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Genes to Cells (2005) 10, 777-783. doi:10.1111/j.1365-2443.2005.00876.x
© 2005 Blackwell Publishing or its licensors
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Wnt signaling regulates the sequential onset of neurogenesis and gliogenesis via induction of BMPs

Mana Kasai, Kiyotoshi Satoh and Tetsu Akiyama*

Laboratory of Molecular and Genetic Information, Institute for Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113, Japan


   Abstract
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 Abstract
Introduction
 Results
 Discussion
 Experimental procedures
 References
 
In the mammalian central nervous system, neurogenesis precedes gliogenesis; neurons are primarily generated at the neural stage, whereas most glial cells are generated perinatally and postnatally. However, the signals that regulate this sequence of events remain unclear. Here we show that Wnt signaling induces neuronal and astroglial differentiation but suppresses oligodendroglial differentiation. We observed that precursor cells infected with a retrovirus encoding ß-catenin differentiated into neurons, while astrocytes developed from uninfected precursor cells surrounding infected cells. As neurogenesis proceeded, expression of the bone morphogenetic proteins (BMPs), BMP2, 4 and 7, progressively increased in the cells infected with the retrovirus encoding ß-catenin. Furthermore, treatment of cells with Noggin, a BMP antagonist, completely inhibited astroglial differentiation but partially restored oligodendroglial differentiation. These results suggest that Wnt signaling indirectly regulates gliogenesis by inducing BMPs in neuronal cells. Thus, cooperation between Wnt and BMP signaling may play a key role in determining the sequence of neurogenesis and gliogenesis.


   Introduction
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 Abstract
 Introduction
Results
 Discussion
 Experimental procedures
 References
 
During development of the mammalian central nervous system (CNS), neurons and glia are generated from a common neural precursor cell in a process that occurs with precise timing. In the mouse cerebral cortex, for example, neurogenesis begins at about embryonic day 12 (E12), peaks at about E15, and finishes at about birth, whereas cortical astrocytes are first detected around E16 and oligodendrocytes around birth (Jacobson 1985; Qian et al. 2000). These processes are tightly regulated by a complex interplay of various signals.

The maintenance and proliferation of neural stem cells are regulated by basic fibroblast growth factor (bFGF) signaling, epidermal growth factor (EGF) signaling and Notch signaling (Gage et al. 1995; McKay 1997; Ciccolini & Svendsen 1998; Tropepe et al. 1999; Hitoshi et al. 2002). On the other hand, astroglial differentiation of neural precursor cells (NPCs) is induced by ciliary neurotrophic factor (CNTF) and bone morphogenetic proteins (BMPs), a group of secreted signaling molecules that are members of the transforming growth factor-ß (TGF-ß) superfamily (Gross et al. 1996; Bonni et al. 1997; Nakashima et al. 1999, 2001). Neuronal differentiation is regulated by the bHLH proteins neurogenin 1 and 2 as well as the homeodomain proteins Pax6 and Emx (Schuurmans & Guillemot 2002), although the extrinsic signals that activate these transcription factors remain unknown.

Wnt signaling plays a crucial role in a number of developmental processes, including development of the CNS, body axis formation and axial specification in limb development (Stark et al. 1994; Miller & Moon 1996; Cadigan & Nusse 1997; Eastman & Grosschedl 1999; Peifer & Polakis 2000; Huelsken & Birchmeier 2001; Aubert et al. 2002; Kielman et al. 2002; Satoh et al. 2004). Wnt signaling stabilizes ß-catenin, which in turn associates with the TCF/LEF family of transcription factors, ultimately altering the expression of Wnt target genes. It has been reported that Wnt signaling plays an important role in regulating proliferation or differentiation of NPCs. Transgenic mice expressing a stabilized ß-catenin in NPCs develop enlarged brains, suggesting that Wnt signaling regulates cerebral cortical size by controlling the generation of neural precursor cells (Chenn & Walsh 2002; Zechner et al. 2003). On the other hand, Wnt signaling promotes neuronal differentiation of NPCs in the absence of bFGF (Hirabayashi et al. 2004; Israsena et al. 2004; Muroyama et al. 2004). Wnt-1, 3a and 5a regulate the proliferation and differentiation of dopaminergic neuron development during ventral midbrain neurogenesis (Castelo-Branco et al. 2003). In addition, Wnt signaling promotes neuronal differentiation of embryonic carcinoma P19 cells (Tang et al. 2002; Lyu et al. 2003). Thus, Wnt signaling appears to regulate proliferation and differentiation of neuronal lineages in a stage-specific and cellular context-dependent manner.

Although there are many studies investigating neural proliferation and differentiation, the molecular mechanisms that orchestrate the sequential production of neurons and glial cells from NPCs remain elusive. In the present study, we analyzed NPCs infected with a retrovirus encoding ß-catenin and demonstrated that Wnt signaling regulates the sequential onset of neurogenesis and gliogenesis by inducing production of BMPs in neurons.


   Results
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 Abstract
 Introduction
 Results
Discussion
 Experimental procedures
 References
 
ß-catenin promotes neuronal and astroglial differentiation and inhibits oligodendroglial differentiation

NPCs derived from E14.5 mouse striatum were infected with a retrovirus encoding a Flag-tagged active form of ß-catenin (Ret-Flag-ß-catenin-S33Y) and cultured with bFGF and EGF for 2 days, and then without growth factors for further 0–4 days to induce differentiation. Consistent with previous reports (Hirabayashi et al. 2004; Israsena et al. 2004; Muroyama et al. 2004), immunostaining and RT-PCR analysis revealed that expression of the neuronal marker ßIII-tubulin/TuJ1 antigen was rapidly increased in cells infected with Ret-ß-catenin-S33Y (Figs 1A,B, 2A and 3). We also found that ß-catenin expression induced the astrocyte marker glial fibrillary acidic protein (GFAP), but suppressed the oligodendrocyte markers proteolipid protein 1 (Plp) and myelin basic protein (MBP) (Fig. 1A–C).



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  		Figure 1  ß-catenin promotes neuronal and astroglial differentiation and induces BMP expression. (A) NPCs infected with a control virus or Ret-ß-catenin-S33Y were cultured in the absence of growth factor. The day on which growth factors were withdrawn is designated day 0. Expression of several neural markers and BMPs were analyzed by RT-PCR. Wnt signaling induced expression of ßIII-tubulin and GFAP, but suppressed expression of Plp. Wnt signaling also induced expression of BMP2, 4 and 7. (B) NPCs infected with a control virus or Ret-ß-catenin-S33Y were cultured without growth factors for 2 days, and immunostained for ßIII-tubulin (green) and GFAP (red). Bar, 50 µm. (C) NPCs infected with a control virus or Ret-ß-catenin-S33Y were cultured without growth factors for 4 days, and immunostained for MBP (green). Bar, 50 µm.

 
ß-catenin indirectly promotes astroglial differentiation

We next explored whether Wnt signaling induces neurons and astrocytes by the same mechanism. NPCs were double-stained with anti-ß-catenin and anti-ßIII-tubulin antibodies or with anti-FLAG and anti-GFAP antibodies. NPCs infected with Ret-ß-catenin-S33Y were found to be positive for ßIII-tubulin but not GFAP (Fig. 2A,B). By contrast, uninfected NPCs surrounding infected cells stained positive for GFAP (Fig. 2B). These results suggest that NPCs expressing ß-catenin do not differentiate into astrocytes and that astrocytes are differentiated from non-infected NPCs surrounding the ß-catenin-expressing cells. Thus, Wnt signaling may induce neurons directly and astrocytes indirectly.



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  		Figure 2  ß-catenin directly promotes neuronal differentiation and indirectly promotes astroglial differentiation. (A) NPCs infected with Ret-ß-catenin-S33Y were cultured without growth factors for 2 days, and immunostained with anti-ß-catenin (red) and anti-ßIII-tubulin (green) antibodies. NPCs infected with Ret-ß-catenin-S33Y differentiated into neurons. Bar, 50 µm. (B) NPCs infected with Ret-ß-catenin-S33Y were cultured without growth factors for 2 days, and immunostained with anti-Flag (ß-catenin) (green) and anti-GFAP (red) antibodies. Astrocytes were derived from uninfected NPCs surrounding infected cells. Bar, 50 µm.

 
ß-catenin promotes astroglial differentiation via BMPs expression

It has been reported that BMPs promote the differentiation of astrocytes with concurrent suppression of oligodendroglial differentiation (Gross et al. 1996; Gomes et al. 2003). Furthermore, Wnt signaling has been shown to induce BMP4 expression in the chick epiblast and in human cancer cells (Wilson et al. 2001; Kim et al. 2002). We therefore examined whether BMP expression is up-regulated in NPCs infected with Ret-ß-catenin-S33Y. RT-PCR analysis revealed that concomitant with neurogenesis, not only BMP4 but also BMP2 and 7 were induced in NPCs infected with Ret-ß-catenin-S33Y (Fig. 1A). To examine whether expression of BMPs are induced in cells expressing ß-catenin, we selected NPCs infected with Ret-ß-catenin-S33Y by culturing with 1 µg/mL puromycin. As shown in Fig. 3, expression of BMP2, 4 and 7 were indeed induced in cells infected with Ret-ß-catenin-S33Y. By contrast, expression of the BMP type I (Alk2, 3 and 6) and II receptors was not significantly changed in these cells. These findings raise the possibility that BMPs secreted from ß-catenin-expressing cells promote astroglial differentiation of surrounding cells.



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  		Figure 3  BMPs are induced in cells expressing ß-catenin. NPCs infected with a control virus or Ret-ß-catenin-S33Y were cultured with puromycin in the absence of growth factors for 2 days. ßIII-tubulin, BMP and BMP-R expression was analyzed by RT-PCR. BMP2, 4 and 7 were induced in the cells infected with Ret-ß-catenin-S33Y.

 
To prove the above possibility, we examined the effect of Noggin, a BMP antagonist, on astroglial differentiation. We cultured NPCs infected with Ret-ß-catenin-S33Y in the presence of Noggin and the absence of growth factors, and examined marker expression by immunostaining and RT-PCR. Noggin treatment increased expression levels of ßIII-tubulin, but strongly inhibited GFAP expression in a dose-dependent manner (Fig. 4A–C). In addition, RT-PCR analysis revealed that Noggin partially restored Plp expression (Fig. 4D). Thus, Noggin promoted neurogenesis, while it inhibited astroglial differentiation and partially restored oligodendroglial differentiation. These results support the notion that BMPs induced by ß-catenin may be responsible for gliogenesis.



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  		Figure 4  BMPs secreted from ß-catenin-expressing cells promote astroglial differentiation. (A) NPCs infected with a control virus or Ret-ß-catenin-S33Y were cultured with Noggin (0–200 ng/mL) in the absence of growth factors for 2 days. Cells were immunostained for ßIII-tubulin (green) and GFAP (red). Bar, 100 µm. (B, C) The proportion of ßIII-tubulin+(B) or GFAP+(C) cells is shown as the mean ± SEM of three cultures. *P < 0.01 in comparison to the result with a control virus, when analyzed by Student's t-test. (D) NPCs infected with a control virus or Ret-ß-catenin-S33Y were cultured with or without Noggin (500 ng/mL) in the absence of growth factors. The day on which growth factors were withdrawn is designated day 0. Several neural markers were analyzed by RT-PCR. Noggin treatment strongly inhibited astroglial differentiation and partially restored oligodendroglial differentiation.

 

   Discussion
Top
 Abstract
 Introduction
 Results
 Discussion
Experimental procedures
 References
 
In the present study, we investigated the molecular mechanisms that regulate the sequential production of neurons and glial cells from NPCs. Based on our findings, we propose the following model (Fig. 5).



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  		Figure 5  Sequential production of neurons and glial cells from NPCs. Wnt signaling triggers neuronal differentiation of NPCs and induces BMPs in neurons. BMPs secreted from neurons regulate glial differentiation of surrounding cells.

 

Thus, the cooperation between Wnt and BMP signaling may play an important role in determining the sequence of neural differentiation.

While Noggin inhibited astroglial differentiation, it promoted neurogenesis and partially restored oligodendroglial differentiation. Promotion of neuronal differentiation by Noggin treatment may be due to the low levels of active BMP remaining in culture medium (Chang et al. 2003). On the other hand, partial restoration of oligodendroglial differentiation by Noggin treatment suggests that other genes functioning downstream in Wnt signaling also participate in the suppression of oligodendroglial differentiation.

In conclusion, we found that Wnt signaling indirectly regulates gliogenesis by inducing BMPs in neuronal cells. It would be intriguing to examine whether the cooperation between Wnt and BMP signaling is relevant for the sequential onset of differentiation in other tissues.


   Experimental procedures
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 Abstract
 Introduction
 Results
 Discussion
 Experimental procedures
References
 
Retrovirus production

Flag-tagged ß-catenin-S33Y, in which Ser-33 is replaced with Tyr (Morin et al. 1997), was cloned into the pMX-puro retoroviral vector encoding a puromycin resistance gene (Ret-ß-catenin-S33Y). For retrovirus production, Plat-E packaging cells were transfected with ß-catenin-S33Y using FuGENE 6 (Roche) (Morita et al. 2000). Viral supernatant was used for infection.

Cell culture

NPC culture was performed as previously described (Nakashima et al. 2001). In brief, cells prepared from the striatum of embryonic day 14.5 (E14.5) CD1 mice were mechanically dissociated in N2-supplemented DMEM/F12 medium containing 20 ng/mL bFGF (Roche) and 20 ng/mL EGF (Roche). Cells were plated on dishes coated with poly L-ornithine (Sigma) and fibronectin (Nitta Gelatin Inc), and cultured for 4 days for expansion of NPCs. NPCs were then mechanically dissociated and replated at 4 x 104 cells/cm2 on coverslips or dishes coated with poly-L-ornithine and fibronectin, and cultured in the presence of bFGF and EGF. Five hours after replating, NPCs were infected with Ret-ß-catenin-S33Y in the presence of 4 µg/mL polybrene for 2 h, and cultured in fresh medium containing bFGF and EGF for 2 days. Finally, infected NPCs were cultured without growth factors for further 0–4 days to induce differentiation.

Immunostaining of cultured cells

Cultured cells were fixed with 4% paraformaldehyde in PBS for 15 min and permeabilized with 0.5% Triton X-100 for 15 min. Dilution of antibodies was as follows; mouse monoclonal antibody (mAb) to ßIII-tubulin (Babco), 1 : 600; rabbit polyclonal antibody (pAb) to GFAP (DAKO), 1 : 200; pAb to MBP (CHEMICON), 1 : 200; pAb to ß-catenin (Santa Cruz), 1 : 100; mAb to Flag (Eastman Kodak Company), 1 : 1000. Secondary antibodies were rhodamine red- or FITC-conjugated (ICN). The nuclei were stained with 4',6-diamidino-2-phenylindole (DAPI).

RNA extraction and semiquantitative RT-PCR analysis

Total cellular RNA was prepared using NucleoSpin RNA II (MACHEREY-NAGEL). For cDNA synthesis, random hexamer primers were used to prime reverse transcriptase reactions. cDNA synthesis was carried out using Moloney murine leukemia virus (M-MLV) Superscript III reverse transcriptase (Invitrogen) following the manufacturer's instructions. Cycling parameters for PCR were as follows; denaturation at 94 °C for 20 s, annealing at 60–70 °C for 20 s, depending on the primer, and elongation at 72 °C for 2 min. The number of cycles varied between 25 and 35, depending on the respective mRNA abundance.


   Acknowledgements
 
We thank S. Adachi for his helpful discussion. Supported by Grants-in-Aid for Scientific Research on Priority Areas and the Organization for Pharmaceutical Safety and Research.


   Footnotes
 
Communicated by: Tadashi Yamamoto

* Correspondence: E-mail: akiyama{at}iam.u-tokyo.ac.jp


   References
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 Abstract
 Introduction
 Results
 Discussion
 Experimental procedures
 References
 
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Received: 16 February 2005
Accepted: 17 April 2005




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