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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Rakic, P. Evolution of the neocortex: a perspective from developmental biology. Nat. Rev. Neurosci. 10, 724–735 (2009).
Lui, J.H., Hansen, D.V. & Kriegstein, A.R. Development and evolution of the human neocortex. Cell 146, 18–36 (2011).
Ma, T. et al. Subcortical origins of human and monkey neocortical interneurons. Nat. Neurosci. 16, 1588–1597 (2013).
Hansen, D.V. et al. Non-epithelial stem cells and cortical interneuron production in the human ganglionic eminences. Nat. Neurosci. 16, 1576–1587 (2013).
Miller, J.A. et al. Transcriptional landscape of the prenatal human brain. Nature 508, 199–206 (2014).
Zuccato, C., Valenza, M. & Cattaneo, E. Molecular mechanisms and potential therapeutical targets in Huntington′s disease. Physiol. Rev. 90, 905–981 (2010).
Schuurmans, C. & Guillemot, F. Molecular mechanisms underlying cell fate specification in the developing telencephalon. Curr. Opin. Neurobiol. 12, 26–34 (2002).
Kang, H.J. et al. Spatio-temporal transcriptome of the human brain. Nature 478, 483–489 (2011).
Johnson, M.B. et al. Functional and evolutionary insights into human brain development through global transcriptome analysis. Neuron 62, 494–509 (2009).
Colantuoni, C. et al. Temporal dynamics and genetic control of transcription in the human prefrontal cortex. Nature 478, 519–523 (2011).
Teschendorff, A.E., Miremadi, A., Pinder, S.E., Ellis, I.O. & Caldas, C. An immune response gene expression module identifies a good prognosis subtype in estrogen receptor negative breast cancer. Genome Biol. 8, R157 (2007).
Wang, J. et al. The bimodality index: a criterion for discovering and ranking bimodal signatures from cancer gene expression profiling data. Cancer Inform. 7, 199 (2009).
Hellwig, B. et al. Comparison of scores for bimodality of gene expression distributions and genome-wide evaluation of the prognostic relevance of high-scoring genes. BMC Bioinformatics 11, 276 (2010).
Nobrega-Pereira, S. et al. Origin and molecular specification of globus pallidus neurons. J. Neurosci. 30, 2824–2834 (2010).
Zhang, B. & Horvath, S. A general framework for weighted gene co-expression network analysis. Stat. Appl. Genet. Mol. Biol. 4, 17 (2005).
Simeone, A., Acampora, D., Gulisano, M., Stornaiuolo, A. & Boncinelli, E. Nested expression domains of four homeobox genes in developing rostral brain. Nature 358, 687–690 (1992).
Zhang, X. et al. Pax6 is a human neuroectoderm cell fate determinant. Cell Stem Cell 7, 90–100 (2010).
Bayatti, N. et al. Progressive loss of PAX6, TBR2, NEUROD and TBR1 mRNA gradients correlates with translocation of EMX2 to the cortical plate during human cortical development. Eur. J. Neurosci. 28, 1449–1456 (2008).
Dou, C. et al. BF-1 interferes with transforming growth factor beta signaling by associating with Smad partners. Mol. Cell. Biol. 20, 6201–6211 (2000).
Arlotta, P., Molyneaux, B.J., Jabaudon, D., Yoshida, Y. & Macklis, J.D. Ctip2 controls the differentiation of medium spiny neurons and the establishment of the cellular architecture of the striatum. J. Neurosci. 28, 622–632 (2008).
Ip, B.K. et al. Investigating gradients of gene expression involved in early human cortical development. J. Anat. 217, 300–311 (2010).
Zecevic, N., Chen, Y. & Filipovic, R. Contributions of cortical subventricular zone to the development of the human cerebral cortex. J. Comp. Neurol. 491, 109–122 (2005).
Wang, H.F. & Liu, F.C. Developmental restriction of the LIM homeodomain transcription factor Islet-1 expression to cholinergic neurons in the rat striatum. Neuroscience 103, 999–1016 (2001).
Kreitzer, A.C. Physiology and pharmacology of striatal neurons. Annu. Rev. Neurosci. 32, 127–147 (2009).
Jakovcevski, I., Mayer, N. & Zecevic, N. Multiple origins of human neocortical interneurons are supported by distinct expression of transcription factors. Cereb. Cortex 21, 1771–1782 (2011).
Delgado, A., Sierra, A., Querejeta, E., Valdiosera, R.F. & Aceves, J. Inhibitory control of the GABAergic transmission in the rat neostriatum by D2 dopamine receptors. Neuroscience 95, 1043–1048 (2000).
Oldham, M.C. et al. Functional organization of the transcriptome in human brain. Nat. Neurosci. 11, 1271–1282 (2008).
Somel, M. et al. MicroRNA, mRNA, and protein expression link development and aging in human and macaque brain. Genome Res. 20, 1207–1218 (2010).
Berghoff, E.G. et al. Evf2 (Dlx6as) lncRNA regulates ultraconserved enhancer methylation and the differential transcriptional control of adjacent genes. Development 140, 4407–4416 (2013).
Spigoni, G., Gedressi, C. & Mallamaci, A. Regulation of Emx2 expression by antisense transcripts in murine cortico-cerebral precursors. PLoS ONE 5, e8658 (2010).
Shimamura, K. & Rubenstein, J.L. Inductive interactions direct early regionalization of the mouse forebrain. Development 124, 2709–2718 (1997).
Rakic, S. & Zecevic, N. Emerging complexity of layer I in human cerebral cortex. Cereb. Cortex 13, 1072–1083 (2003).
Fertuzinhos, S. et al. Selective depletion of molecularly defined cortical interneurons in human holoprosencephaly with severe striatal hypoplasia. Cereb. Cortex 19, 2196–2207 (2009).
Hisaoka, T., Nakamura, Y., Senba, E. & Morikawa, Y. The forkhead transcription factors, Foxp1 and Foxp2, identify different subpopulations of projection neurons in the mouse cerebral cortex. Neuroscience 166, 551–563 (2010).
Aubry, L. et al. Striatal progenitors derived from human ES cells mature into DARPP32 neurons in vitro and in quinolinic acid-lesioned rats. Proc. Natl. Acad. Sci. USA 105, 16707–16712 (2008).
Delli Carri, A. et al. Developmentally coordinated extrinsic signals drive human pluripotent stem cell differentiation toward authentic DARPP-32+ medium-sized spiny neurons. Development 140, 301–312 (2013).
Ma, L. et al. Human embryonic stem cell-derived GABA neurons correct locomotion deficits in quinolinic acid-lesioned mice. Cell Stem Cell 10, 455–464 (2012).
Moore, A.R., Zhou, W.L., Jakovcevski, I., Zecevic, N. & Antic, S.D. Spontaneous electrical activity in the human fetal cortex in vitro. J. Neurosci. 31, 2391–2398 (2011).
Shin, S. et al. Whole genome analysis of human neural stem cells derived from embryonic stem cells and stem and progenitor cells isolated from fetal tissue. Stem Cells 25, 1298–1306 (2007).
Ericsson, J., Silberberg, G., Robertson, B., Wikstrom, M.A. & Grillner, S. Striatal cellular properties conserved from lampreys to mammals. J. Physiol. (Lond.) 589, 2979–2992 (2011).
Mariani, J. et al. Modeling human cortical development in vitro using induced pluripotent stem cells. Proc. Natl. Acad. Sci. USA 109, 12770–12775 (2012).
Shi, Y., Kirwan, P., Smith, J., Robinson, H.P. & Livesey, F.J. Human cerebral cortex development from pluripotent stem cells to functional excitatory synapses. Nat. Neurosci. 15, 477–486 (2012).
Bayer, A.S. & Altman, J. Atlas of Human Central Nervous System Development (CRC Press, 2008).
Letinic, K., Zoncu, R. & Rakic, P. Origin of GABAergic neurons in the human neocortex. Nature 417, 645–649 (2002).
Sidman, R.L. & Rakic, P. Neuronal migration, with special reference to developing human brain: a review. Brain Res. 62, 1–35 (1973).
Saeed, A.I. et al. TM4 microarray software suite. Methods Enzymol. 411, 134–193 (2006).
Fraley, C., Scrucca, A.R. & Murphy, T.B. mclust: normal mixture modeling for model-based clustering, classification, and density estimation. https://www.stat.washington.edu/research/reports/2012/tr597.pdf (Technical Report 597, Dept. of Statistics, Univ. of Washington, Seattle, 2012).
Canty, A.J. An S-Plus Library for Resampling Methods (Fairfax, Interface Foundation North America, 1998).
Langfelder, P. & Horvath, S. WGCNA: an R package for weighted correlation network analysis. BMC Bioinformatics 9, 559 (2008).
Eden, E., Navon, R., Steinfeld, I., Lipson, D. & Yakhini, Z. GOrilla: a tool for discovery and visualization of enriched GO terms in ranked gene lists. BMC Bioinformatics 10, 48 (2009).
Csardi, G. & Nepusz, T. The igraph software package for complex network research, InterJournal, Complex Systems 1695. http://igraph.org/ (2006).
Delli Carri, A. et al. Human pluripotent stem cell differentiation into authentic striatal projection neurons. Stem Cell Rev. 9, 461–474 (2013).
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).
The authors declare no competing financial interests.
Integrated supplementary information
Supplementary Figure 1 Genome-wide gene expression analysis on human fetal striatal and cortical areas.
(a) Principal component analysis of collected human striatal (ST) and neocortical (CX) samples and (b) hierarchical clustering (HCL). (c) Enriched pathways in the DEGs of ST vs. CX. The orange bars indicate the statistical significance (−log10 of p-value). In the Ratio column, green indicates the number of DEGs in each category and red indicates the total number of genes in that category present in the database, compared to CX. (d) Top 25 enriched GO biological processes in the ST and CX BEGs. The orange bars indicate the statistical significance (−log10 of p-value). In the Ratio column, green indicates the number of BEGs in each category and red indicates the total number of genes in that category present in the database. (e) (Left panel) Expression of the ST-upregulated bimodal lincRNA LINC00403 (Note: The genomic position of LINC00403 is relative to the release GRCh37, March 2009). (Right panel) Expression value among the samples and density of LINC00403 expression. GO, gene ontology, DEGs, differentially expressed genes; BEGs, bimodally expressed genes.
Supplementary Figure 2 Global coexpression networks and gene modules in human fetal striatal and cortical tissue.
(a) Trait correlation of the gene modules (indicated by different colors and corresponding numbers) with tissue of origin, array batch (i.e. different Illumina beadchips, see Supplementary Table 1b), chip hybridization date, samples collection date, operator, sample developmental age, and inferred gender. Correlation coefficient and Bonferroni corrected p-value are indicated. (b) Plot shows the correlation between gene expression values in M35 and tissue of origin. Each symbol represents one gene: genes differentially expressed between ST and CX (DEGs) are represented by colored dots, non-DEGs are represented by gray dots. (c) Network representation of selected genes from M35 module. The size of each vertex is directly proportional to the intramodular connectivity value for a particular gene. Thickness and color of each line are directly proportional to the topological overlap measure between the two connected genes. DEGs between ST and CX are represented in cyan. Genes names are showed for top 60% genes by intramodular connectivity. ST, striatum; CX, neocortex.
Supplementary Figure 3 Temporal expression profile of TFs in human embryos from neural fold stage.
Images of coronal (a-l) and horizontal (m-p) sections of human embryos at (a-d) 2w+5d, (e-j) 3w+3d and (k-p) 3w+4d. (a-d) OTX2 is expressed in the N-cadherin+ neural folds (NF) at 2w+5d. (e,f) At 3w+3d neural tube neuroepithelial progenitors (NEPs) are positive for SOX2 and (g) most of them are PH3+ on the luminal side. (h) At this stage, NEPs are polarized, as demonstrated by the luminal-high to basal-low β-catenin and N-cadherin expression. (i,j) OTX2 expression at 3w+3d is detectable in the prospective diencephalon (Di) and optic recesses (OR). (k,l) PAX6 clearly demarcates nestin+ neural tube structures, optic vesicles (OV), lens placodes (LP), and cephalic preplacodes (CPP) on 3w+4d coronal sections. (m-p) PAX6 expression in horizontal sections of a 3w+4d embryo, labeling the neuraxis posteriorly to the mesencephalon (Me) and the otic vesicles (OT). Nestin labels the entire neural tube and the mesenchyme. w+d, post-conceptional week+day; R, rhombencephalon; SOM, somite; NT, notochord; SC, spinal cord. Scale bar: 50 µm.
Supplementary Figure 4 Delineation of TF expression pattern in human fetal telencephalon at 8 w.
Immunohistochemistry performed on 8w sections. (a) GSX2 and PAX6 show a complementary expression in LGE and pallium, with very few double positive cells at the pallium-subpallium boundary (PSB). (b) GSX2 expression delimitates the boundary between the VZ and the SVZ, where ASCL1+ cells accumulate. (c) ASCL1 expression in VZ/SVZ of the LGE. (d-g) SP8 expression domain is distinct from those of GSX2, ASCL1, and PAX6. (h) ISL1 expression is observed both in the SVZ and MZ of the developing ST. (i) GSX2 and CTIP2 show a mutually exclusive expression in the VZ and the MZ, respectively. (j) Micrograph of NKX2-1/ISL1 expression. NKX2-1 is strongly expressed in the entire MGE. NKX2-1+ cells are observed also in the caudate (Ca) and putamen (Pu), but excluded from LGE VZ/SVZ. (k,l) EBF1 is expressed both in the SVZ and MZ, but few positive cells are observed in the VZ. In the Ca/Pu EBF1 is co-expressed together with IKZ1. (m) CTIP2 expression pattern in an 8w telencephalic coronal section. (n) DARPP-32+ CX neurons in the CP express CTIP2. (o) GABAergic cells do not co-express CTIP2. w, post-conceptional week; LGE, lateral ganglionic eminence; VZ, ventricular zone; SVZ subventricular zone; MZ, mantle zone; ST, striatum; CX, neocortex; CP, cortical plate; IZ, intermediate zone; SP, subplate. Scale bar: 50 μm (insets: 25 μm).
Supplementary Figure 5 NKX2-1 mRNA and protein expression analysis in human LGE and MGE.
In situ hybridization performed on 7w+6d (a), 8w+3d (b) and 10w (c) coronal sections. (a) NKX2-1 sense probe hybridization (b,c) NKX2-1 antisense probe hybridization revealing mRNA expression in MGE and LGE. (d) NKX2-1 protein expression is confirmed by full-length Western blot on 8w MGE and LGE samples. w+d, post-conceptional week+day; LGE, lateral ganglionic eminence; MGE, medial ganglionic eminence; Ca, caudate; Pu, putamen; I.C., internal capsule. Scale bar: 300 μm.
Supplementary Figure 6 Proliferating compartments in the LGE during human early fetal development.
Immunohistochemistry performed on 7w (a-d) and 8w (e-j) sections. (a-d) Micrographs of Ki67 (a), MAP2 (b) and GABA (c) in telencephalic coronal hemisections. (e) CTIP2+ ST neurons in the MZ are Ki67−. (f) ISL1+ cells localized in the MZ of the developing ST do not co-express Ki67. (g-i) FOXG1+ and GSX2+ progenitors are Ki67+. ASCL1 is expressed both by Ki67+ ST progenitors and post-mitotic cells (arrowheads in i indicate ASCL1+/Ki67− cells). (j) GABA+ cells are present in the VZ and SVZ; they also co-express Ki67 (arrowheads). w, post-conceptional week; LGE, lateral ganglionic eminence; VZ, ventricular zone; SVZ subventricular zone; MZ, mantle zone; CX, neocortex; ST, striatum; MGE, medial ganglionic eminence; LV, lateral ventricle. Scale bar: 50 μm (insets: 25 μm).
Supplementary Figure 7 Delineation of TF expression pattern in human fetal telencephalon at 11 w.
Immunohistochemistry performed on 11w sections. (a,b) FOXG1 and OTX2 expression in the telencephalic VZ. (c) GSX2 expression delimitates the boundary between the LGE and the CX. (d,e) EBF1 is expressed both in the SVZ and in the Ca-Pu. (f,g) FOXP1 and FOXP2 expression in the developing ST. (h) GABA+ cells in the CX VZ and SVZ. w, post-conceptional week; LV, lateral ventricle; LGE, lateral ganglionic eminence; VZ, ventricular zone; SVZ subventricular zone; Ca, caudate; Pu, putamen; I.C., internal capsule; ST, striatum; CX, neocortex. Scale bar: 50 μm.
Supplementary Figure 8 Definitive developmental factor expression pattern in human telencephalon at midfetal stage.
Immunohistochemistry performed on 20w sections. (a) ASCL1 is expressed in the LGE of the developing ST. At this stage, no accumulation of ASCL1+ cells at the VZ/SVZ boundary is observed. (b,c) FOXP2 is expressed in scattered cells in the ST. Cells showing high FOXP2 expression are CTIP2low (arrowheads). No co-expression with EBF1 is observed. (d) CALB and CTIP2 are co-expressed in the ST. (e-g) Co-expression profile of DARPP-32 MSNs in the ST (arrowheads indicate co-expression). (h) The percentage of DARPP-32+ ST neurons that express different TFs in the human ST (mean ± s.d.). (i) The interneuronal marker CR is not expressed in IKZ1+ MSNs. (j) CTIP2+ ST neurons are contacted by TH+ neurites. w, post-conceptional week; SVZ subventricular zone; ST, striatum; TF, transcription factor. Scale bar: 50 μm (insets: 25 μm).
Supplementary Figure 9 Striatal interneuron profiling at midfetal stage.
Immunohistochemistry performed on 20w sections. (a,b) The MSN marker CTIP2 is not co-expressed with the interneuronal TFs SOX6 and COUPTFII. (c-g) SST+ neurons express SOX6 but not COUPTFII, NKX2-1, FOXP2, and CTIP2. (h) The percentage of SST+ interneurons that express TFs (mean ± s.d.). (i-l) The majority of CR+ interneurons expresses NKX2-1 but does not express FOXP2, CTIP2 or SOX6. (m) The percentage of CR+ interneurons that express TFs (mean ± s.d.). (n,o) NPY+ neurons do not express CTIP2 and COUPTFII. (p) SST+/NPY+ in the 20w ST. Scale bar: 25 μm.
Supplementary Figure 10 Temporal expression profile during fetal cortical development.
Immunohistochemistry performed on 8w, 11w, and 20w sections. (a-e) Immunohistochemistry on 20w sections. (a,b) Expression of CALB and CR in CX. (c) Expression profile of SATB2 and TBR1 in the CP. (d,e) In the CP, strong DARPP-32 expression is observed; rare neurons also co-express CTIP2 (arrowheads). (f-h) CTIP2 and TBR1 are co-expressed in the CP at 8w (f) and 11w (g), but at 20w (h) they segregate. (i-k) TBR2 is expressed in the SVZ at all the developmental stages analyzed. w, post-conceptional week; cMZ, cortical marginal zone; IZ, intermediate zone; CP, cortical plate; SP, subplate; VZ, ventricular zone; SVZ subventricular zone; CX, neocortex; ST, striatum. Scale bar: 50 μm (insets: 25 μm).
Supplementary Figure 11 Functional benchmarking of human primary neurons.
(a-c) ST hPNs display CTIP2/GAD65/67, DARPP-32/MAP2, and CTIP2/ DARPP-32 expression after 30 days in vitro (DIV). (d,e) CX hPNs are TBR1+/βIII-tub+ and CTIP2+/VGLUT1+. (f-i) Recorded ST or CX hPNs were injected with biocytin and post-labeled for DARPP-32 (f,g) or VGLUT1 (h,i), respectively. (j) Representative voltage responses of CX hPNs under current-clamp conditions following a depolarizing current injection of +50 pA from a holding potential (Vh) of −78 mV; stimulation protocol is shown on the top. (k) Total inward and outward currents obtained during depolarizing voltage steps to −80 mV and +50 mV (10 mV step) from a holding potential of −90 mV (protocol on the top), recorded from the same cell as in (j) after switching from current-clamp to voltage-clamp. (l) Mean current density/voltage (I/V) relationship for voltage-gated Na+ channels in CX hPNs (filled circles; n = 9, Vh = −90 mV) and ST hPNs (dashed line). (m) Mean I/V relationship for voltage-gated Ca2+ channels in CX hPNs (filled circles; n=3, Vh= −90 mV), and ST hPNs (dashed line). (n) Representative traces of K+ currents elicited from a ST hPN at different test potentials ranging from −70 to +40 mV and starting from a Vh of – 110 mV in (panel 2) and from a conditioning potential of −40 mV in (panel 3) to inactivate KA-type channels. (o) Mean KA current density/voltage relationship in CX hPNs (filled circles; n=9, Vh= −110 mV) and ST hPNs (dashed line). (p) Effect of the KA channel blocker 4AP (1 mM) in a CX hPN. Voltage responses during current injection (protocol on the top) elicited in control extracellular saline (Ctrl) and during application of 4AP (+4AP). Notice the reduced delay in spike generation. (q) Representative GABAergic current traces elicited in a CX hPN voltage-clamped at the potentials indicated and during focal perfusion with 20 µM GABA. The horizontal bars over the current traces indicate the time course of drug application. (r) Expression of functional glutamatergic AMPA receptors in a CX hPN. Upper trace: inward AMPA glutamatergic current elicited at the holding potential of −70 mV during application of 50 µM AMPA. Lower trace: voltage response of the same cell after switching from voltage- to current-clamp mode during AMPA application. The horizontal bars over the current and voltage races indicate the time course of drug application. (s) Spontaneous glutamatergic post-synaptic currents in a CX hPN voltage-clamped at – 80 mV. (t) Representation of the ion channels and receptors found in ST hPNs. The vertical bars in (l), (m), and (o) indicate the s.e.m.. hPNs, human primary neurons; ST, striatum; CX, neocortex; DIV, days in vitro. Scale bar: 50 μm, (insets and f-i: 25 μm).
Supplementary Figure 12 Transcriptional properties of striatal and cortical human primary neurons.
(a,b) Heatmaps show the DEGs that discriminate (a) ST and (b) CX 30-DIV hPNs versus 8w ST and CX tissue samples, respectively. (c) Manually-curated list of genes significantly up-regulated in ST or CX hPNs compared to 8w ST or CX brain tissue samples, respectively. ST, striatum; CX, neocortex; DIV, days in vitro; DEGs, differentially expressed genes.
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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. (XLSX 39 kb)
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. (XLSX 159 kb)
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. (XLSX 65 kb)
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. (XLSX 152 kb)
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Onorati, M., Castiglioni, V., Biasci, D. et al. Molecular and functional definition of the developing human striatum. Nat Neurosci 17, 1804–1815 (2014). https://doi.org/10.1038/nn.3860
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