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Developmental Requirement of Gp130 Signaling in Neuronal Survival and Astrocyte Differentiation

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Developmental Requirement of Gp130 Signaling in Neuronal Survival and Astrocyte Differentiation The Journal of Neuroscience, July 1, 1999, 19(13):5429–5434 Developmental Requirement of gp130 Signaling in Neuronal Survival and Astrocyte Differentiation Kinichi Nakashima,1,2 Stefan Wiese,3 Makoto Yanagisawa,1 Hirokazu Arakawa,1 Naoki Kimura,1 Tatsuhiro Hisatsune,4 Kanji Yoshida,5 Tadamitsu Kishimoto,6 Michael Sendtner,3 and Tetsuya Taga1 1Department of Molecular Cell Biology and 2Cell Fate Modulation Research Unit, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, 101–0062, Japan, 3Clinical Research Unit for Neuroregeneration, Department of Neurology, University of Wu¨ rzburg, Wu¨ rzburg, 97080, Germany, 4Division of Integrated Biosciences, Graduate School for Frontier Science, The University of Tokyo, Tokyo, 113–8657, Japan, and 5Department of Molecular Immunology, Research Institute for Microbial Diseases, 6Osaka University, Osaka, 565–0871, Japan gp130 is a signal-transducing receptor component used in loss was detectable on day 14.5, suggesting a physiological common by the interleukin-6 (IL-6) family of hematopoietic and role of gp130 in supporting newly generated neurons during the neurotrophic cytokines, including IL-6, IL-11, leukemia- late phase of development when naturally occurring cell death inhibitory factor, ciliary neurotrophic factor, oncostatin-M, and takes place. Moreover, expression of an astrocyte marker, cardiotrophin-1. We have examined in this study a role of gp130 GFAP, was severely reduced in the brain of gp130 2/2 mice. in the nervous system by analyzing developmental cell death of Our data demonstrate that gp130 expression is essential for several neuronal populations and the differentiation of astro- survival of subgroups of differentiated motor and sensory neu- cytes in gp130-deficient mice. A significant reduction was ob- rons and for the differentiation of major populations of astro- served in the number of sensory neurons in L5 dorsal root cytes in vivo. ganglia and motoneurons in the facial nucleus, the nucleus ambiguus, and the lumbar spinal cord in gp130 2/2 mice on Key words: gp130; deficient mice; cytokine; astrocyte; motor embryonic day 18.5. On the other hand, no significant neuronal neuron; sensory neuron The interleukin-6 (IL-6) family of cytokines, i.e., IL-6, IL-11, stimulating cytokines (Stewart et al., 1992; Escary et al., 1993; leukemia inhibitory factor (LIF), ciliary neurotrophic factor Masu et al., 1993; Kopf et al., 1994). In contrast, mice lacking (CNTF), oncostatin-M (OSM), and cardiotrophin-1 (CT-1), dis- gp130 or LIFR die during development or shortly after birth (Li play an array of biological functions (Taga et al., 1989; Kishimoto et al., 1995; Ware et al., 1995; Yoshida et al., 1996, 1998; Ka- et al., 1994; Taga and Kishimoto, 1997). All these cytokines use wasaki et al., 1997). gp130-deficient mice exhibit defects in myo- gp130 in their respective receptor complexes as a signal- cardium and hematopoiesis (Yoshida et al., 1996, 1998). Mice transducing component (Taga et al., 1989, 1992; Kishimoto et al., deficient for gp130 or LIFR show placental defects and reduced 1994; Stahl and Yancopoulos, 1994; Taga and Kishimoto, 1997), bone mass (Ware et al., 1995; Kawasaki et al., 1997; Yoshida et which explains their functional overlaps. These cytokines signal al., 1998). through either homodimers of gp130 (for IL-6 and IL-11) or Within the nervous system, LIF, CNTF, CT-1, and OSM heterodimers comprising gp130 and a dimer partner, such as an support survival of several types of neurons in vitro (Ernsberger et LIF receptor (LIFR) (for LIF, CNTF, OSM, and CT-1) and an al., 1989; Martinou et al., 1992; Taga, 1996; Horton et al., 1998). OSM-specific receptor component (OSMR) (for OSM) (Davis et They induce cholinergic properties in cultured autonomic neu- al., 1993; Murakami et al., 1993; Kishimoto et al., 1994; Taga and rons (Yamamori et al., 1989; Patterson, 1994). CNTF induces Kishimoto, 1997). differentiation of autonomic neurons (Ernsberger et al., 1989). Mice lacking IL-6, LIF, or CNTF displayed phenotypes less IL-6 and IL-11 promote neuronal differentiation of pheochromo- severe than expected from pleiotropic nature of each cytokine, cytoma and hippocampal precursors, respectively (Satoh et al., presumably because of compensation by the remaining gp130- 1988; Mehler et al., 1993). Stimulation of gp130 also induces differentiation of astrocytes (Johe et al., 1996; Bonni et al., 1997; Received Jan. 13, 1999; revised April 14, 1999; accepted April 20, 1999. McKay, 1997). Mice deficient for either CNTF or LIF were born This work has been supported by a grant-in-aid from the Ministry of Education, Science, and Culture, Human Frontier Science Program, Cell Science Research normally (Stewart et al., 1992; Escary et al., 1993; Masu et al., Foundation, Kowa Life Science foundation, and Cell Fate Modulation Research 1993), showing no developmental abnormalities in the nervous Unit of Medical Research Institute of Tokyo Medical and Dental University. We system, but exhibited mild loss of motor neurons in the adulthood thank Dr. Hiroshi Kiyama for helpful comments and discussions and Dr. Kiyoshi Yasukawa for generously providing us with sIL-6R. We are very grateful to Yuko (Masu et al., 1993). Crossing these two lines accelerated motor Nakamura for her excellent secretarial assistance. We also thank Kyoko Saito for neuron degeneration, but the defect was still moderate (Sendtner technical help. Preparation of histological samples was done with generous help and suggestions of Tayoko Tajima, Hiromi Tanizawa, Dr. Toshihiro Kuroiwa, and Dr. et al., 1996). In contrast, CNTF receptor (CNTFR) knock-outs Riki Okeda. showed neonatal lethality and significant reduction in the number Correspondence should be addressed to Dr. Tetsuya Taga, Department of Mo- of motor neurons (DeChiara et al., 1995). A similar neurological lecular Cell Biology, Medical Research Institute, Tokyo Medical and Dental Uni- versity, 2–3-10 Kanda-Surugadai, Chiyoda-ku Tokyo 101–0062, Japan. defect was observed in LIFR-deficient mice (Li et al., 1995), Copyright © 1999 Society for Neuroscience 0270-6474/99/195429-06$05.00/0 suggesting the presence of a cytokine, other than CNTF, which 5430 J. Neurosci., July 1, 1999, 19(13):5429–5434 Nakashima et al. • Neurological Defects in Mice Lacking gp130 binds to CNTFR and signals through an LIFR–gp130 complex. and occasionally tapped to suspend DRG fragments in every 5 min. After m LIFR-deficient mice exhibited astrocyte loss as well (Ware et al., 10–15 min, 50 l of FCS was added to each well to stop trypsinization. DRG cells were gently suspended with 1 ml pipet tip (Gilson) and passed 1995; Koblar et al., 1998). Although mitotic oligodendrocytes through #300 nylon mesh to remove debris and aggregates. Cells were were moderately reduced in the postnatal optic nerve of CNTF- plated in duplicates in flat-bottom 96-well Biocoat poly-D-lysine–mouse deficient mice, astrocytes looked normal (Barres et al., 1996). It is laminin plates (Becton Dickinson, Cockeysville, MD) at a final density of thus of much interest to analyze neurological defects in gp130 200 cells per well in 200 ml of DMEM–F-12 containing 10% FCS. The m m knock-out mice in which all the signals from gp130/gp130, gp130/ following factors were used: 1 g/ml IL-6, 1 g/ml sIL-6R, 300 ng/ml OSM (Peprotech, Rocky Hill, NJ), 300 ng/ml LIF (Genzyme), 300 ng/ml LIFR, and gp130/OSMR dimers are lost. The present study has CNTF (Genzyme), and 100 ng/ml NGF (Toyobo, Tokyo, Japan). Cells been done for this purpose. were incubated for 20 hr, and large bright cells observed under phase- contrast microscopy were counted. MATERIALS AND METHODS Animals. The effect of gp130 deficiency on the nervous system has not RESULTS been extensively examined, partly because the gp130 knock-out mice on Impairment of astrocyte differentiation in the absence which we reported previously were on the genetic background of the of gp130 signaling mixture of 129 and C57BL/6 and died during development (Yoshida et al., 1996, 1998). In the present study, gp130 knock-out mice on the Neuroepithelial cells from E14.5 fetal telencephalon are consid- genetic background of ICR were used. On this genetic background, some ered to contain neuroglial stem cells and have been shown to gp130 null mice survive through the late stages of development to term differentiate into astrocytes when cultured with LIF and CNTF at an incidence of 9% in total live newborns from gp130 1/2 intercross- ings (Kawasaki et al., 1997). Even in this case, the live newborns die (Johe et al., 1996; Bonni et al., 1997; McKay, 1997). To examine shortly after birth, as observed previously with LIFR- and CNTFR- the effect of gp130 deficiency on astrocyte differentiation, we deficient mice. Mice were treated according to the guidelines of the cultured neuroepithelial cells from the gp130 knock-out mice. In Tokyo Medical and Dental University Animal Committee. these cells, gp130 signaling is completely missing. As shown in Cell culture. Neuroepithelial cells were prepared and cultured as de- Figure 1A, no tyrosine phosphorylation of gp130 or STAT3 was scribed previously (Johe et al., 1996). In brief, telencephalons from 2 2 embryonic day 14.5 (E14.5) mice were triturated in HBSS by mild and observed in gp130 / neuroepithelial cells stimulated with frequent pipetting with 1 ml pipet tip (Gilson, Middleton, WI). Dissoci- either LIF or a combination of IL-6 and sIL-6R, unlike in the ated cells were cultured for4dinN2-supplemented DMEM–F-12 case of the wild-type control. In LIF-stimulated normal control medium containing 10 ng/ml basic FGF (bFGF) (R & D Systems, cells, tyrosine phosphorylation of LIFR was also observed, which Minneapolis, MN) (N2–DMEM–F-12–bFGF) on a 10 cm dish that had 2 2 been precoated with poly-L-ornithine (Sigma, St. Louis, MO) and fi- was completely missing in gp130 / cells.
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