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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.

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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.

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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.

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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

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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)

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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

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