Evolution of Osteocrin as an activity-regulated factor in the primate brain


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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Figure 1: OSTN is an activity-regulated factor in human neocortex.
Figure 2: Primate-specific enhancer regulation by MEF2 drives neuronal activity-dependent induction of OSTN.
Figure 3: OSTN expression is induced by sensory experience in the primate cortex.
Figure 4: OSTN regulates activity-dependent dendritic growth.

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Gene Expression Omnibus

Data deposits

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


  1. 1

    Defelipe, J. The evolution of the brain, the human nature of cortical circuits, and intellectual creativity. Front. Neuroanat. 5, 29 (2011)

    PubMed  PubMed Central  Google Scholar 

  2. 2

    Bufill, E., Agustí, J. & Blesa, R. Human neoteny revisited: The case of synaptic plasticity. Am. J. Hum. Biol. 23, 729–739 (2011)

    PubMed  Google Scholar 

  3. 3

    Geschwind, D. H. & Rakic, P. Cortical evolution: judge the brain by its cover. Neuron 80, 633–647 (2013)

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4

    Johnson, M. B. et al. Single-cell analysis reveals transcriptional heterogeneity of neural progenitors in human cortex. Nat. Neurosci. 18, 637–646 (2015)

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5

    Pollen, A. A. et al. Molecular identity of human outer radial glia during cortical development. Cell 163, 55–67 (2015)

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6

    Kwan, K. Y. et al. Species-dependent posttranscriptional regulation of NOS1 by FMRP in the developing cerebral cortex. Cell 149, 899–911 (2012)

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7

    Flavell, S. W. et al. Genome-wide analysis of MEF2 transcriptional program reveals synaptic target genes and neuronal activity-dependent polyadenylation site selection. Neuron 60, 1022–1038 (2008)

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8

    Kim, T.-K. K. et al. Widespread transcription at neuronal activity-regulated enhancers. Nature 465, 182–187 (2010)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  9. 9

    Greer, P. L. & Greenberg, M. E. From synapse to nucleus: calcium-dependent gene transcription in the control of synapse development and function. Neuron 59, 846–860 (2008)

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

    Banzet, S. et al. Musclin gene expression is strongly related to fast-glycolytic phenotype. Biochem. Biophys. Res. Commun. 353, 713–718 (2007)

    CAS  PubMed  Google Scholar 

  11. 11

    Subbotina, E. et al. Musclin is an activity-stimulated myokine that enhances physical endurance. Proc. Natl Acad. Sci. USA 112, 16042–16047 (2015)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  12. 12

    Moffatt, P. et al. Osteocrin is a specific ligand of the natriuretic peptide clearance receptor that modulates bone growth. J. Biol. Chem. 282, 36454–36462 (2007)

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13

    Kang, H. J. et al. Spatio-temporal transcriptome of the human brain. Nature 478, 483–489 (2011)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  14. 14

    Molliver, M. E., Kostović, I. & van der Loos, H. The development of synapses in cerebral cortex of the human fetus. Brain Res. 50, 403–407 (1973)

    CAS  PubMed  Google Scholar 

  15. 15

    Hong, E. J., McCord, A. E. & Greenberg, M. E. A biological function for the neuronal activity-dependent component of Bdnf transcription in the development of cortical inhibition. Neuron 60, 610–624 (2008)

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16

    Gossett, L. A., Kelvin, D. J., Sternberg, E. A. & Olson, E. N. A new myocyte-specific enhancer-binding factor that recognizes a conserved element associated with multiple muscle-specific genes. Mol. Cell. Biol. 9, 5022–5033 (1989)

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17

    Andzelm, M. M. et al. MEF2D drives photoreceptor development through a genome-wide competition for tissue-specific enhancers. Neuron 86, 247–263 (2015)

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Flavell, S. W. et al. Activity-dependent regulation of MEF2 transcription factors suppresses excitatory synapse number. Science 311, 1008–1012 (2006)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Potthoff, M. J. & Olson, E. N. MEF2: a central regulator of diverse developmental programs. Development 134, 4131–4140 (2007)

    CAS  PubMed  Google Scholar 

  20. 20

    Horton, J. C. & Hocking, D. R. Monocular core zones and binocular border strips in primate striate cortex revealed by the contrasting effects of enucleation, eyelid suture, and retinal laser lesions on cytochrome oxidase activity. J. Neurosci. 18, 5433–5455 (1998)

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    Takahata, T., Higo, N., Kaas, J. H. & Yamamori, T. Expression of immediate-early genes reveals functional compartments within ocular dominance columns after brief monocular inactivation. Proc. Natl Acad. Sci. USA 106, 12151–12155 (2009)

    ADS  CAS  PubMed  Google Scholar 

  22. 22

    Kaas, J. H. The evolution of neocortex in primates. Prog. Brain Res. 195, 91–102 (2012)

    PubMed  PubMed Central  Google Scholar 

  23. 23

    Kolb, H., Fernandez, E. & Nelson, R. Webvision: The Organization of the Retina and Visual System (University of Utah Health Sciences Center, 1995)

  24. 24

    Tochitani, S., Liang, F., Watakabe, A., Hashikawa, T. & Yamamori, T. The occ1 gene is preferentially expressed in the primary visual cortex in an activity-dependent manner: a pattern of gene expression related to the cytoarchitectonic area in adult macaque neocortex. Eur. J. Neurosci. 13, 297–307 (2001)

    CAS  PubMed  Google Scholar 

  25. 25

    Kostović, I. & Judaš, M. The development of the subplate and thalamocortical connections in the human foetal brain. Acta Paediatr. 99, 1119–1127 (2010)

    PubMed  Google Scholar 

  26. 26

    Moore, A. R. et al. Connexin hemichannels contribute to spontaneous electrical activity in the human fetal cortex. Proc. Natl Acad. Sci. USA 111, E3919–E3928 (2014)

    CAS  PubMed  Google Scholar 

  27. 27

    O’Leary, T., van Rossum, M. C. & Wyllie, D. J. Homeostasis of intrinsic excitability in hippocampal neurones: dynamics and mechanism of the response to chronic depolarization. J. Physiol. (Lond.) 588, 157–170 (2010)

    Google Scholar 

  28. 28

    Zweier, M. et al. Mutations in MEF2C from the 5q14.3q15 microdeletion syndrome region are a frequent cause of severe mental retardation and diminish MECP2 and CDKL5 expression. Hum. Mutat. 31, 722–733 (2010)

    CAS  PubMed  Google Scholar 

  29. 29

    Bienvenu, T., Diebold, B., Chelly, J. & Isidor, B. Refining the phenotype associated with MEF2C point mutations. Neurogenetics 14, 71–75 (2013)

    PubMed  Google Scholar 

  30. 30

    Parikshak, N. N. et al. Integrative functional genomic analyses implicate specific molecular pathways and circuits in autism. Cell 155, 1008–1021 (2013)

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

    Lund, J. S., Holbach, S. M. & Chung, W. W. Postnatal development of thalamic recipient neurons in the monkey striate cortex: II. Influence of afferent driving on spine acquisition and dendritic growth of layer 4C spiny stellate neurons. J. Comp. Neurol. 309, 129–140 (1991)

    CAS  PubMed  Google Scholar 

  32. 32

    Herculano-Houzel, S. Neuronal scaling rules for primate brains: the primate advantage. Prog. Brain Res. 195, 325–340 (2012)

    PubMed  Google Scholar 

  33. 33

    Srinivasan, S., Carlo, C. N. & Stevens, C. F. Predicting visual acuity from the structure of visual cortex. Proc. Natl Acad. Sci. USA 112, 7815–7820 (2015)

    ADS  CAS  PubMed  Google Scholar 

  34. 34

    Mardinly, A. R. et al. Sensory experience regulates cortical inhibition by inducing IGF1 in VIP neurons. Nature 531, 371–375 (2016)

    ADS  CAS  PubMed  PubMed Central  Google Scholar 

  35. 35

    Berry, B. J. et al. Morphological and functional characterization of human induced pluripotent stem cell-derived neurons (iCell Neurons) in defined culture systems. Biotechnol. Prog. 31, 1613–1622 (2015)

    CAS  PubMed  Google Scholar 

  36. 36

    Brewer, G. J. & Torricelli, J. R. Isolation and culture of adult neurons and neurospheres. Nat. Protocols 2, 1490–1498 (2007)

    CAS  PubMed  Google Scholar 

  37. 37

    Gray, J. M. et al. SnapShot-Seq: a method for extracting genome-wide, in vivo mRNA dynamics from a single total RNA sample. PLoS One 9, e89673 (2014)

    ADS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Robinson, M. D., McCarthy, D. J. & Smyth, G. K. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 26, 139–140 (2010)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. 39

    McCarthy, D. J., Chen, Y. & Smyth, G. K. Differential expression analysis of multifactor RNA-Seq experiments with respect to biological variation. Nucleic Acids Res. 40, 4288–4297 (2012)

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40

    Spiegel, I. et al. Npas4 regulates excitatory-inhibitory balance within neural circuits through cell-type-specific gene programs. Cell 157, 1216–1229 (2014)

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Meijering, E. et al. Design and validation of a tool for neurite tracing and analysis in fluorescence microscopy images. Cytometry A 58, 167–176 (2004)

    CAS  PubMed  Google Scholar 

  42. 42

    Ferreira, T. A. et al. Neuronal morphometry directly from bitmap images. Nat. Methods 11, 982–984 (2014)

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43

    Boulting, G. L. et al. A functionally characterized test set of human induced pluripotent stem cells. Nat. Biotechnol. 29, 279–286 (2011)

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44

    Maroof, A. M. et al. Directed differentiation and functional maturation of cortical interneurons from human embryonic stem cells. Cell Stem Cell 12, 559–572 (2013)

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    Malik, A. N. et al. Genome-wide identification and characterization of functional neuronal activity-dependent enhancers. Nat. Neurosci. 17, 1330–1339 (2014)

    CAS  PubMed  PubMed Central  Google Scholar 

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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.

Author information




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.

Corresponding author

Correspondence to Michael E. Greenberg.

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Competing interests

The authors declare no competing financial interests.

Additional information

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 figures and tables

Extended Data Figure 1 hFBCs are mixed neuronal cultures that show high reproducibility.

a, Gestational week and sex of hFBC samples used in profiling of activity-dependent gene expression. b, Representative images of DIV6 hFBC neurons immunostained with the neuronal marker MAP2 alone or together with the glial marker GFAP and DAPI nuclear dye. Scale bar, 75 μm. c, Quantification of MAP2- and GFAP-positive cells in hFBCs. Mean ± s.d. from three independent cultures shown. d, Representative image of hFBC neurons immunostained with MAP2 (green), SATB2 (red) and CTIP2 (blue). Scale bar, 57 μm. e, Quantification of the SATB2- and CTIP-immunoreactive subpopulations of MAP2-positive hFBC neurons. Mean ± s.d. from three independent cultures shown. f, Heatmap showing the Spearman correlation rS of coding gene expression profiles among five biological hFBC replicates (H1–H5) (unstimulated neurons). g, Dendrogram of correlations among the gene expression profiles of hFBC replicates (H1–H5) and 10 human tissues, including whole brain37, based on hierarchical clustering with distance measure 1 − rS.

Extended Data Figure 2 hFBCs are mixed neuronal cultures with a substantial representation of cortical neuronal subtypes.

a, Quantile distribution constructed from combined log-gene expression levels of five unstimulated hFBC samples, with associated colour scale (see Methods). be, Expression of selected marker genes classified by neuronal subtype (b), glial cell type (c), brain region (d), neural progenitor cell type (e), and non-neural cell type (f).

Extended Data Figure 3 RNA-seq profiling of activity-dependent gene expression in human neuronal cultures.

a, b, RNA-seq analysis of membrane depolarization-induced hFBC gene expression changes after 1 h (a) or 6 h (b). Scatterplots depict the geometric mean of genes’ non-zero expression values ± s.e.m. from five independent hFBC cultures. Fold change is proportional to distance from the diagonal. Genes passing filters for expression and significant activity-dependent changes are highlighted in red (BH-corrected P values controlled for FDR ≤ 0.15 based on a negative binomial model38, magnitude of change (ratio ≥ 2.0 or ≤ 0.5), and above-background expression (RPKM > 0.57) on either axis, total reads ≥ 3 per time point). Selected genes exhibiting activity-regulated expression in human neurons but not in mouse neurons are indicated in blue. c, d, Pie charts showing the predicted subcellular localization of hFBC activity-responsive gene products induced following 1 h (c) or 6 h (d) KCl treatment. Analysis was performed using Ingenuity and GeneCards databases.

Extended Data Figure 4 Ostn is neither expressed nor activity-regulated in mouse cortical neurons in vitro and in vivo.

a, UCSC genome browser tracks for RNA-seq data from DIV7 cultured mouse cortical neurons depolarized for 0, 1 or 6 h with 55 mM KCl. The Ostn locus (grey) shows neither basal expression nor activity-dependent induction. The known activity-regulated gene Npas4 shows clear activity-dependent induction at 1 and 6 h. Finally, the cortex-enriched transcription factor Mef2C and the layer IV marker RorB show no significant expression changes in response to depolarization. b, UCSC genome browser tracks for RNA-seq data from visual cortices of dark-adapted (P42–P56) mice that were exposed to light for 0, 1, and 7.5 h. RNAs from excitatory and inhibitory neurons were isolated through the expression of a RiboTag transgene using Emx and Gad2 Cre-lines, respectively34. The Ostn (grey), Npas4, Mef2C and RorB loci show similar responses as in a. All genome browser tracks y-axis min = 0 and max = 10. c, FISH images of radial sections from primary visual cortex of dark-adapted (P42–P56) mice exposed to light for 0 and 7.5 h. Upper panels, grey-scale images of Npas4 (left) and Ostn (right) probes. Lower panels, green-coloured images from upper panels, with nuclei marked with DAPI (magenta). Scale bar, 110 μm; cortical layers I–VI are indicated.

Extended Data Figure 5 Differentiation and characterization of human iPSC-derived cortical neurons.

a, Schematic of the iPSC cortical neuron differentiation protocol44 (see Methods). b, Immunostaining of DIV82 iPSC-derived neurons shows expression of cortical layer markers TBR1 (layer VI), CTIP2 (layer V), and SATB2 (layers II–IV). c, Quantitative RT–PCR analysis of known activity-dependent genes from DIV82 iPSC-derived neurons 0, 1, and 6 h after membrane depolarization with 55 mM KCl. Data shown as mean ± s.e.m. from two independent iPSC lines. Scale bar, 100 μm.

Extended Data Figure 6 OSTN is primarily expressed in the neocortex of human brain.

BrainSpan (http://www.brainspan.org) RNA-seq data showing expression levels of OSTN (red) and BDNF (grey) in 6 human brain regions (af; neocortex, hippocampus (HIP), amygdala (AMY), striatum (STR), mediodorsal nucleus of the thalamus (MD), and cerebellar cortex (CBC)) and OSTN in subregions of the human cortex from 8 pcw through 40 years old (g). Loess-fit curves depict mean expression with bands showing one s.e.m. h, FISH images showing OSTN expression in a radial section of human fetal brain (pcw16) illustrating selective enrichment of OSTN in the developing cortical plate of the paracentral lobule. Isolated OSTN signal also appears to be localized to migrating neurons (arrowheads) of the subplate. Scale bar, 200 μm. MZ, marginal zone; CP, cortical plate; SP, subplate; IZ, intermediate zone; SVZ, subventricular zone; VZ, ventricular zone.

Extended Data Figure 7 Luciferase and ChIP assays in human and mouse neurons.

Direct comparison of the ability of the human and mouse −2kb regulatory sequences to drive reporter expression in mouse (a; n = 8) and human (b; n = 3) neuronal cultures in response to KCl depolarization. n = number of biological replicates. Mean normalized firefly luciferase activity (Fluc/Ren) ± s.e.m., Student’s t-test, NS, not significant, *P < 0.05, **P < 0.01, ***P < 0.001. c, Luciferase assays performed in mouse neurons in the presence of calcineurin inhibitors (CsA and FK506, red) or vehicle (DMSO, black), Student’s t-test, *P < 0.05. d, ChIP–seq using a pan-MEF2 antibody (purple), an MEF2C-specific antibody (fuschia), and an antibody specific for H3K27ac (green) in hFBCs (left) and mouse cortical neuron cultures (right) shows enrichment for MEF2 binding at the known MEF2-regulated gene Nr4a1 (also known as Nur77). Y-axis scales here and in Fig. 2e were adjusted for each experiment to normalize for variability in ChIP efficiency between these two different culture systems. We chose scales by setting MEF2 and H3K27ac enrichment to approximately equal levels at this positive-control locus, yielding all human tracks at max 10, mouse pan-Mef2, Mef2c, and input tracks at max 20, and mouse active chromatin (H3K27ac) at max 50. e, UCSC genome browser tracks for RNA-seq, ChIP–seq and vertebrate evolutionary conservation at the mouse Ostn locus, shaded yellow. RNA-seq tracks show no Ostn expression or induction in DIV7 mouse cortical neuron cultures following KCl depolarization (0, 1 and 6 h). ChIP–seq tracks45 show H3K27ac peaks that mark active cis-regulatory regions at two time points: 0 h and 2 h after KCl depolarization. The nearby genes Uts2b and Ccdc50 are also shown for comparison. No active cis-regulatory sites were found surrounding the Ostn locus. H3K27ac tracks are shown with max 5 and RNA-seq tracks with max 10.

Extended Data Figure 8 Luciferase reporter constructs and the complete set of assays.

a, Detailed summary of all luciferase assay reporter construct variants of the human genomic sequence −2 kb upstream of the OSTN transcription start site. b, Summary of all luciferase assays performed in mouse cortical cultures. Categories of construct modifications are indicated and grouped by colour. Biological replicate numbers are indicated on the graph. Significant differences tested for by one-way ANOVA DF = (33, 266) and P < 1.0 × 10−13. Pair-wise comparisons were made using Holm–Sidak test for multiple comparisons using an overall error rate of 0.05, ***P < 1.22 × 10−5. All values are mean ± s.e.m.

Extended Data Figure 9 FISH for OSTN mRNA in macaque brain.

Layer IVC of active ocular dominance columns in primary visual cortex (V1) shows expression of OSTN after monocular inactivation of monkey#1 (a) and monkey#2 (b). Scale bar, 1,000 μm. c, Expanded panel shows detail of partially tangential portion of tissue section in which OSTN is expressed in layer IVC ocular dominance column stripes. Scale bar, 1,000 μm. d, OSTN expression is also enriched in layer IV of the multimodal parietal cortex. Scale bar, 250 μm. eh, Representative FISH images of layer IVC neurons from the active columns, showing co-expression of OSTN with various cell-type markers, including VGLUT1 (glutamatergic neurons, e; 94.2 ± 2.8% of OSTN+ cells were VGLUT1+, n = 170), RORB (layer IV, f; 93.3 ± 6.1% of OSTN+ cells were RORB+, n = 92), MEF2C (g; 100% ± 0 of OSTN+ cells were MEF2C+, n = 148), and MEF2A (h; 100% ± 0 of OSTN+ cells were MEF2A+, n = 148). Data are represented as mean ± s.d. Nuclei are visualized with DAPI. Scale bar (eh), 2 μm.

Extended Data Figure 10 Biochemical detection and immunolocalization of endogenous OSTN protein in human neurons.

a, ELISA quantification of secreted OSTN in the culture medium of hFBCs under CAP conditions in two biological replicates (Rep#1 and #2). Rat monoclonal anti-OSTN antibody and rat monoclonal anti-CD31 (control antibody) were used as the detection antibodies. n = number of biological replicates. Mean ± s.e.m., Student’s t-test ***P < 0.001. b, Quantitative RT–PCR analysis of OSTN induction in hFBC neurons treated with scrambled siRNA (n = 5) or two independent siRNAs against the OSTN transcript (#1; n = 5 and #2; n = 4) for three days in the presence and absence of CAP. OSTN expression is normalized to GAPDH. c, d, Immunofluorescence images of DIV28 hFBC neurons transfected with −2kbhOSTN:GFP and left untreated (c) or maintained under CAP conditions (d). eg, Immunofluorescence images of DIV28 hFBC neurons transfected with −2kbhOSTN:GFP (arrows) and treated with CAP for 3 days with (f) or without (e) treatment with siRNA targeting OSTN. Endogenous OSTN is predominantly localized in the soma and primary dendrites. Scale bar, 15 μm. (g) Higher magnification of OSTN immunostaining after 3 day CAP treatment reveals punctate structures (arrowheads) in the dendrites. Scale bars, 48 μm (c, d), 23 μm (e, f), 15 μm (g).

Supplementary information

Supplementary Table 1

Complete list of genes that are upregulated or downregulated in response to 1 hr or 6 hr KCl depolarization in hFBCs. (XLSX 31 kb)

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. (XLSX 157 kb)

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. (XLSX 134 kb)

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. (XLSX 44 kb)

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Ataman, B., Boulting, G., Harmin, D. et al. Evolution of Osteocrin as an activity-regulated factor in the primate brain. Nature 539, 242–247 (2016). https://doi.org/10.1038/nature20111

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