Skip to main content

Advertisement

SpringerLink
Log in

Regulation of cytokine signaling components in developing rat retina correlates with transient inhibition of rod differentiation by CNTF

  • Regular Article
  • Published:
Cell and Tissue Research Aims and scope Submit manuscript

Abstract

Ciliary neurotrophic factor (CNTF) is known to inhibit the differentiation of rod photoreceptors from postmitotic precursor cells. During early postnatal development, photoreceptor precursors lose their responsiveness to CNTF. The underlying events causing this change in responsiveness are unknown. Moreover, whether rods express CNTF receptor α, a prerequisite for a direct response to the factor, is controversial. Since morphological studies have previously produced conflicting results, we have analyzed the expression of cytokine receptor components and potential ligands in the rat photoreceptor layer by real-time reverse transcription with the polymerase chain reaction after laser microdissection and by immunoblotting. Cytokine effects on rods were studied in explant cultures from newborn rat retina. CNTF receptor α (CNTFRα) and leukemia inhibitory factor receptor ß (LIFRß) were expressed in immature photoreceptors. Expression of the CNTF-specific α-subunit (but not of LIFRß) was downregulated specifically in the photoreceptor layer in parallel with the appearance of opsin-positive rods. The decrease of CNTFRα levels in explant cultures was closely correlated with the loss of precursor cell responsiveness to CNTF. Increasing the CNTF concentration in the culture medium led to prolonged CNTFRα expression and, concomitantly, to persistent inhibition of rod differentiation. Application of CNTF and LIF in vitro induced phosphorylation of STAT3. Inducibility of STAT3 activation by CNTF decreased with photoreceptor maturation, whereas the LIF effect persisted. Our results thus indicate that CNTF acts directly on photoreceptor precursors inhibiting their differentiation via activation of the JAK/STAT3 signal transduction pathway, and that this effect is temporally limited because of the downregulation of CNTFRα.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Altshuler D, Cepko C (1992) A temporally regulated, diffusible activity is required for rod photoreceptor development in vitro. Development 114:947–957

    PubMed  CAS  Google Scholar 

  • Beltran WA, Zhang Q, Kijas JW, Gu D, Rohrer H, Jordan JA, Aguirre GD (2003) Cloning, mapping, and retinal expression of the canine ciliary neurotrophic factor receptor α (CNTFRα). Invest Ophthalmol Vis Sci 44:3642–3649

    Article  PubMed  Google Scholar 

  • Beltran WA, Rohrer H, Aguirre GD (2005) Immunlocalization of ciliary neurotrophic factor receptor α (CNTFRα) in mammalian photoreceptor cells. Mol Vision 11:232–244

    CAS  Google Scholar 

  • Cayouette M, Barres BA, Raff M (2003) Importance of intrinsic mechanisms in cell fate decision in the developing rat retina. Neuron 40:897–904

    Article  PubMed  CAS  Google Scholar 

  • Cepko CL, Austin CP, Yang XJ, Alexiades M, Ezzeddine D (1996) Cell fate determination in the vertebrate retina. Proc Natl Acad Sci USA 93:589–595

    Article  PubMed  CAS  Google Scholar 

  • Davis S, Aldrich TH, Stahl N, Pan L, Taga T, Kishimoto T, Ip NY, Yancopoulos GD (1993) LIFRβ and gp130 as heterodimerizing signal transducers of the tripartite CNTF receptor. Science 260:1805–1808

    Article  PubMed  CAS  Google Scholar 

  • Derouet D, Rousseau F, Alfonis F, Froger J, Hermann J, Barbier F, Perret D, Diveu C, Guillet C, Preisser L, Dumont A, Barbado M, Morel A, deLapeyriere O, Gascan H, Chevalier S (2004) Neuropoietin, a new IL-6-related cytokine signaling through the ciliary neurotrophic factor receptor. Proc Natl Acad Sci USA 101:4827–4832

    Article  PubMed  CAS  Google Scholar 

  • Elson GCA, Lelievre E, Guillet C, Chevalier S, Plun-Favreau H, Froger J, Suard I, Coignac AB de, Delneste Y, Bonnefoy J-Y, Gauchat J-F, Gascan H (2000) CLC associates with CLF to from a functional heteromeric ligand for the CNTF receptor complex. Nat Neurosci 3:867–872

    Article  PubMed  CAS  Google Scholar 

  • Ezzedine ZD, Yang X, DeChiara T, Yancopoulos G, Cepko CL (1997) Postmitotic cells fated to become rod photoreceptors can be respecified by CNTF treatment of the retina. Development 124:1055–1067

    Google Scholar 

  • Fontaine V, Kinkl N, Sahel J, Dreyfus H, Hicks D (1998) Survival of purified rat photoreceptors in vitro is stimulated directly by fibroblast growth factor-2. J Neurosci 18:9662–9672

    PubMed  CAS  Google Scholar 

  • Graham DR, Overbeek PA, Ash JD (2005) Leukemia inhibitory factor blocks expression of crx and nrl transcription factors to inhibit photoreceptor differentiation. Invest Ophthalmol Vis Sci 46:2601–2610

    Article  PubMed  Google Scholar 

  • Harada T, Harada C, Kohsaka S, Wada E, Yoshida K, Ohno S, Mamada H, Tanaka K, Parada LF, Wada K (2002) Microglia-Muller glia cell interactions control neurotrophic factor production during light-induced retinal degeneration. J Neurosci 22:9228–9236

    PubMed  CAS  Google Scholar 

  • Harris WA (1997) Cellular diversification in the vertebrate retina. Curr Opin Genet Dev 7:651–658

    Article  PubMed  CAS  Google Scholar 

  • Heinrich PC, Behrmann I, Müller-Newen G, Schaper F, Graeve L (1998) Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. Biochem J 334:297–314

    PubMed  CAS  Google Scholar 

  • Hofmann H-D, Schulz-Key S, Hertle D, Kirsch M (2005) Organotypic cultures of the rat retina. In: Poindron P, Piguet P, Förster E (eds) New methods for culturing cells from nervous tissue. Karger, Basel, pp 58–73

    Chapter  Google Scholar 

  • Ip NY, McClain J, Barrezueta NX, Aldrich TH, Pan L, Li Y, Wiegand SJ, Friedman B, Davis S, Yancopoulos GD (1993) The α component of the CNTF receptor is required for signaling and defines potential CNTF targets in the adult and during development. Neuron 10:89–102

    Article  PubMed  CAS  Google Scholar 

  • Ju W-K, Kim K-Y, Lee M-Y, Hofmann H-D, Kirsch M, Cha J-H, Oh S-J, Chun M-H (2000) Up-regulated CNTF plays a protective role for retrograde degeneration in the axotomized retina. Neuroreport 11:3893–3896

    Article  PubMed  CAS  Google Scholar 

  • Kamimura D, Ishihara K, Hirano T (2003) IL-6 signal transduction and its physiological roles: the signal orchestration model. Rev Physiol Biochem Pharmacol 149:1–38

    Article  PubMed  CAS  Google Scholar 

  • Kirsch M, Fuhrmann S, Wiese A, Hofmann H-D (1996) CNTF exerts opposite effects on in vitro development of rat and chick photoreceptors. Neuroreport 7:697–700

    Article  PubMed  CAS  Google Scholar 

  • Kirsch M, Lee M-Y, Meyer V, Wiese A, Hofmann H-D (1997) Evidence for multiple local functions of ciliary neurotrophic factor (CNTF) in retinal development: expression of CNTF and its receptor and in vitro effects on target cells. J Neurochem 68:979–990

    Article  PubMed  CAS  Google Scholar 

  • Levine EM, Fuhrmann S, Reh TA (2000) Soluble factors and the development of rod photoreceptors. Cell Mol Life Sci 57:224–234

    Article  PubMed  CAS  Google Scholar 

  • Livesey FJ, Cepko CL (2001) Vertebrate neural cell fate determination: lessons from the retina. Nat Neurosci Rev 2:109–118

    Article  CAS  Google Scholar 

  • Mey J, Thanos S (1993) Intravitreal injections of neurotrophic factors support the survival of axotomized retinal ganglion cells in adult rats in vivo. Brain Res 602:304–317

    Article  PubMed  CAS  Google Scholar 

  • Meyer-Franke A, Kaplan MR, Pfrieger FW, Barres BA (1995) Characterization of the signaling interactions that promote the survival and growth of developing retinal ganglion cells in culture. Neuron 15:805–819

    Article  PubMed  CAS  Google Scholar 

  • Monville C, Coulpier M, Conti L, De-Fraja C, Dreyfus P, Fages C, Riche D, Tardy M, Cattaneo E, Peschanski M (2001) Ciliary neurotrophic factor may activate mature astrocytes via binding with the leukemia inhibitory factor receptor. Mol Cell Neurosci 17:373–384

    Article  PubMed  CAS  Google Scholar 

  • Morrow EM, Belliveau MJ, Cepko CL (1998) Two phases of rod photoreceptor differentiation during rat retinal development. J Neurosci 18:3738–3748

    PubMed  CAS  Google Scholar 

  • Neophytou C, Vernallis AB, Smith A, Raff MC (1997) Müller-cell-derived leukemia inhibitory factor arrests rod photoreceptor differentiation at a postmitotic stage of development. Development 124:2345–2354

    PubMed  CAS  Google Scholar 

  • Ozawa Y, Nakao K, Shimazaki T, Takeda J, Akira S, Ishihara K, Hirano T, Oguchi Y, Okano H (2004) Downregulation of STAT3 activation is required for presumptive rod photoreceptor cells to differentiate in the postnatal retina. Mol Cell Neurosci 26:258–270

    Article  PubMed  CAS  Google Scholar 

  • Peterson WM, Wang Q, Tzekova R, Wiegand SJ (2000) Ciliary neurotrophic factor and stress stimuli activate the JAK-STAT pathway in retinal neurons. J Neurosci 20:4081–4090

    PubMed  CAS  Google Scholar 

  • Pinzon-Duarte G, Kohler K, Arango-Gonzalez B, Guenther E (2000) Cell differentiation, synaptogenesis, and influence of the retinal pigment epithelium in rat organotypic retina culture. Vision Res 40:3455–3465

    Article  PubMed  CAS  Google Scholar 

  • Reh TA (1992) Cellular interactions determine neuronal phenotypes in rodent retinal cultures. J Neurobiol 23:1067–1083

    Article  PubMed  CAS  Google Scholar 

  • Rhee KD, Yang XJ (2003) Expression of cytokine signal transduction components in the postnatal mouse retina. Mol Vision 9:715–722

    CAS  Google Scholar 

  • Rhee KD, Goureau O, Chen S, Yang X-J (2004) Cytokine-induced activation of signal transducer and activator of transcription in photoreceptor precursors regulates rod differentiation in the developing mouse retina. J Neurosci 24:9779–9788

    Article  PubMed  CAS  Google Scholar 

  • Schulz-Key S, Hofmann H-D, Beisenherz-Huss C, Barbisch C, Kirsch M (2002) Ciliary neurotrophic factor as a transient negative regulator of rod development in rat retina. Invest Ophthalmol Vis Sci 43:3099–3108

    PubMed  Google Scholar 

  • Turner DL, Snyder EY, Cepko CL (1990) Lineage-independent determination of cell type in the embryonic mouse retina. Neuron 4:833–845

    Article  PubMed  CAS  Google Scholar 

  • Valter K, Bisti S, Stone J (2003) Location of CNTFRα on outer segments: evidence of the site of action of CNTF in rat retina. Brain Res 985:169–175

    Article  PubMed  CAS  Google Scholar 

  • Wahlin KJ, Campochiaro PA, Zack DJ, Adler R (2000) Neurotrophic factors cause activation of intracellular signaling pathways in Müller cells and other cells of the inner retina, but not in photoreceptors. Invest Ophthalmol Vis Sci 41:927–936

    PubMed  CAS  Google Scholar 

  • Wahlin KJ, Lim L, Grice EA, Campochiaro PA, Zack DJ, Adler R (2004) A method for analysis of gene expression in isolated mouse photoreceptor and Müller cells. Mol Vision 10:366–375

    CAS  Google Scholar 

  • Waid DK, McLoon SC (1995) Immediate differentiation of ganglion cells following mitosis in the developing retina. Neuron 14:117–124

    Article  PubMed  CAS  Google Scholar 

  • Walsh N, Valter K, Stone J (2001) Cellular and subcelluar patterns of expression of the bFGF and CNTF in the normal and light stressed adult rat retina. Exp Eye Res 72:495–501

    Article  PubMed  CAS  Google Scholar 

  • Wang Y, Smith SB, Ogilvie JM, McCool DJ, Sarthy V (2002) Ciliary neurotrophic factor induces glial fibrillary acidic protein in retinal Muller cells through the JAK/STAT signal transduction pathway. Curr Eye Res 24:305–312

    Article  PubMed  CAS  Google Scholar 

  • Watanabe T, Raff MC (1990) Rod photoreceptor development in vitro: intrinsic properties of proliferating neuroepithelial cells change as development proceeds in the rat retina. Neuron 4:461–467

    Article  PubMed  CAS  Google Scholar 

  • Watanabe T, Raff MC (1992) Diffusible rod-promoting signals in the developing rat retina. Development 114:899–906

    PubMed  CAS  Google Scholar 

  • Wetts R, Fraser SE (1988) Multipotent precursors can give rise to all major cell types in the frog retina. Science 239:1142–1145

    Article  PubMed  CAS  Google Scholar 

  • Yang X-J (2004) Roles of cell-intrinsic growth factors in vertebrate eye pattern formation and retinogenesis. Semin Cell Dev Biol 15:91–103

    Article  PubMed  CAS  Google Scholar 

  • Young RW (1985) Cell differentiation in the retina of the mouse. Anat Rec 212:199–205

    Article  PubMed  CAS  Google Scholar 

  • Zhang SSM, Wei J, Quin H, Zhang L, Xie B, Hui P, Deisseroth A, Barnstable CJ, Fu X-Y (2004) STAT3-mediated signaling in the determination of rod photoreceptor cell fate in the mouse retina. Invest Ophthalmol Vis Sci 45:2407–2412

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank S. Zenker for excellent technical assistance.

Author information

Authors and Affiliations

  1. Institute of Anatomy and Cell Biology, University of Freiburg, P.O. Box 111, 79001, Freiburg, Germany

    Daniel Hertle, Michael Schleichert, Andreas Steup, Matthias Kirsch & Hans-Dieter Hofmann

Authors
  1. Daniel Hertle
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael Schleichert
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andreas Steup
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Matthias Kirsch
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hans-Dieter Hofmann
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hans-Dieter Hofmann.

Additional information

This study was supported by a grant from the Deutsche Forschungsgemeinschaft, SFB 505/A4.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hertle, D., Schleichert, M., Steup, A. et al. Regulation of cytokine signaling components in developing rat retina correlates with transient inhibition of rod differentiation by CNTF. Cell Tissue Res 334, 7–16 (2008). https://doi.org/10.1007/s00441-008-0651-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00441-008-0651-3

Keywords

Search

Navigation