The complexity of the human brain derives from the intricate interplay of molecular instructions during development. Here we systematically investigated gene expression changes in the prenatal human striatum and cerebral cortex during development from post-conception weeks 2 to 20. We identified tissue-specific gene coexpression networks, differentially expressed genes and a minimal set of bimodal genes, including those encoding transcription factors, that distinguished striatal from neocortical identities. Unexpected differences from mouse striatal development were discovered. We monitored 36 determinants at the protein level, revealing regional domains of expression and their refinement, during striatal development. We electrophysiologically profiled human striatal neurons differentiated in vitro and determined their refined molecular and functional properties. These results provide a resource and opportunity to gain global understanding of how transcriptional and functional processes converge to specify human striatal and neocortical neurons during development.

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We thank N. Sestan and S. Piccolo for critical reading of the first version of the manuscript. We also thank C. Laterza for assistance with Illumina chip hybridization, M. Caiazzo for micrograph acquisition assistance, V. Broccoli for providing tdTomato and GFP lentiviral constructs, M. Binetti for help in sample collection, M. Molinari for the interactive striatum map, and M. Ascagni, from the Centro Interdipartimentale Microscopia Avanzata of the Department of Bioscience, University of Milan, for assistance in confocal imaging. We also thank the families of our Huntington's disease patients for their support. This study received funding from NeuroStemcell (EU Seventh Framework Programme, grant agreement no. 222943), from Cure Huntington's Disease Initiative (CHDI, U.S.A., ID: A-4529), from the Ministero dell'Istruzione dell'Università e della Ricerca (MIUR 2010JMMZLY_001, Italy), to E. Cattaneo; from NeuroStemcellRepair (European Union Seventh Framework Programme, grant agreement no. 602278) to E. Cattaneo and R.A.B.; from Fondo per gli Investimenti della Ricerca di Base (FIRB, RBFR10A01S, Italy) to M.O.; and partially from TargetBrain (EU Framework 7 project HEALTH-F2-2012–279017) to G.M. D.B. was supported by a Marie Curie Fellowship (TranSVIR FP7-PEOPLE-ITN-2008 #238756, EU). We acknowledge the contribution of Tavola Valdese (2010–2013) and support from Unicredit Banca S.p.A. (2010–2011, Italy).

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Author notes

    • Marco Onorati

    Present address: Department of Neurobiology, Yale School of Medicine, New Haven, Connecticut, USA.

    • Marco Onorati
    •  & Valentina Castiglioni

    These authors contributed equally to this work.


  1. Department of Biosciences and Center for Stem Cell Research, Università degli Studi di Milano, Italy.

    • Marco Onorati
    • , Valentina Castiglioni
    •  & Elena Cattaneo
  2. Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.

    • Daniele Biasci
    •  & Paul A Lyons
  3. Department of Biology and Biotechnologies, University of Pavia, Pavia, Italy.

    • Elisabetta Cesana
    • , Francesca Talpo
    • , Mauro Toselli
    •  & Gerardo Biella
  4. Institute of Experimental Neurology, San Raffaele Scientific Institute, Milan, Italy.

    • Ramesh Menon
    • , Luca Muzio
    • , Gianvito Martino
    •  & Cinthia Farina
  5. John van Geest Centre for Brain Repair, University of Cambridge, Cambridge, UK.

    • Romina Vuono
    • , Rocio Laguna Goya
    •  & Roger A Barker
  6. Department of Health Sciences, Università degli Studi di Milano–San Paolo Hospital, Milan, Italy.

    • Gaetano P Bulfamante


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D.B., E. Cesana and R.M. contributed equally to this work. M.O., V.C. and E. Cattaneo designed the research program and wrote the manuscript. M.O. and V.C. performed the experiments that comprise the main body of this work. D.B., R.M., C.F., G.M. and P.A.L. assisted in transcriptional study design and acquired and interpreted transcriptional data. E. Cesana, F.T., M.T. and G.B. did the electrophysiological analysis and acquired and interpreted experimental data. R.V., R.L.G., R.A.B. and G.P.B. provided and processed the human specimens and helped in their staging. L.M. performed in situ hybridization experiments. All authors contributed to the revision of the manuscript up to its final form. E. Cattaneo provided guidance and conceptual support and approved the final version of the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Elena Cattaneo.

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    Supplementary Figures 1–12

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  1. 1.

    Supplementary Table 1: List of the human fetal brain samples and their analyses.

    (a) List of the human fetal brain samples collected in this study. (b) List of human fetal tissue and human primary neuron samples used for transcriptional analysis. (c) List of human fetal brain samples used for immunohistochemical analysis. (d) List of human fetal samples used for human primary neuron derivation. (e) List of human primary neurons used for electrophysiological recording.

  2. 2.

    Supplementary Table 2: List of differentially and bimodally expressed genes between fetal striatum and neocortex.

    (a) List of differentially expressed genes between ST and CX tissues. (b) List of bimodally expressed genes between ST and CX tissues. (c) List of bimodally expressed genes unrelated to ST/CX separation.

  3. 3.

    Supplementary Table 3: List of all gene members for each module.

  4. 4.

    Supplementary Table 4: Quantification of striatal marker expression in human fetal brain samples.

    (a) Counts of MSN markers co-expression on 8w brain samples. (b) Counts of MSN markers co-expression on 20w brain samples. (c) Counts of DARPP-32+ MSN co-expression on 20w brain samples. (d) Counts of interneuronal marker co-expression on 20w brain samples.

  5. 5.

    Supplementary Table 5: List of differentially expressed genes and enriched gene ontology analyses in human primary neurons.

    (a) List of differentially expressed genes between ST tissue and human primary neurons. (b) List of differentially expressed genes between CX tissue and human primary neurons. (c) Enriched GO biological processes in the ST tissue vs. human primary neuron DEGs. (d) Enriched GO biological processes in the CX tissue vs. human primary neuron DEGs.

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