TWEAK regulates proliferation and differentiation of adult neural progenitor cells
Introduction
TNF-like weak inducer of apoptosis (TWEAK) is a member of the TNF family of cytokines and binds to the membrane receptor Fn14, a member of the TNF receptor superfamily (Winkles, 2008). TWEAK was originally named after its pro-apoptotic activity (Chicheportiche et al., 1997) but soon other properties were described as well. TWEAK affects cell proliferation, migration, differentiation, and survival (Winkles, 2008). Moreover, several lines of evidence suggest that TWEAK plays an important role in tissue repair (Burkly et al., 2007). It is a potent pro-angiogenic and pro-inflammatory agent (Winkles, 2008) and TWEAK can enhance tissue regeneration. According to published reports, it also stimulates the proliferation of liver progenitor cells in models of liver injury (Jakubowski et al., 2005, Tirnitz-Parker et al., 2010). In skeletal muscle, Fn14-deficient mice exhibit delayed muscle regeneration after injury, consistent with TWEAK's ability to stimulate the proliferation of myoblasts and inhibit their differentiation (Girgenrath et al., 2006). During development, age-dependent effects of TWEAK on proliferation and differentiation of neural progenitor cells (NPC) were reported (Hamill et al., 2007). In this study, TWEAK inhibited the proliferation of postnatal day 1 NPC but had no effect on E12 NPC. In contrast, TWEAK induced neurite outgrowth of E12 but not in P1 progenitor cells. The effect of TWEAK on adult neural progenitor cells is unknown but potentially of interest because TWEAK is expressed in the adult brain by neurons and astrocytes. Furthermore, TWEAK and its receptor Fn14 are up-regulated in the context of cerebral ischemia and experimental autoimmune encephalomyelitis, a model of multiple sclerosis (Desplat-Jego et al., 2002, Inta et al., 2008, Potrovita et al., 2004).
Neurogenesis persists in two areas of the adult brain, the subventricular zone (SVZ) and the subgranular zone of the dentate gyrus. Because an increase in neurogenesis after stroke and other brain injuries may contribute to recovery, there is considerable interest in how neurogenesis is regulated (Lindvall and Kokaia, 2008). So far, neurogenesis has been linked to spatial learning and odor discrimination (Clelland et al., 2009, Gheusi et al., 2000, Zhang et al., 2008) but many questions concerning the function of neurogenesis in the normal and injured brain remain to be answered.
In order to characterize the role of the TWEAK/Fn14 pathway in the regulation of adult neurogenesis we have investigated its effect on adult NPC in vitro. TWEAK inhibited the proliferation of adult progenitor cells and stimulated their neuronal differentiation. The reduced proliferation upon TWEAK treatment is mediated by the transcription factor NF-κB. A lower number of newborn neuroblasts in the SVZ of Fn14−/− mice suggests that the TWEAK-Fn14 axis is important for regulating adult neurogenesis in vivo.
Section snippets
TWEAK inhibits the proliferation of adult neural progenitor cells
To investigate the effect of TWEAK on adult NPC, we dissected the subventricular zone of adult mice and cultivated NPC as neurospheres. Proliferation was determined by measuring BrdU incorporation. We found that TWEAK inhibited proliferation of adult NPC (Fig. 1A). At the mRNA level neural progenitor cells expressed the TWEAK receptor Fn14 but not CD163, which has been reported to be an alternative TWEAK receptor (Bover et al., 2007) (Fig. 1B). Parallel investigation of wild-type and
Discussion
TWEAK has been shown to control the proliferation of progenitor cells. Postnatal, but not embryonic NPC proliferate less in the presence of TWEAK (Hamill et al., 2007). The effect of TWEAK on adult NPC was unknown. Because TWEAK is expressed in the adult brain by neurons and glial cells (Desplat-Jego et al., 2002, Potrovita et al., 2004, Yepes et al., 2005) and is up-regulated after cerebral ischemia and experimental autoimmune encephalomyelitis (Desplat-Jego et al., 2002, Inta et al., 2008,
Mice
Adult male C57BL/6 or Fn14−/− mice (Girgenrath et al., 2006) were used to prepare NPC and for in vivo BrdU labeling. Fn14−/− mice were kindly provided by Biogen Idec. They have been backcrossed for 10 generations on a C57BL/6 background.
BrdU labeling in vivo
At an age of 9–12 weeks C57BL/6J or Fn14−/− mice were injected intraperitoneally twice a day for 7 days with 50 μg BrdU (Sigma, Munich, Germany) per g body weight. Mice were age matched. One day after the last BrdU injection mice were perfused with 20 ml Ringer
Acknowledgments
We thank Linda Burkly, Biogen Idec, for providing recombinant human TWEAK and Fn14−/− mice as well as helpful comments on the manuscript and Anne Régnier-Vigouroux, Heidelberg, for providing primary microglia. The research leading to these results received funding from the European Union's Seventh Framework Program FP7/2007–2013 under grant agreements 201024 and 202213 (European Stroke Network). MNS is a member of the postdoc program of the Medical Faculty, University of Heidelberg. MS is a
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