Retinoic Acid Selectively Promotes the Survival and Proliferation of Neurogenic Precursors in Cultured Neural Crest Cell Populations

doi:10.1006/dbio.1994.1024

Developmental Biology

Volume 161, Issue 1, January 1994, Pages 243-250

https://doi.org/10.1006/dbio.1994.1024 Get rights and content

Abstract

The neural crest produces both neuronal and nonneuronal derivatives in response to a variety of environmental cues. Here, we have analyzed the effects of retinoic acid on the differentiative behavior of quail trunk neural crest cells in vitro. We show that retinoic acid selectively increases neurogenesis in cultured neural crest cell populations, probably by promoting the survival and stimulating the proliferation of neuronal precursors. Our results suggest that neural crest-derived neurogenic precursors are specific targets for retinoic acid in vitro and raise the possibility that retinoic acid promotes the generation of peripheral neurons in vivo.

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Cyanobacterial blooms are known sources of environmentally-occurring retinoid compounds, including all-trans and 9-cis retinoic acids (RAs). The developmental hazard for aquatic organisms has been described, while the implications for human health hazard assessment are not yet sufficiently characterized. Here, we employ a human neural stem cell model that can differentiate in vitro into a mixed culture of neurons and glia. Cells were exposed to non-cytotoxic 8–1000 nM all-trans or 9-cis RA for 9–18 days (DIV13 and DIV22, respectively). Impact on biomarkers was analyzed on gene expression (RT-qPCR) and protein level (western blot and proteomics) at both time points; network patterning (immunofluorescence) on DIV22. RA exposure significantly concentration-dependently increased gene expression of retinoic acid receptors and the metabolizing enzyme CYP26A1, confirming the chemical-specific response of the model. Expression of thyroid hormone signaling-related genes remained mostly unchanged. Markers of neural progenitors/stem cells (PAX6, SOX1, SOX2, NESTIN) were decreased with increasing RA concentrations, though a basal population remained. Neural markers (DCX, TUJ1, MAP2, NeuN, SYP) remained unchanged or were decreased at high concentrations (200–1000 nM). Conversely, (astro-)glial marker S100β was increased concentration-dependently on DIV22. Together, the biomarker analysis indicates an RA-dependent promotion of glial cell fates over neural differentiation, despite the increased abundance of neural protein biomarkers during differentiation. Interestingly, RA exposure induced substantial changes to the cell culture morphology: while low concentrations resulted in a network-like differentiation pattern, high concentrations (200–1000 nM RA) almost completely prevented such network patterning. After functional confirmation for implications in network function, such morphological features could present a proxy for network formation assessment, an apical key event in (neuro-)developmental Adverse Outcome Pathways. The described application of a human in vitro model for (developmental) neurotoxicity to emerging environmentally-relevant retinoids contributes to the evidence-base for the use of differentiating human in vitro models for human health hazard and risk assessment.
Neuroblastoma differentiation in vivo excludes cranial tumors
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NCCs respond to myriad signaling factors and differentiate into a variety of derivatives that include peripheral nervous system neurons (Kasemeier-Kulesa et al., 2005; Saxena et al., 2013; Teillet et al., 1987). BDNF promotes a sensory neuron fate in NCCs (Liebl et al., 2000; Sieber-Blum, 1991; Sieber-Blum et al., 1993), and RA may also have some ability to contribute to NC differentiation (Henion and Weston, 1994; Ito and Morita, 1995). Thus, we hypothesize that mutated NCCs transformed into malignant NB cells in human embryos retain some ability to respond to differentiating signals.
Neuroblastoma (NB), the most common cancer in the first year of life, presents almost exclusively in the trunk. To understand why an early-onset cancer would have such a specific localization, we xenotransplanted human NB cells into discrete neural crest (NC) streams in zebrafish embryos. Here, we demonstrate that human NB cells remain in an undifferentiated, tumorigenic state when comigrating posteriorly with NC cells but, upon comigration into the head, differentiate into neurons and exhibit decreased survival. Furthermore, we demonstrate that this in vivo differentiation requires retinoic acid and brain-derived neurotrophic factor signaling from the microenvironment, as well as cell-autonomous intersectin-1-dependent phosphoinositide 3-kinase-mediated signaling, likely via Akt kinase activation. Our findings suggest a microenvironment-driven explanation for NB’s trunk-biased localization and highlight the potential for induced differentiation to promote NB resolution in vivo.
The orchestra of lipid-transfer proteins at the crossroads between metabolism and signaling
2016, Progress in Lipid Research
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Two good examples are the epidermal FABP5 and CRABP2, which translocate to the nucleus upon binding to retinoic acid and tunnel it to the peroxisome proliferator-activated receptor δ (PPARD) and the retinoic acid receptor-activated receptor α (RARΑ), respectively [86–89]. The two nuclear receptors activate opposing signaling cascades: RARΑ activates a pro-apoptotic cascade, whereas PPARD promotes cell survival [90–92], cell proliferation and tumorigenesis [93]. The ratio between FABP5 and CRABP2 thus determines pro- and anti-apoptotic responses.
Within the eukaryotic cell, more than 1000 species of lipids define a series of membranes essential for cell function. Tightly controlled systems of lipid transport underlie the proper spatiotemporal distribution of membrane lipids, the coordination of spatially separated lipid metabolic pathways, and lipid signaling mediated by soluble proteins that may be localized some distance away from membranes. Alongside the well-established vesicular transport of lipids, non-vesicular transport mediated by a group of proteins referred to as lipid-transfer proteins (LTPs) is emerging as a key mechanism of lipid transport in a broad range of biological processes. More than a hundred LTPs exist in humans and these can be divided into at least ten protein families. LTPs are widely distributed in tissues, organelles and membrane contact sites (MCSs), as well as in the extracellular space. They all possess a soluble and globular domain that encapsulates a lipid monomer and they specifically bind and transport a wide range of lipids. Here, we present the most recent discoveries in the functions and physiological roles of LTPs, which have expanded the playground of lipids into the aqueous spaces of cells.
In vitro characteristics of Valproic acid and all-trans-retinoic acid and their combined use in promoting neuronal differentiation while suppressing astrocytic differentiation in neural stem cells
2015, Brain Research
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Moreover, the expression levels of neural growth factors, especially brain-derived neurotrophic factor (BDNF), are also up-regulated by VPA, resulting in improved neuronal survival and maturation and neurite outgrowth (Chen et al., 2006; Lv et al., 2012; Yasuda et al., 2009). All-trans-retinoic acid (ATRA) also induces neuronal differentiation while blocking astrocyte production in NSCs (Christie et al., 2010; Henion and Weston, 1994; Takahashi et al., 1999; Wohl and Weiss, 1998), and ATRA facilitates neuronal survival and neurite outgrowth in cultured neurons (Chen et al., 2008; Erceg et al., 2008; Quinn and De Boni, 1991; Wuarin and Sidell, 1991). The underlying mechanism involves the stimulation of β-catenin expression (Israsena et al., 2004), the transcriptional activation of NeuroD (Kuwabara et al., 2009) and the subsequent up-regulation of p21Cip/WAF1 (Takahashi et al., 1999; Zhang et al., 2009).
Multipotent neural stem cells (NSCs) are currently under investigation as a candidate treatment for central nervous system (CNS) injury because of their potential to compensate for neuronal damage and to reconstruct disrupted neuronal connections. To maximize the regenerative effect of the derived neurons and to minimize the side effects of the derived astrocytes, it is necessary to regulate the fate determination of NSCs to produce more neurons and fewer astrocytes. Both valproic acid (VPA) and all-trans-retinoic acid (ATRA), two clinically established drugs, induce neuronal differentiation and facilitate neurite outgrowth at the expense of astrocytic differentiation in NSCs. However, the time-dependent activities and the long-term treatment effects of these drugs have not been explored in NSCs. More importantly, the efficacies of VPA and ATRA in neuronal promotion and astrocytic suppression remain unclear. In this study, we compare the time-dependent characteristics of VPA and ATRA in NSC differentiation and neurite outgrowth in vitro and, for the first time, demonstrate the improved efficacy of their combined application in neuronal induction and astrocytic suppression. These significant effects are closely coupled to the altered expression of a neurogenic transcription factor, a Wnt signaling component, a cell cycle regulator and a neural growth factor, indicating an underlying cross-talk between the mechanisms of action of ATRA and VPA. These findings indicate that a novel strategy combining these two therapeutic drugs may improve the restorative effect of NSC transplantation by altering the expression of their interconnected targets for fate determination.
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Much of the peripheral nervous system (PNS) is derived from trunk neural crest. Trunk neural crest is an initially multipotent cell population that must migrate and undergo cell fate decisions in order to generate the diversity of cell types that exists in the PNS. Here, we discuss the generation of the sympathetic chain ganglia and the dorsal root ganglia (DRG) from neural crest, specifically focusing on the gene regulatory network that contributes to their development. Neural crest is induced to develop as sympathetic neurons by BMP emanating from the aorta. This initiates a transcription factor cascade beginning with Ascl1. This network involves extensive cross-regulation terminating in the expression of tyrosine hydroxylase and dopamine-β-hydroxylase. DRG are induced to develop by unknown signals; expression of the Neurogenin transcription factors initiates a more sequential cascade ending in the expression of Trk receptors, which are restricted to neuronal subtypes carrying different sensory modalities.
Quantification of retinoid concentrations in human serum and brain tumor tissues
2012, Analytica Chimica Acta
Citation Excerpt :
Retinoic acid is essential for proper development of the central nervous system (CNS) [1–3] and aberrant retinoic acid signaling is a characteristic of a variety of tumors [4–6] including brain tumors [7].
Retinoic acid signaling is essential for central nervous system (CNS) differentiation and appears to be impaired in tumors. Thus far, there are no established methods to quantify relevant retinoids (all-trans-retinoic acid, 9-cis-retinoic acid, 13-cis retinoic acid, and retinol) in human brain tumors. We developed a single step extraction and quantification procedure for polar and apolar retinoids in normal tissue, lipid-rich brain tumor tissues, and serum. This quantification procedure is based on high performance liquid chromatography (HPLC) with diode-array detection (DAD) using all-trans-acitretin as an internal standard and extraction by liquid–liquid partition with ethyl acetate and borate buffer at pH 9. Recovery with this extraction procedure was higher than earlier (two-step) liquid–liquid extraction procedures based on hexane, NaOH, and HCl. The overall quantification procedure was validated according to Food and Drug Administration (FDA) guidelines and fulfilled all criteria of accuracy, precision, selectivity, recovery, and stability. The overall method accuracy varied between −5.6% and +5.4% for serum and −3.8% and +6.2% for tissues, and overall precision ranged from 3.1% to 6.9% for serum and 2.1% to 8.3% for tissues (%CV batch-to-batch). The lower limit of quantification for all compounds in tumor tissue (and serum) was 3.9 ng g⁻¹ (ng mL⁻¹). Using this assay, photodegradation of the retinoids was evaluated and endogenous polar and apolar retinoids were quantified in sera and brain tumor tissues of patients and compared with serum and tonsil tissue concentrations of controls. It may thus serve as a suitable method for the characterization of retinoid uptake and metabolism in the respective compartments.

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Full PapersRetinoic Acid Selectively Promotes the Survival and Proliferation of Neurogenic Precursors in Cultured Neural Crest Cell Populations

Abstract

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Retinoic Acid Selectively Promotes the Survival and Proliferation of Neurogenic Precursors in Cultured Neural Crest Cell Populations