Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

A positive autoregulatory loop of Jak-STAT signaling controls the onset of astrogliogenesis

Nature Neuroscience volume 8, pages 616–625 (2005)Cite this article

Abstract

During development of the CNS, neurons and glia are generated in a sequential manner. The mechanism underlying the later onset of gliogenesis is poorly understood, although the cytokine-induced Jak-STAT pathway has been postulated to regulate astrogliogenesis. Here, we report that the overall activity of Jak-STAT signaling is dynamically regulated in mouse cortical germinal zone during development. As such, activated STAT1/3 and STAT-mediated transcription are negligible at early, neurogenic stages, when neurogenic factors are highly expressed. At later, gliogenic periods, decreased expression of neurogenic factors causes robust elevation of STAT activity. Our data demonstrate a positive autoregulatory loop whereby STAT1/3 directly induces the expression of various components of the Jak-STAT pathway to strengthen STAT signaling and trigger astrogliogenesis. Forced activation of Jak-STAT signaling leads to precocious astrogliogenesis, and inhibition of this pathway blocks astrocyte differentiation. These observations suggest that autoregulation of the Jak-STAT pathway controls the onset of astrogliogenesis.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The late onset of astrocyte differentiation in vitro.
Figure 2: Dynamic regulation of the Jak-STAT pathway during development.
Figure 3: Sequential activation of the Jak-STAT pathway in vivo correlates with the timing of astrogliogenesis.
Figure 4: The positive autoregulatory loop of the Jak-STAT machinery.
Figure 5: Inhibition of the Jak-STAT pathway suppresses astrogliogenesis.
Figure 6: Constitutively active STAT3C leads to precocious astrocyte differentiation in the presence of LIF.
Figure 7: De-repression of the Jak-STAT pathway owing to reduced neurogenin-1 and neurogenin-2 expression during the switch from neurogenesis to gliogenesis.

References

  1. Sauvageot, C.M. & Stiles, C.D. Molecular mechanisms controlling cortical gliogenesis. Curr. Opin. Neurobiol. 12, 244–249 (2002).

    Article  CAS  PubMed  Google Scholar 

  2. Temple, S. The development of neural stem cells. Nature 414, 112–117 (2001).

    Article  CAS  PubMed  Google Scholar 

  3. Temple, S. & Alvarez-Buylla, A. Stem cells in the adult mammalian central nervous system. Curr. Opin. Neurobiol. 9, 135–141 (1999).

    Article  CAS  PubMed  Google Scholar 

  4. Barres, B.A. & Smith, S.J. Neurobiology. Cholesterol—making or breaking the synapse. Science 294, 1296–1297 (2001).

    Article  CAS  PubMed  Google Scholar 

  5. Ullian, E.M., Sapperstein, S.K., Christopherson, K.S. & Barres, B.A. Control of synapse number by glia. Science 291, 657–661 (2001).

    Article  CAS  PubMed  Google Scholar 

  6. Shu, T. & Richards, L.J. Cortical axon guidance by the glial wedge during the development of the corpus callosum. J. Neurosci. 21, 2749–2758 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Qian, X. et al. Timing of CNS cell generation: a programmed sequence of neuron and glial cell production from isolated murine cortical stem cells. Neuron 28, 69–80 (2000).

    Article  CAS  PubMed  Google Scholar 

  8. Takizawa, T. et al. DNA methylation is a critical cell-intrinsic determinant of astrocyte differentiation in the fetal brain. Dev. Cell 1, 749–758 (2001).

    Article  CAS  PubMed  Google Scholar 

  9. Sun, Y.E., Martinowich, K. & Ge, W. Making and repairing the mammalian brain–signaling toward neurogenesis and gliogenesis. Semin. Cell Dev. Biol. 14, 161–168 (2003).

    Article  CAS  PubMed  Google Scholar 

  10. Li, W., Cogswell, C.A. & LoTurco, J.J. Neuronal differentiation of precursors in the neocortical ventricular zone is triggered by BMP. J. Neurosci. 18, 8853–8862 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Mabie, P.C., Mehler, M.F. & Kessler, J.A. Multiple roles of bone morphogenetic protein signaling in the regulation of cortical cell number and phenotype. J. Neurosci. 19, 7077–7088 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Sun, Y. et al. Neurogenin promotes neurogenesis and inhibits glial differentiation by independent mechanisms. Cell 104, 365–376 (2001).

    Article  CAS  PubMed  Google Scholar 

  13. Molne, M. et al. Early cortical precursors do not undergo LIF-mediated astrocytic differentiation. J. Neurosci. Res. 59, 301–311 (2000).

    Article  CAS  PubMed  Google Scholar 

  14. Viti, J., Feathers, A., Phillips, J. & Lillien, L. Epidermal growth factor receptors control competence to interpret leukemia inhibitory factor as an astrocyte inducer in developing cortex. J. Neurosci. 23, 3385–3393 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Ge, W. et al. Notch signaling promotes astrogliogenesis via direct CSL-mediated glial gene activation. J. Neurosci. Res. 69, 848–860 (2002).

    Article  CAS  PubMed  Google Scholar 

  16. Kamakura, S. et al. Hes binding to STAT3 mediates crosstalk between Notch and Jak-STAT signalling. Nat. Cell Biol. 6, 547–554 (2004).

    Article  CAS  PubMed  Google Scholar 

  17. Tanigaki, K. et al. Notch1 and Notch3 instructively restrict bFGF-responsive multipotent neural progenitor cells to an astroglial fate. Neuron 29, 45–55 (2001).

    Article  CAS  PubMed  Google Scholar 

  18. Gaiano, N., Nye, J.S. & Fishell, G. Radial glial identity is promoted by Notch1 signaling in the murine forebrain. Neuron 26, 395–404 (2000).

    Article  CAS  PubMed  Google Scholar 

  19. Song, M.R. & Ghosh, A. FGF2-induced chromatin remodeling regulates CNTF-mediated gene expression and astrocyte differentiation. Nat. Neurosci. 7, 229–235 (2004).

    Article  PubMed  Google Scholar 

  20. Kuhn, H.G., Winkler, J., Kempermann, G., Thal, L.J. & Gage, F.H. Epidermal growth factor and fibroblast growth factor-2 have different effects on neural progenitors in the adult rat brain. J. Neurosci. 17, 5820–5829 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Bartlett, P.F. et al. Regulation of neural stem cell differentiation in the forebrain. Immunol. Cell Biol. 76, 414–418 (1998).

    Article  CAS  PubMed  Google Scholar 

  22. Chambers, C.B. et al. Spatiotemporal selectivity of response to Notch1 signals in mammalian forebrain precursors. Development 128, 689–702 (2001).

    CAS  PubMed  Google Scholar 

  23. Johe, K.K., Hazel, T.G., Muller, T., Dugich-Djordjevic, M.M. & McKay, R.D. Single factors direct the differentiation of stem cells from the fetal and adult central nervous system. Genes Dev. 10, 3129–3140 (1996).

    Article  CAS  PubMed  Google Scholar 

  24. Bonni, A. et al. Regulation of gliogenesis in the central nervous system by the Jak-STAT signaling pathway. Science 278, 477–483 (1997).

    Article  CAS  PubMed  Google Scholar 

  25. Bugga, L., Gadient, R.A., Kwan, K., Stewart, C.L. & Patterson, P.H. Analysis of neuronal and glial phenotypes in brains of mice deficient in leukemia inhibitory factor. J. Neurobiol. 36, 509–524 (1998).

    Article  CAS  PubMed  Google Scholar 

  26. Koblar, S.A. et al. Neural precursor differentiation into astrocytes requires signaling through the leukemia inhibitory factor receptor. Proc. Natl. Acad. Sci. USA 95, 3178–3181 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Nakashima, K. et al. Developmental requirement of gp130 signaling in neuronal survival and astrocyte differentiation. J. Neurosci. 19, 5429–5434 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Nakashima, K. et al. Synergistic signaling in fetal brain by STAT3-Smad1 complex bridged by p300. Science 284, 479–482 (1999).

    Article  CAS  PubMed  Google Scholar 

  29. Wen, Z., Zhong, Z. & Darnell, J.E., Jr. Maximal activation of transcription by Stat1 and Stat3 requires both tyrosine and serine phosphorylation. Cell 82, 241–250 (1995).

    Article  CAS  PubMed  Google Scholar 

  30. Yokogami, K., Wakisaka, S., Avruch, J. & Reeves, S.A. Serine phosphorylation and maximal activation of STAT3 during CNTF signaling is mediated by the rapamycin target mTOR. Curr. Biol. 10, 47–50 (2000).

    Article  CAS  PubMed  Google Scholar 

  31. Decker, T. & Kovarik, P. Serine phosphorylation of STATs. Oncogene 19, 2628–2637 (2000).

    Article  CAS  PubMed  Google Scholar 

  32. Yamaguchi, M., Saito, H., Suzuki, M. & Mori, K. Visualization of neurogenesis in the central nervous system using nestin promoter-GFP transgenic mice. Neuroreport 11, 1991–1996 (2000).

    Article  CAS  PubMed  Google Scholar 

  33. Ichiba, M., Nakajima, K., Yamanaka, Y., Kiuchi, N. & Hirano, T. Autoregulation of the Stat3 gene through cooperation with a cAMP-responsive element-binding protein. J. Biol. Chem. 273, 6132–6138 (1998).

    Article  CAS  PubMed  Google Scholar 

  34. O'Brien, C.A. & Manolagas, S.C. Isolation and characterization of the human gp130 promoter. Regulation by STATS. J. Biol. Chem. 272, 15003–15010 (1997).

    Article  CAS  PubMed  Google Scholar 

  35. Bromberg, J.F. et al. Stat3 as an oncogene. Cell 98, 295–303 (1999).

    Article  CAS  PubMed  Google Scholar 

  36. Yuan, Z.L., Guan, Y.J., Chatterjee, D. & Chin, Y.E. Stat3 dimerization regulated by reversible acetylation of a single lysine residue. Science 307, 269–273 (2005).

    Article  CAS  PubMed  Google Scholar 

  37. Hermanson, O., Jepsen, K. & Rosenfeld, M.G. N-CoR controls differentiation of neural stem cells into astrocytes. Nature 419, 934–939 (2002).

    Article  CAS  PubMed  Google Scholar 

  38. Nieto, M., Schuurmans, C., Britz, O. & Guillemot, F. Neural bHLH genes control the neuronal versus glial fate decision in cortical progenitors. Neuron 29, 401–413 (2001).

    Article  CAS  PubMed  Google Scholar 

  39. Bayer, S.A. Neocortical Development (Raven, New York, 1991).

    Google Scholar 

  40. Bertrand, N., Castro, D.S. & Guillemot, F. Proneural genes and the specification of neural cell types. Nat. Rev. Neurosci. 3, 517–530 (2002).

    Article  CAS  PubMed  Google Scholar 

  41. Ross, S.E., Greenberg, M.E. & Stiles, C.D. Basic helix-loop-helix factors in cortical development. Neuron 39, 13–25 (2003).

    Article  CAS  PubMed  Google Scholar 

  42. Mattar, P. et al. A screen for downstream effectors of Neurogenin2 in the embryonic neocortex. Dev. Biol. 273, 373–389 (2004).

    Article  CAS  PubMed  Google Scholar 

  43. Turnley, A.M., Faux, C.H., Rietze, R.L., Coonan, J.R. & Bartlett, P.F. Suppressor of cytokine signaling 2 regulates neuronal differentiation by inhibiting growth hormone signaling. Nat. Neurosci. 5, 1155–1162 (2002).

    Article  CAS  PubMed  Google Scholar 

  44. Morrow, T., Song, M.R. & Ghosh, A. Sequential specification of neurons and glia by developmentally regulated extracellular factors. Development 128, 3585–3594 (2001).

    CAS  PubMed  Google Scholar 

  45. Doetsch, F. The glial identity of neural stem cells. Nat. Neurosci. 6, 1127–1134 (2003).

    Article  CAS  PubMed  Google Scholar 

  46. Doetsch, F. A niche for adult neural stem cells. Curr. Opin. Genet. Dev. 13, 543–550 (2003).

    Article  CAS  PubMed  Google Scholar 

  47. Alvarez-Buylla, A., Garcia-Verdugo, J.M. & Tramontin, A.D. A unified hypothesis on the lineage of neural stem cells. Nat. Rev. Neurosci. 2, 287–293 (2001).

    Article  CAS  PubMed  Google Scholar 

  48. Doetsch, F., Caille, I., Lim, D.A., Garcia-Verdugo, J.M. & Alvarez-Buylla, A. Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 97, 703–716 (1999).

    Article  CAS  PubMed  Google Scholar 

  49. ten Hoeve, J. et al. Identification of a nuclear Stat1 protein tyrosine phosphatase. Mol. Cell. Biol. 22, 5662–5668 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We would like to thank L. Zipursky, H. Herschman and K. Shuai at UCLA for critical reading of the manuscript and providing suggestions, and L. Hutnick at UCLA for cloning the S100β promoter. We would like to acknowledge J. Wong (Baylor College of Medicine), J.E. Johnson (University of Texas Southwestern), D. Levy (New York University), K. Shuai (University of California at Los Angeles), J.E. Darnell, Jr. (Rockefeller University), J. Bromberg (Memorial Sloan-Kettering Cancer Center) and S.C. Landis (National Institute of Neurological Disorders and Stroke) for sharing critical reagents. This work is supported by National Institutes of Health (NIH) RO1 grant (MH066196), a Beckman Young Investigator Award, a Sloan Research Fellowship, a Klingenstein award and a National Alliance for Research on Schizophrenia and Depression award to Y.E.S., NIH program project grant (HD006576) to J.d.V. and Y.E.S. and NIH NS44405 to G.F.

Author information

Author notes

  1. Sara Becker-Catania

    Present address: Edward Hines Veterans Administration Hospital, University of Illinois at Chicago, Hines, Illinois, 60141, USA

Authors and Affiliations

  1. Departments of Molecular & Medical Pharmacology and Psychiatry & Behavioral Sciences, Neuropsychiatric Institute, University of California Los Angeles, Los Angeles, 90024, California, USA

    Fei He, Weihong Ge, Keri Martinowich, Volkan Coskun, Wenyu Zhu, Hao Wu & Yi E Sun

  2. Department of Human Genetics, David Geffen School of Medicine, Neuropsychiatric Institute, University of California Los Angeles, Los Angeles, 90024, California, USA

    Guoping Fan

  3. Mental Retardation Research Center, Neuropsychiatric Institute, University of California Los Angeles, Los Angeles, 90024, California, USA

    Fei He, Weihong Ge, Keri Martinowich, Sara Becker-Catania, Volkan Coskun, Wenyu Zhu, Hao Wu, Jean de Vellis & Yi E Sun

  4. Division of Molecular Neurobiology, National Institute for Medical Research, Mill Hill, London, NW7 1AA, UK

    Diogo Castro & Francois Guillemot

Authors
  1. Fei He
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Weihong Ge
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Keri Martinowich
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sara Becker-Catania
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Volkan Coskun
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Wenyu Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hao Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Diogo Castro
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Francois Guillemot
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Guoping Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Jean de Vellis
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Yi E Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yi E Sun.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Astrocyte differentiation is impaired in LIFR-β knockout, CNTF/LIF compound knockout and STAT3 conditional knockout. (a) Western blot analysis of GFAP in the P0 mouse spinal cord from LIFR-β knockout mice and P3 mouse cortices from CNTF/LIF double knockout mice show defect in astrogliogenesis. (b) Immunostaining analysis of GFAP (green) in spinal cord sections of E18 STAT3 mutant mice. (PDF 808 kb)

Supplementary Fig. 2

A schematic representation of the JAK-STAT pathway. Cytokine LIF binding to the cell surface receptor gp130 and LIFRβ induces sequential heterodimerization of LIFRβ and gp130, which leads to tyrosine phosphorylation and activation of the associated JAK tyrosine kinases. Once activated, JAK stimulates phosphorylation of gp130, LIFRβ, and STATs (STAT1/3). pSTATs then dimerize and translocate to the nucleus to activate gene transcription after recruiting the transcription coactivator CBP/p300. (PDF 279 kb)

Supplementary Fig. 3

STAT binding site within the Jak1 promoter is conserved between human and mouse. (PDF 73 kb)

Supplementary Fig. 4

Constitutively active STAT3C significantly increased GFAP promoter activity in cortical progenitor cell cultures at 6 DIV. Luciferase analysis of GFAP promoter in primary E11 neural progenitor cell culture infected with control or STAT3C virus, either with or without LIF treatment (100ng/ml) for 1 d before harvesting at 6 DIV. Results indicate that GFAP transcriptional activity is significantly increased upon STAT3C expression plus LIF treatment in the 6-d long-term culture (*: p<0.05 as compared to the rest of the group). (PDF 62 kb)

Supplementary Fig. 5

A schematic summarizing the inverse relationship between the activity of proneural bHLH genes and that of the Jak-STAT astrogliogenic machinery during cortical development. (PDF 165 kb)

Supplementary Fig. 6

Reduced Ngn1 expression and indications for precocious astrogliogenesis in the Neurogenin2 knockout mice. Tissue sections of E14.5 cortex from wild-type and Neurogenin2 knockout embryos were stained with anti-Ngn2, anti-Ngn1, and anti-BLBP antibodies (red). Nuclei were stained by Hoechst (blue). Ngn2 staining confirms the knockout identity. Ngn1 expression is markedly reduced in Ngn2 knockout cortices. Anti-BLBP staining showed an earlier retraction of the radial processes, which could be characteristic of a precocious conversion from radial glia to astrocytes in the Ngn2 mutant (as indicated by arrows). (PDF 1070 kb)

Supplementary Fig. 7

Model of a positive autoregulation loop of JAK-STAT signaling pathway driving astroglial differentiation. The activation of JAKs after binding of LIF to the cell surface receptors gp130 and LIFR results in the phosphorylation of the receptors as well as STAT1/3. Phospho-STAT1/3 dimerize and translocate to the nucleus to activate gene transcription via association with the transcription coactivator CBP/p300. Proneural bHLH genes Neurogenin1 and 2 (Ngn) suppress the JAK-STAT pathway during the neurogenic period. Reduced expression of Ngn at later developmental stages leads to de-repression of the astrogliogenic JAK-STAT signaling. As such, activation of the JAK-STAT pathway leads to increased expression of STAT1/3 and also the cell surface receptor gp130 and tyrosine kinase JAK, which will further enhance the activity of the JAK-STAT pathway. This positive feedback loop will gradually accumulate above the threshold level to initiate the astroglial differentiation program. (PDF 250 kb)

Supplementary Fig. 8

Suppression of JAK-STAT signaling by neuroD is potentially involved in reactivating the adult neurogenic program. (a) Immunostaining of neuroD in the neurogenic zone of the adult hippocampal dentate gyrus. (b) Western analyses indicate that neuroD inhibits the JAK-STAT pathway in neural progenitors. (PDF 260 kb)

Supplementary Methods (PDF 52 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

He, F., Ge, W., Martinowich, K. et al. A positive autoregulatory loop of Jak-STAT signaling controls the onset of astrogliogenesis. Nat Neurosci 8, 616–625 (2005). https://doi.org/10.1038/nn1440

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn1440

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing