Sensory stimuli drive the maturation and function of the mammalian nervous system in part through the activation of gene expression networks that regulate synapse development and plasticity. These networks have primarily been studied in mice, and it is not known whether there are species- or clade-specific activity-regulated genes that control features of brain development and function. Here we use transcriptional profiling of human fetal brain cultures to identify an activity-dependent secreted factor, Osteocrin (OSTN), that is induced by membrane depolarization of human but not mouse neurons. We find that OSTN has been repurposed in primates through the evolutionary acquisition of DNA regulatory elements that bind the activity-regulated transcription factor MEF2. In addition, we demonstrate that OSTN is expressed in primate neocortex and restricts activity-dependent dendritic growth in human neurons. These findings suggest that, in response to sensory input, OSTN regulates features of neuronal structure and function that are unique to primates.

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Gene Expression Omnibus

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Raw and processed RNA-seq data have been submitted to the NCBI Gene Expression Omnibus under accession number GSE78688.


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We thank E. Curran, T. Hartmann, P. Schade, P. Zhang, J. M. Gray, M. Hemberg, X. Adiconis, J. Z. Levin, J. Zieg, D. R. Hochbaum, T. J. Cherry and M. M. Andzelm for their technical assistance or advice. This work was supported by grants from the NIH: P50MH106933 and 1RC2MH089952 (M.E.G.), 5F32NS086270 (G.L.B.), EY16187 (M.S.L.), EY12196 (V.K.B.), and T32GM007753 (A.N.M. and E.D.). B.A. is supported by The Ellen R. and Melvin J. Gordon Center for the Cure and Treatment of Paralysis.

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Author notes

    • Bulent Ataman
    •  & Gabriella L. Boulting

    These authors contributed equally to this work.


  1. Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Bulent Ataman
    • , Gabriella L. Boulting
    • , David A. Harmin
    • , Marty G. Yang
    • , Mollie Baker-Salisbury
    • , Ee-Lynn Yap
    • , Athar N. Malik
    • , Kevin Mei
    • , Alex A. Rubin
    • , Ivo Spiegel
    • , Ershela Durresi
    • , Nikhil Sharma
    • , Linda S. Hu
    • , Eric C. Griffith
    • , Vladimir K. Berezovskii
    • , Margaret S. Livingstone
    •  & Michael E. Greenberg
  2. Department of Neuroscience and Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, Connecticut 06510, USA

    • Mihovil Pletikos
    •  & Nenad Sestan
  3. Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Jennifer N. Partlow
    •  & Christopher A. Walsh
  4. Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA

    • Christine R. Stevens
  5. University of Virginia, School of Medicine, Department of Biochemistry and Molecular Genetics, Charlottesville, Virginia 22903, USA

    • Mazhar Adli
  6. McDermott Center for Human Growth and Development, Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA

    • Maria Chahrour


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B.A., G.L.B., and M.E.G. performed or directed all experiments and wrote the manuscript with E.C.G. B.A., D.A.H. and M.G.Y. performed or analysed gene expression experiments. G.L.B. performed iPSC differentiation and luciferase reporter assays with assistance from M.G.Y., K.M. and M.B.-S. V.K.B., G.L.B. and M.S.L. performed monocular inactivation experiments. B.A., M.G.Y. and G.L.B. performed FISH. B.A. and M.G.Y. performed dendritic growth assays. E.-L.Y. and N.Sh. contributed to overexpression studies. A.N.M. and A.A.R. cloned initial reporter constructs. I.S. provided RiboTag-Seq data and mouse brain sections. L.S.H. generated the OSTN antibody. M.P. and N.Se. provided human brain sections. M.C., J.N.P. and C.A.W. provided human tissue for initial culture experiments. M.A., B.A., M.G.Y., and E.D. performed ChIP experiments. C.R.S. assisted with RNA-seq experiments.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Michael E. Greenberg.

Reviewer Information Nature thanks M. Oldham, F. Polleux and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Extended data

Supplementary information

Excel files

  1. 1.

    Supplementary Table 1

    Complete list of genes that are upregulated or downregulated in response to 1 hr or 6 hr KCl depolarization in hFBCs.

  2. 2.

    Supplementary Table 2

    Complete list of genes that are upregulated or downregulated in response to 1 hr or 6 hr KCl depolarization in cultured mouse cortical neurons.

  3. 3.

    Supplementary Table 3

    Complete list of genes that are upregulated or downregulated in response to 1 hr or 6 hr KCl depolarization in cultured rat cortical neurons.

  4. 4.

    Supplementary Table 4

    Comparison of activity-induced genes in hFBCs following 1 or 6 hrs of KCl-induced depolarization with genes induced under similar conditions in mouse and rat cultures.

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