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BMP2 and FGF2 Cooperate to Induce Neural-Crest-Like Fates from Fetal and Adult CNS Stem Cells

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BMP2 and FGF2 Cooperate to Induce Neural-Crest-Like Fates from Fetal and Adult CNS Stem Cells Research Article 5849 BMP2 and FGF2 cooperate to induce neural-crest-like fates from fetal and adult CNS stem cells Martin H. M. Sailer1,2,3, Thomas G. Hazel1, David M. Panchision1,4, Daniel J. Hoeppner1, Martin E. Schwab2,3 and Ronald D. G. McKay1,* 1Laboratory of Molecular Biology, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA 2Brain Research Institute, University of Zurich, 8057 Zurich, Switzerland 3Department of Biology, Swiss Federal Institute of Technology, 8057 Zurich, Switzerland 4Center for Neuroscience Research, Children’s Research Institute, Children’s National Medical Center, Washington DC, 20010, USA *Author for correspondence (e-mail: [email protected]) Accepted 21 September 2005 Journal of Cell Science 118, 5849-5860 Published by The Company of Biologists 2005 doi:10.1242/jcs.02708 Summary CNS stem cells are best characterized by their ability to stem cells from E14.5 cortex, E18.5 cortex and adult self-renew and to generate multiple differentiated subventricular zone, but with a progressive shift toward derivatives, but the effect of mitogenic signals, such as gliogenesis that is characteristic of normal development. fibroblast growth factor 2 (FGF2), on the positional identity These data indicate that FGF2 confers competence for of these cells is not well understood. Here, we report that dorsalization independently of its mitogenic action. This bone morphogenetic protein 2 (BMP2) induces rapid and efficient induction of dorsal fates may allow telencephalic CNS stem cells to fates characteristic of identification of positional identity effectors that are co- neural crest and choroid plexus mesenchyme, a cell type of regulated by FGF2 and BMP2. undetermined lineage in rodents. This induction occurs both in dissociated cell culture and cortical explants of embryonic day 14.5 (E14.5) embryos, but only when cells have been exposed to FGF2. Neither EGF nor IGF1 can Supplementary material available online at substitute for FGF2. An early step in this response is http://jcs.biologists.org/cgi/content/full/118/24/5849/DC1 activation of ␤-catenin, a mediator of Wnt activity. The CNS stem cells first undergo an epithelial-to-mesenchymal Key words: Forebrain, Neural stem cell, Cranial neural crest, transition and subsequently differentiate to smooth-muscle Choroid plexus mesenchyme (CPm), Epithelial-mesenchymal and non-CNS glia cells. Similar responses are seen with transition (EMT), Snai1, Snai2 Journal of Cell Science Introduction midline of the neural tube (Lee and Jessell, 1999b; Meulemans Clonal analysis shows that stem cells can be derived from the and Bronner-Fraser, 2004). In the anterior neural tube, central nervous system (CNS) and maintained in culture by the including the telencephalon, choroid plexus (CP) is the dorsal- mitogenic actions of FGF2 (Johe et al., 1996). FGF2 and most region. BMP signaling is both necessary and sufficient epidermal growth factor (EGF) are the only known growth for the generation of the CP (Hebert et al., 2002; Panchision et factors that, by themselves, can drive the mitogenic expansion al., 2001). In the more posterior neural tube, BMPs induce roof of neural precursor cells in vitro (Panchision and McKay, plate and neural crest cells (Lee and Jessell, 1999a). Neural 2002). The use of FGF2 as an exogenous mitogen is supported crest cells are a specialized dorsal cell type, unique to by its actions in vivo. FGF2 is expressed together with FGF1 vertebrates, that delaminate from the neural and/or non-neural in the ventricular zone of the developing cortex (Dono, 2003; ectoderm border from regions posterior to the mid- Grove and Fukuchi-Shimogori, 2003). Mice lacking FGF2 diencephalon, and then migrate to distant sites in the embryo show a cerebral cortex size that is diminished by about 45%, (Bronner-Fraser, 2002; Knecht and Bronner-Fraser, 2002; affecting both neurons and glia cells (Vaccarino et al., 1999). Trainor et al., 2002; Wu et al., 2003). The neural crest gives However, it has also been proposed that FGFs can act as rise to peripheral nervous system (PNS) derivatives such as ventralizing signals in mouse cortical explants and cultured peripheral neurons and Schwann cells, along with non-neural neural precursors (Gabay et al., 2003; Kessaris et al., 2004; derivatives such as melanocytes, craniofacial chondrocytes, Kuschel et al., 2003). osteocytes and perivascular cells (smooth muscle, pericytes, Cell fate in the developing CNS is specified in part by connective tissue) (Gammill and Bronner-Fraser, 2003; Le growth factors that are localized in distinct dorsal and ventral Douarin and Kalcheim, 1999; Meulemans and Bronner-Fraser, organizer domains (Lee and Jessell, 1999b; Wilson and 2004; Trainor et al., 2002; Wu et al., 2003). Rubenstein, 2000). Bone morphogenetic proteins (BMPs) are Previous work has shown that BMPs promote the generation secreted factors expressed in the prospective epidermis at the of mesenchymal derivatives with neural-crest-like phenotypes lateral edges of the neural plate, then subsequently in the dorsal from CNS precursors in vitro (Gajavelli et al., 2004; Mujtaba 5850 Journal of Cell Science 118 (24) et al., 1998; Rajan et al., 2003). This is in contrast to other recombinant mouse noggin at 2.5 ng/ml; rhIGF1 at 330 ng/ml; bovine studies that have shown CNS neuronal or glial differentiation pancreatic insulin at 25 ␮g/ml (Sigma). To promote neuronal survival after BMP treatment (Gross et al., 1996; Li et al., 1998; Mehler and maturation, we used B27 supplement (1:100 dilution, Invitrogen), et al., 2000), suggesting a context-dependent component to the 40 nM retinoic acid (Sigma), 10 ng/ml nerve growth factor (rhNGF), ␤ BMP response. In this study, we show that exposure to FGF2 10 ng/ml heregulin 1 (rhHRG), 10 ng/ml recombinant rat brain- is required for BMPs to generate neural-crest-like cells in derived growth factor (BDNF) and 10 ng/ml glial-cell-line-derived neurotrophic factor (rrGDNF). cortical explants or cultured stem cells. Co-treatment with FGF2 and BMP2 rapidly upregulates ␤-catenin, a mediator of Wnt activity (Moon et al., 2004) and of Bmp2 itself, suggesting Culture of cortical explants a positive feedback of BMP-signaling. This is consistent with E14.5 rat telencephalon was dissected to be completely free of a role for Wnt-signaling in regulating dorso-ventral identity in meninges. A cortex section of about 800 ␮m by 3200 ␮m along the the developing telencephalon of chick and mouse (Backman et length of the medial ganglionic eminence (MGE) in a distance of al., 2005; Gunhaga et al., 2003). FGF2 and BMP2 treatment about 800 ␮m from the MGE and starting at the anterior MGE pole initially induces genes associated with the epithelial- was dissected (Fig. 1). This section was used for explants of 400-800 ␮ mesenchymal transition (EMT) to a neural-crest-like state m in diameter. The explants were generated by cutting the cortex (Nieto, 2002), followed by terminal differentiation into tissue section into smaller pieces with a microsurgical needle (tungsten); they were grown in the same conditions as CNS stem cells derivatives such as smooth muscle and non-CNS glia. (see below), except for the omission of insulin, progesterone, Forebrain stem cells from multiple ages retain the competence putrescine and selenium from the medium (basal medium). for this dorsal respecification. Peripheral neurons are not Transferrin, an iron-binding protein necessary for efficient iron generated under these conditions, but can be induced at low metabolism, was maintained in culture because its removal caused frequency when stem cells are co-treated with the growth retardation and some cell death (data not shown). Medium posteriorizing factor retinoic acid. Thus, although these cell with growth factors was replaced every other day. The explants were types are characteristic of neural crest, the anterior origin of washed twice with basal medium between the first and second phase the responding cells biases the FGF-BMP-Wnt-induced dorsal of treatment (see Table 1). The responses to growth factors were transition to a phenotype most similar to cranial mesenchyme recorded by phase-contrast microscopy using a Zeiss Axiovert 10 or choroid plexus mesenchyme (CPm). microscope (Carl Zeiss Inc.). Culture of CNS stem cells Materials and Methods Both fetal and adult CNS stem cells were isolated and cultured as Growth factors previously described (Johe et al., 1996; Kim et al., 2003) in Dulbecco’s Growth factors were used at the following concentrations (all from modifies Eagle’s medium (DMEM) F12 with N2 supplements (Kim et R&D Systems with BSA as carrier protein, if not otherwise stated): al., 2003), unless otherwise noted. We used E14.5- (Taconic E15) and recombinant human (rh) FGF2 at 10 ng/ml (146 aa) for fetal and at E18.5- (Taconic E19) timed pregnant Sprague Dawley rats (Taconic, 20 ng/ml for adult stem cells; rhBMP2, BMP4, BMP7 at 20 ng/ml; Germantown, NY; noon of day of plug detection equals E0.5). Adult rats Journal of Cell Science Fig. 1. Expression of p75NGFR, SMA and GFAP in the E14.5 rat forebrain and cranial mesenchyme. Fluorescent antibody staining of E14.5 rat embryo at the telencephalic level. Illustration at upper left orients panels A-G. Red rectangle with asterisk illustrates the cortical region dissected for all experiments. (A) p75NGFR (green) and smooth muscle ␣-actin (red) show little or no expression in brain but high levels of p75NGFR in cranial mesenchyme and peripheral ganglia. Arrow indicates choroid plexus. (B-D) Higher magnification, showing (B) cranial mesenchyme, (C) choroid plexus (arrow) and confocal image of choroid plexus epithelium (CPe) and (D-F) mesenchyme. Notice that some CPm cells are p75NGFR+/SMA+, whereas the CPe shows fainter staining for these markers. (G) CPe shows moderate co-expression of p75NGFR (green) and GFAP (red), whereas the CPm is strongly p75NGFR+/GFAP+. Cranial mesenchyme is stongly p75NGFR+ but only weakly GFAP+.
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