and is strongly related to poor clinical diagnosis (3). MYCN is expressed in the migrating neural crest and encodes a phosphoprotein that belongs to the Myc network of helix-loop-helix leucine zipper transcriptional regulators, which play key roles in governing cell growth, apoptosis, and differentiation (4). Transcriptional activation is mediated by binding of the Myc/Max dimer to the consensus E-box sequence CA(C/T)GTG in target gene promoters while the mechanism of Myc-mediated transcriptional r...

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Section: Discussionmentioning

confidence: 99%

MYCN-regulated microRNAs repress estrogen receptor-α ( ESR1 ) expression and neuronal differentiation in human neuroblastoma

Lovén

Zinin

Wahlström

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

122

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“…The ERb knockout mice show regional neuronal hypocellularity, especially in the cerebral cortex, suggesting that ERb has a role in developmental and physiologic neurogenesis (Wang et al, 2003). Both ERa and b are expressed in embryonic and adult rat neural stem cells (Brannvall et al, 2002;Galea, 2008;Merchenthaler et al, 2004) derived from the adult SVZ; however, the role of ERs in physiological NG in vivo remains a subject of debate.…”

Section: Discussionmentioning

confidence: 99%

Estrogen Enhances Neurogenesis and Behavioral Recovery after Stroke

Siegel

Yuan

et al. 2010

J Cereb Blood Flow Metab

121

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Stroke is a leading cause of permanent disability and death. It is well accepted that the principal mammalian estrogen (E2), 17-b estradiol, provides robust neuroprotection in a variety of brain injury models in animals of both sexes. E2 enhances neurogenesis after stroke in the subventricular zone; however, it is unknown if these cells survive long-term or enhance functional recovery. In this study, we examined stroke-induced neurogenesis in male, gonadally intact female, and ovariectomized female mice 2 and 6 weeks after stroke. Treatment with 17-b estradiol increased 5-bromo-2 0 -deoxyuridine-labeled cells at both time points in both the dentate gyrus and subventricular zone; the majority were colabeled with doublecortin at 2 weeks and with NeuN at 6 weeks. Stroke-induced neurogenesis was reduced in estrogen receptor knockout mice, as well as in mice lacking the gene for aromatase, which converts testosterone into E2. Improved behavioral deficits were seen in E2-treated mice, suggesting that E2-induced increases in poststroke neurogenesis contribute to poststroke recovery.

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“…Estrogens induce the neuronal phenotype in embryonic stem cell culture and enhance proliferation of embryonic neural stem cells, increasing the ratio of neurons to glial cells (120,121). In combination with poly-L-ornithine/fibronectin, estrogens also have been shown to accelerate differentiation and maturation of neurons (121).…”

Section: Neural Stem Cellsmentioning

confidence: 99%

Sex Steroids and Stem Cell Function

Ray

Novotny

Crisostomo

et al. 2008

Mol Med

103

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Gender dimorphisms exist in the pathogenesis of a variety of cardiovascular, cardiopulmonary, neurodegenerative, and endocrine disorders. Estrogens exert immense influence on myocardial remodeling following ischemic insult, partially through paracrine growth hormone production by bone marrow mesenchymal stem cells (MSCs) and endothelial progenitor cells. Estrogens also facilitate the mobilization of endothelial progenitor cells to the ischemic myocardium and enhance neovascularization at the ischemic border zone. Moreover, estrogens limit pathological myocardial remodeling through the inhibitory effects on the proliferation of the cardiac fibroblasts. Androgens also may stimulate endothelial progenitor cell migration from the bone marrow, yet the larger role of androgens in disease pathogenesis is not well characterized. The beneficial effects of sex steroids include alteration of lipid metabolism in preadipocytes, modulation of bone metabolism and skeletal maturation, and prevention of osteoporosis through their effects on osteogenic precursors. In an example of sex steroid-specific effects, neural stem cells exhibit enhanced proliferation in response to estrogens, whereas androgens mediate inhibitory effects on their proliferation. Although stem cells can offer significant therapeutic benefits in various cardiovascular, neurodegenerative, endocrine disorders, and disorders of bone metabolism, a greater understanding of sex hormones on diverse stem cell populations is required to improve their ultimate clinical efficacy. In this review, we focus on the effects of estrogen and testosterone on various stem and progenitor cell types, and their relevant intracellular mechanisms.

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Estrogen-Receptor-Dependent Regulation of Neural Stem Cell Proliferation and Differentiation

Cited by 213 publications

References 34 publications

MYCN-regulated microRNAs repress estrogen receptor-α ( ESR1 ) expression and neuronal differentiation in human neuroblastoma

MYCN-regulated microRNAs repress estrogen receptor-α ( ESR1 ) expression and neuronal differentiation in human neuroblastoma

Estrogen Enhances Neurogenesis and Behavioral Recovery after Stroke

Sex Steroids and Stem Cell Function

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