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Suppressor of cytokine signaling 2 regulates neuronal differentiation by inhibiting growth hormone signaling

Nature Neuroscience volume 5, pages 1155–1162 (2002)Cite this article

Abstract

The intracellular mechanisms that determine the response of neural progenitor cells to growth factors and regulate their differentiation into either neurons or astrocytes remain unclear. We found that expression of SOCS2, an intracellular regulator of cytokine signaling, was restricted to mouse progenitor cells and neurons in response to leukemia inhibitory factor (LIF)-like cytokines. Progenitors lacking SOCS2 produced fewer neurons and more astrocytes in vitro, and Socs2−/− mice had fewer neurons and neurogenin-1 (Ngn1)-expressing cells in the developing cortex, whereas overexpression of SOCS2 increased neuronal differentiation. We also report that growth hormone inhibited Ngn1 expression and neuronal production, and this action was blocked by SOCS2 overexpression. These findings indicate that SOCS2 promotes neuronal differentiation by blocking growth hormone–mediated downregulation of Ngn1.

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Figure 1: Analysis of Socs gene expression and regulation in neural cells.
Figure 5: SOCS2 blocks GH inhibition of neuronal differentiation, and GH and GHR are expressed in progenitor cells.
Figure 2: Decreased neuron production and increased astrocyte production in Socs2−/− neurospheres.
Figure 3: Decreased neuron numbers in adult Socs2−/− cortex.
Figure 4: Overexpression of SOCS2 induces neuronal differentiation.
Figure 6: Ngn1 levels are regulated by GH and SOCS2.

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References

  1. Lee, J.E. et al. Conversion of Xenopus ectoderm into neurons by NeuroD, a basic helix-loop-helix protein. Science 268, 836–844 (1995).

    Article  CAS  Google Scholar 

  2. Ma, Q., Kintner, C. & Anderson, D.J. Identification of neurogenin, a vertebrate neuronal determination gene. Cell 87, 43–52 (1996).

    Article  CAS  Google Scholar 

  3. Cai, L., Morrow, E.M. & Cepko, C.L. Misexpression of basic helix-loop-helix genes in the murine cerebral cortex affects cell fate choices and neuronal survival. Development 127, 3021–3030 (2000).

    CAS  Google Scholar 

  4. 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  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  7. 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  Google Scholar 

  8. 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  Google Scholar 

  9. Williams, B.P. et al. A PDGF-regulated immediate early gene response initiates neuronal differentiation in ventricular zone progenitor cells. Neuron 18, 553–562 (1997).

    Article  CAS  Google Scholar 

  10. Richards, L.J. et al. Leukaemia inhibitory factor or related factors promote the differentiation of neuronal and astrocytic precursors within the developing murine spinal cord. Eur. J. Neurosci. 8, 291–299 (1996).

    Article  CAS  Google Scholar 

  11. 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  Google Scholar 

  12. Faux, C.H., Turnley, A.M., Epa, R., Cappai, R. & Bartlett, P.F. Interactions between fibroblast growth factors and Notch regulate neuronal differentiation. J. Neurosci. 21, 5587–5596 (2001).

    Article  CAS  Google Scholar 

  13. Nakashima, K. et al. BMP2-mediated alteration in the developmental pathway of fetal mouse brain cells from neurogenesis to astrocytogenesis. Proc. Natl. Acad. Sci. USA 98, 5868–5873 (2001).

    Article  CAS  Google Scholar 

  14. Solecki, D.J., Liu, X., Tomoda, T., Fang, Y. & Hatten, M.E. Activated notch2 signaling inhibits differentiation of cerebellar granule neuron precursors by maintaining proliferation. Neuron 31, 557–568 (2001).

    Article  CAS  Google Scholar 

  15. 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  Google Scholar 

  16. Rajan, P. & McKay, R.D. Multiple routes to astrocytic differentiation in the CNS. J. Neurosci. 18, 3620–3629 (1998).

    Article  CAS  Google Scholar 

  17. Endo, T.A. et al. A new protein containing an SH2 domain that inhibits JAK kinases. Nature 387, 921–924 (1997).

    Article  CAS  Google Scholar 

  18. Naka, T. et al. Structure and function of a new STAT-induced STAT inhibitor. Nature 387, 924–929 (1997).

    Article  CAS  Google Scholar 

  19. Starr, R. et al. A family of cytokine-inducible inhibitors of signaling. Nature 387, 917–921 (1997).

    Article  CAS  Google Scholar 

  20. Hilton, D.J. et al. Twenty proteins containing a C-terminal SOCS box form five structural classes. Proc. Natl. Acad. Sci. USA 95, 114–119 (1998).

    Article  CAS  Google Scholar 

  21. Krebs, D.L. & Hilton, D.J. SOCS proteins: negative regulators of cytokine signaling. Stem Cells 19, 378–387 (2001).

    Article  CAS  Google Scholar 

  22. Polizzotto, M.N., Bartlett, P.F. & Turnley, A.M. Expression of “suppressor of cytokine signaling” (SOCS) genes in the developing and adult mouse nervous system. J. Comp. Neurol. 423, 348–358 (2000).

    Article  CAS  Google Scholar 

  23. Rietze, R.L. et al. Purification of a pluripotent neural stem cell from the adult mouse brain. Nature 412, 736–739 (2001).

    Article  CAS  Google Scholar 

  24. Reynolds, B.A. & Weiss, S. Clonal and population analyses demonstrate that an EGF-responsive mammalian embryonic CNS precursor is a stem cell. Dev. Biol. 175, 1–13 (1996).

    Article  CAS  Google Scholar 

  25. Metcalf, D. et al. Gigantism in mice lacking suppressor of cytokine signaling-2. Nature 405, 1069–1073 (2000).

    Article  CAS  Google Scholar 

  26. Krulich, L., Dhariwal, A.P. & McCann, S.M. Stimulatory and inhibitory effects of purified hypothalamic extracts on growth hormone release from rat pituitary in vitro. Endocrinology 83, 783–790 (1968).

    Article  CAS  Google Scholar 

  27. Hojvat, S., Baker, G., Kirsteins, L. & Lawrence, A.M. Growth hormone (GH) immunoreactivity in the rodent and primate CNS: distribution, characterization and presence posthypophysectomy. Brain Res. 239, 543–557 (1982).

    Article  CAS  Google Scholar 

  28. Edens, A., Southard, J.N. & Talamantes, F. Mouse growth hormone-binding protein and growth hormone receptor transcripts are produced from a single gene by alternative splicing. Endocrinology 135, 2802–2805 (1994).

    Article  CAS  Google Scholar 

  29. Lobie, P.E. et al. Localization and ontogeny of growth hormone receptor gene expression in the central nervous system. Brain Res. Dev. Brain Res. 74, 225–233 (1993).

    Article  CAS  Google Scholar 

  30. Ram, P.A. & Waxman, D.J. SOCS/CIS protein inhibition of growth hormone-stimulated STAT5 signaling by multiple mechanisms. J. Biol. Chem. 274, 35553–35561 (1999).

    Article  CAS  Google Scholar 

  31. Greenhalgh, C.J. et al. Growth enhancement in SOCS-2-deficient mice is dependent on STAT5b. Mol. Endocrinol. 16, 1394–1406 (2002).

    Article  CAS  Google Scholar 

  32. Nicholson, S.E. et al. Mutational analyses of the SOCS proteins suggest a dual domain requirement but distinct mechanisms for inhibition of LIF and IL-6 signal transduction. EMBO J. 18, 375–385 (1999).

    Article  CAS  Google Scholar 

  33. Hojvat, S. et al. Growth hormone (GH), thyroid-stimulating hormone (TSH), and luteinizing hormone (LH)-like peptides in the rodent brain: non-parallel ontogenetic development with pituitary counterparts. Brain Res. 256, 427–434 (1982).

    Article  CAS  Google Scholar 

  34. Delfs, J., Robbins, R., Connolly, J.L., Dichter, M. & Reichlin, S. Somatostatin production by rat cerebral neurones in dissociated cell culture. Nature 283, 676–677 (1980).

    Article  CAS  Google Scholar 

  35. Ram, P.A. & Waxman, D.J. Role of the cytokine-inducible SH2 protein CIS in desensitization of STAT5b signaling by continuous growth hormone. J. Biol. Chem. 275, 39487–39496 (2000).

    Article  CAS  Google Scholar 

  36. Hansen, J.A., Lindberg, K., Hilton, D.J., Nielsen, J.H. & Billestrup, N. Mechanism of inhibition of growth hormone receptor signaling by suppressor of cytokine signaling proteins. Mol. Endocrinol. 13, 1832–1843 (1999).

    Article  CAS  Google Scholar 

  37. Fode, C. et al. A role for neural determination genes in specifying the dorsoventral identity of telencephalic neurons. Genes Dev. 14, 67–80 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Murphy, M., Drago, J. & Bartlett, P.F. Fibroblast growth factor stimulates the proliferation and differentiation of neural precursor cells in vitro. J. Neurosci. Res. 25, 463–475 (1990).

    Article  CAS  Google Scholar 

  39. Thomas, H.E., Dutton, R., Bartlett, P.F. & Kay, T.W. Interferon regulatory factor 1 is induced by interferon-gamma equally in neurons and glial cells. J. Neuroimmunol. 78, 132–137 (1997).

    Article  CAS  Google Scholar 

  40. Mullen, R.J., Buck, C.R. & Smith, A.M. NeuN, a neuronal specific nuclear protein in vertebrates. Development 116, 201–211 (1992).

    CAS  PubMed  Google Scholar 

  41. West, M.J., Slomianka, L. & Gundersen, H.J. Unbiased stereological estimation of the total number of neurons in thesubdivisions of the rat hippocampus using the optical fractionator. Anat. Rec. 231, 482–497 (1991).

    Article  CAS  Google Scholar 

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Acknowledgements

We would like to thank A. Voss for advice with stereology and M. Ransome for technical assistance. This work was supported by the NH and MRC of Australia, the CRC for Cellular Growth Factors, the Australasian Spinal Research Trust, the Motor Neurone Disease Research Institute of Australia, ANZ Charitable Trusts, the Clive and Vera Ramaciotti Foundation for Biomedical Research and the BHP Community Trust.

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Authors and Affiliations

  1. The Walter and Eliza Hall Institute of Medical Research, P.O. Royal Melbourne Hospital, Melbourne, 3050, Victoria, Australia

    Ann M. Turnley, Clare H. Faux, Rodney L. Rietze, Jason R. Coonan & Perry F. Bartlett

  2. Institute for Brain Research, University of Queensland, St. Lucia, Brisbane, 4072, Queensland, Australia

    Rodney L. Rietze & Perry F. Bartlett

  3. Centre for Neuroscience, The University of Melbourne, 3010, Victoria, Australia

    Ann M. Turnley

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Correspondence to Perry F. Bartlett.

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Turnley, A., Faux, C., Rietze, R. et al. Suppressor of cytokine signaling 2 regulates neuronal differentiation by inhibiting growth hormone signaling. Nat Neurosci 5, 1155–1162 (2002). https://doi.org/10.1038/nn954

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