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Subcortical origins of human and monkey neocortical interneurons

Nature Neuroscience volume 16, pages 1588–1597 (2013)Cite this article

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Abstract

Cortical GABAergic inhibitory interneurons have crucial roles in the development and function of the cerebral cortex. In rodents, nearly all neocortical interneurons are generated from the subcortical ganglionic eminences. In humans and nonhuman primates, however, the developmental origin of neocortical GABAergic interneurons remains unclear. Here we show that the expression patterns of several key transcription factors in the developing primate telencephalon are very similar to those in rodents, delineating the three main subcortical progenitor domains (the medial, lateral and caudal ganglionic eminences) and the interneurons tangentially migrating from them. On the basis of the continuity of Sox6, COUP-TFII and Sp8 transcription factor expression and evidence from cell migration and cell fate analyses, we propose that the majority of primate neocortical GABAergic interneurons originate from ganglionic eminences of the ventral telencephalon. Our findings reveal that the mammalian neocortex shares basic rules for interneuron development, substantially reshaping our understanding of the origin and classification of primate neocortical interneurons.

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Figure 1: Identification of the MGE and the LGE and CGE on the basis of expression of Nkx2-1 and Sp8 in the human fetal brain at GW15.
Figure 2: GABAergic interneurons in GW15 human neocortex appear to derive from the subcortical ganglionic eminences.
Figure 3: Sox6+ neocortical interneurons are derived from the human fetal MGE.
Figure 4: Subcortical origins and migration of human neocortical interneurons.
Figure 5: Classification of human neocortical interneurons on the basis of their ontogenic origins and expression of transcription factors.
Figure 6: Subcortical origins and classification of monkey neocortical interneurons.
Figure 7: Lack of GABA+ cell production within the embryonic monkey neocortex.
Figure 8: The subtypes of monkey neocortical interneurons that express the transcription factors Sox6, COUP-TFII and Sp8.

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References

  1. Marín, O. Interneuron dysfunction in psychiatric disorders. Nat. Rev. Neurosci. 13, 107–120 (2012).

    Article  PubMed  Google Scholar 

  2. Lewis, D.A., Hashimoto, T. & Volk, D.W. Cortical inhibitory neurons and schizophrenia. Nat. Rev. Neurosci. 6, 312–324 (2005).

    Article  CAS  PubMed  Google Scholar 

  3. Rubenstein, J.L. & Merzenich, M.M. Model of autism: increased ratio of excitation/inhibition in key neural systems. Genes Brain Behav. 2, 255–267 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Gelman, D.M. & Marin, O. Generation of interneuron diversity in the mouse cerebral cortex. Eur. J. Neurosci. 31, 2136–2141 (2010).

    Article  PubMed  Google Scholar 

  5. Wonders, C.P. & Anderson, S.A. The origin and specification of cortical interneurons. Nat. Rev. Neurosci. 7, 687–696 (2006).

    Article  CAS  PubMed  Google Scholar 

  6. Rudy, B., Fishell, G., Lee, S. & Hjerling-Leffler, J. Three groups of interneurons account for nearly 100% of neocortical GABAergic neurons. Dev. Neurobiol. 71, 45–61 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Flames, N. et al. Delineation of multiple subpallial progenitor domains by the combinatorial expression of transcriptional codes. J. Neurosci. 27, 9682–9695 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Long, J.E., Cobos, I., Potter, G.B. & Rubenstein, J.L. Dlx1&2 and Mash1 transcription factors control MGE and CGE patterning and differentiation through parallel and overlapping pathways. Cereb. Cortex 19 (suppl. 1), i96–i106 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Kanatani, S., Yozu, M., Tabata, H. & Nakajima, K. COUP-TFII is preferentially expressed in the caudal ganglionic eminence and is involved in the caudal migratory stream. J. Neurosci. 28, 13582–13591 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Miyoshi, G. et al. Genetic fate mapping reveals that the caudal ganglionic eminence produces a large and diverse population of superficial cortical interneurons. J. Neurosci. 30, 1582–1594 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Cai, Y. et al. Nuclear receptor COUP-TFII–expressing neocortical interneurons are derived from the medial and lateral/caudal ganglionic eminence and define specific subsets of mature interneurons. J. Comp. Neurol. 521, 479–497 (2013).

    Article  CAS  PubMed  Google Scholar 

  12. Bayer, S.A. & Altman, J. The Human Brain During the Second Trimester (CRC Press/Taylor & Francis Group, Boca Raton, Florida, USA, 2005).

  13. Letinic, K., Zoncu, R. & Rakic, P. Origin of GABAergic neurons in the human neocortex. Nature 417, 645–649 (2002).

    Article  CAS  PubMed  Google Scholar 

  14. Petanjek, Z., Berger, B. & Esclapez, M. Origins of cortical GABAergic neurons in the cynomolgus monkey. Cereb. Cortex 19, 249–262 (2009).

    Article  PubMed  Google Scholar 

  15. 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).

    Article  PubMed  Google Scholar 

  16. Yu, X. & Zecevic, N. Dorsal radial glial cells have the potential to generate cortical interneurons in human but not in mouse brain. J. Neurosci. 31, 2413–2420 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Zecevic, N., Hu, F. & Jakovcevski, I. Interneurons in the developing human neocortex. Dev. Neurobiol. 71, 18–33 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Butt, S.J. et al. The requirement of Nkx2–1 in the temporal specification of cortical interneuron subtypes. Neuron 59, 722–732 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Sussel, L., Marin, O., Kimura, S. & Rubenstein, J.L. Loss of Nkx2.1 homeobox gene function results in a ventral to dorsal molecular respecification within the basal telencephalon: evidence for a transformation of the pallidum into the striatum. Development 126, 3359–3370 (1999).

    CAS  PubMed  Google Scholar 

  20. Flandin, P., Kimura, S. & Rubenstein, J.L. The progenitor zone of the ventral medial ganglionic eminence requires Nkx2–1 to generate most of the globus pallidus but few neocortical interneurons. J. Neurosci. 30, 2812–2823 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Taniguchi, H., Lu, J. & Huang, Z.J. The spatial and temporal origin of chandelier cells in mouse neocortex. Science 339, 70–74 (2013).

    Article  CAS  PubMed  Google Scholar 

  22. Nóbrega-Pereira, S. et al. Postmitotic Nkx2–1 controls the migration of telencephalic interneurons by direct repression of guidance receptors. Neuron 59, 733–745 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Sahara, S., Kawakami, Y., Izpisua Belmonte, J.C. & O'Leary, D.D. Sp8 exhibits reciprocal induction with Fgf8 but has an opposing effect on anterior-posterior cortical area patterning. Neural Dev. 2, 10 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Borello, U. et al. Sp8 and COUP-TF1 reciprocally regulate patterning and Fgf signaling in cortical progenitors. Cereb. Cortex published online, 10.1093/cercor/bhs412 (10 January 2013).

  25. Zembrzycki, A., Griesel, G., Stoykova, A. & Mansouri, A. Genetic interplay between the transcription factors Sp8 and Emx2 in the patterning of the forebrain. Neural Dev. 2, 8 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Reinchisi, G., Ijichi, K., Glidden, N., Jakovcevski, I. & Zecevic, N. COUP-TFII expressing interneurons in human fetal forebrain. Cereb. Cortex 22, 2820–2830 (2012).

    Article  PubMed  Google Scholar 

  27. McKinsey, G.L. et al. Dlx1&2-dependent expression of Zfhx1b (Sip1, Zeb2) regulates the fate switch between cortical and striatal interneurons. Neuron 77, 83–98 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Azim, E., Jabaudon, D., Fame, R.M. & Macklis, J.D. SOX6 controls dorsal progenitor identity and interneuron diversity during neocortical development. Nat. Neurosci. 12, 1238–1247 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Batista-Brito, R. et al. The cell-intrinsic requirement of Sox6 for cortical interneuron development. Neuron 63, 466–481 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Götz, M., Stoykova, A. & Gruss, P. Pax6 controls radial glia differentiation in the cerebral cortex. Neuron 21, 1031–1044 (1998).

    Article  PubMed  Google Scholar 

  31. Hansen, D.V., Lui, J.H., Parker, P.R. & Kriegstein, A.R. Neurogenic radial glia in the outer subventricular zone of human neocortex. Nature 464, 554–561 (2010).

    Article  CAS  PubMed  Google Scholar 

  32. Fietz, S.A. et al. OSVZ progenitors of human and ferret neocortex are epithelial-like and expand by integrin signaling. Nat. Neurosci. 13, 690–699 (2010).

    Article  CAS  PubMed  Google Scholar 

  33. Wang, C. et al. Identification and characterization of neuroblasts in the subventricular zone and rostral migratory stream of the adult human brain. Cell Res. 21, 1534–1550 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Guerrero-Cázares, H. et al. Cytoarchitecture of the lateral ganglionic eminence and rostral extension of the lateral ventricle in the human fetal brain. J. Comp. Neurol. 519, 1165–1180 (2011).

    Article  PubMed  Google Scholar 

  35. Sanai, N. et al. Corridors of migrating neurons in the human brain and their decline during infancy. Nature 478, 382–386 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Stenman, J., Toresson, H. & Campbell, K. Identification of two distinct progenitor populations in the lateral ganglionic eminence: implications for striatal and olfactory bulb neurogenesis. J. Neurosci. 23, 167–174 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Waclaw, R.R. et al. The zinc finger transcription factor Sp8 regulates the generation and diversity of olfactory bulb interneurons. Neuron 49, 503–516 (2006).

    Article  CAS  PubMed  Google Scholar 

  38. Pei, Z. et al. Homeobox genes Gsx1 and Gsx2 differentially regulate telencephalic progenitor maturation. Proc. Natl. Acad. Sci. USA 108, 1675–1680 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Wang, B. et al. Loss of Gsx1 and Gsx2 function rescues distinct phenotypes in Dlx1/2 mutants. J. Comp. Neurol. 521, 1561–1584 (2013).

    Article  CAS  PubMed  Google Scholar 

  40. Ma, T. et al. A subpopulation of dorsal lateral/caudal ganglionic eminence-derived neocortical interneurons expresses the transcription factor Sp8. Cereb. Cortex 22, 2120–2130 (2012).

    Article  PubMed  Google Scholar 

  41. Cai, Y., Zhang, Y., Shen, Q., Rubenstein, J.L. & Yang, Z. A subpopulation of individual neural progenitors in the mammalian dorsal pallium generates both projection neurons and interneurons in vitro. Stem Cells 31, 1193–1201 (2013).

    Article  CAS  PubMed  Google Scholar 

  42. Kohwi, M. et al. A subpopulation of olfactory bulb GABAergic interneurons is derived from Emx1- and Dlx5/6-expressing progenitors. J. Neurosci. 27, 6878–6891 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Molnár, Z. & Clowry, G. Cerebral cortical development in rodents and primates. Prog. Brain Res. 195, 45–70 (2012).

    Article  PubMed  Google Scholar 

  44. Zeng, H. et al. Large-scale cellular-resolution gene profiling in human neocortex reveals species-specific molecular signatures. Cell 149, 483–496 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Lui, J.H., Hansen, D.V. & Kriegstein, A.R. Development and evolution of the human neocortex. Cell 146, 18–36 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Puelles, L. et al. Pallial and subpallial derivatives in the embryonic chick and mouse telencephalon, traced by the expression of the genes Dlx-2, Emx-1, Nkx-2.1, Pax-6, and Tbr-1. J. Comp. Neurol. 424, 409–438 (2000).

    Article  CAS  PubMed  Google Scholar 

  48. Nieto, M., Schuurmans, C., Britz, O. & Guillemot, F. Neural bHLH genes control the neuronal versus glial fate decision in cortical progenitors. Neuron 29, 401–413 (2001).

    Article  CAS  PubMed  Google Scholar 

  49. Britz, O. et al. A role for proneural genes in the maturation of cortical progenitor cells. Cereb. Cortex 16 (suppl. 1), i138–i151 (2006).

    Article  PubMed  Google Scholar 

  50. Fertuzinhos, S. et al. Selective depletion of molecularly defined cortical interneurons in human holoprosencephaly with severe striatal hypoplasia. Cereb. Cortex 19, 2196–2207 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by the National Basic Research Program of China (2011CB504400 and 2010CB945500) and the National Natural Science Foundation of China (30990261, 31028009, 31121061 and 91232723). We thank the staff at the Chinese Brain Bank Center, Wuhan, China and the Red Cross Society of China, Shanghai Branch at Fudan University for providing access to donated adult human brains.

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Author notes

  1. Tong Ma, Congmin Wang and Lei Wang: These authors contributed equally to this work.

Authors and Affiliations

  1. Institutes of Brain Science, Fudan University, Shanghai, China

    Tong Ma, Congmin Wang, Lei Wang, Xing Zhou, Miao Tian, Qiangqiang Zhang, Yue Zhang, Jiwen Li, Zhidong Liu, Yuqun Cai, Fang Liu, Yan You, Lan Ma & Zhengang Yang

  2. State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China

    Tong Ma, Congmin Wang, Lei Wang, Xing Zhou, Miao Tian, Qiangqiang Zhang, Yue Zhang, Jiwen Li, Zhidong Liu, Yuqun Cai, Fang Liu, Yan You, Lan Ma & Zhengang Yang

  3. Department of Human Anatomy, Hebei Medical University, Shijiazhuang, Hebei, China

    Lei Wang

  4. Department of Neonatology, Children's Hospital of Fudan University, Shanghai, China

    Chao Chen

  5. Division of Developmental Biology, Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA

    Kenneth Campbell

  6. Institute for Cell Engineering and Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Hongjun Song

  7. Department of Psychiatry, Nina Ireland Laboratory of Developmental Neurobiology, University of California San Francisco, San Francisco, California, USA

    John L Rubenstein

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Contributions

T.M. and Z.Y. designed the study, acquired and interpreted experimental data and prepared the manuscript. C.W. and L.W. acquired and interpreted experimental data and prepared the manuscript. X.Z., M.T., Q.Z., Y.Z., J.L., Z.L., Y.C., F.L., Y.Y. and C.C. assisted with experiments and data collection. J.L. and Y.C. carried out slice culture and time-lapse imaging experiments. K.C., H.S., L.M. and J.L.R. designed some experiments and assisted with manuscript preparation. T.M., C.W., L.W., Z.Y. and C.C. collected specimens. C.C. assisted with neuropathological review. Z.Y. wrote the paper.

Corresponding author

Correspondence to Zhengang Yang.

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The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 Identification of the dLGE/dCGE and vLGE based on expression of Sp8, Pax6 and Islet-1 in the human fetal brain at GW15.

(a–d) Pax6 and Sp8 double-immunostained brain sections spanning the rostral-caudal extent of the brain at GW15. (e) Higher magnification of the boxed area in (c) showing that Pax6 was expressed in proliferative zones of the neocortex and dLGE. (f, g) Islet-1 and Sp8 double-immunostained GW15 human brain sections. (h) Higher magnification of the boxed area in (f) showing weakly Islet-1+ cells in the vLGE SVZ and strongly Islet-1+ cells in the striatum. LV, lateral ventricle; Sep, septum. St, striatum. Scale bars, 1 mm (a–d, f, g); 100 μm (e, h).

Supplementary Figure 2 Expression of COUP-TFII and Sp8 in the human fetal brain at GW15.

(a–h) COUP-TFII and Sp8 double-immunostaining was performed on GW15 human brain sections. Note expression of COUP-TFII in an increasing rostral-to-caudal gradient from dLGE to dCGE. The RMS contained massive Sp8+ cells and very few COUP-TFII+ cells suggesting that COUP-TFII+ cells in the dLGE/dCGE migrate mainly into the cortex. (i) COUP-TFII+ cells in the dCGE were mainly located in the SVZ; the majority of them did not express Ki67. (h) In the vCGE, COUP-TFII+ cells were in the VZ and SVZ; many of them expressed Ki67. LV, lateral ventricle; Sep, septum; St, striatum; Th, thalamus.

Supplementary Figure 3 COUP-TFII+ cells are also observed in the MGE at GW15.

(a, b) COUP-TFII and Nkx2-1 double-immunostained GW15 human brain sections. (c, d) Higher magnification of the boxed areas in (a, b). (e) Higher magnification of the boxed area in (c). Note a large population of COUP-TFII+/Nkx2-1+ cells in the caudal MGE. (f) Diagram of subcortical progenitor domains of the human fetal brain at GW15 based on expression patterns of Sp8, COUP-TFII, Islet-1, Nkx2-1 and Sox6. Am, amygdala; Nc, neocortex; IZ, intermediate zone; LV, lateral ventricle; SP, subplate; St, striatum; Th, thalamus; TL, temporal lobe. Scale bars, 1 mm (a, b); 200 μm (c); 50 μm (d, e).

Supplementary Figure 4 Identification of the MGE in the human fetal brain at GW18 and GW24 based on expression of Nkx2-1.

(a) Nkx2-1 and Sp8 double-immunostained sections spanning the rostral-caudal extent of the human fetal brain at GW18. (b) Nkx2-1 and Sp8 double-immunostained sections spanning the rostral-caudal extent of the human fetal brain at GW24.

Supplementary Figure 5 A small number of Nkx2-1+ cells are observed in the dLGE SVZ and neocortex of the human fetal brain at GW24.

(a) Coronal GW24 brain section double-immunostained with COUP-TFII and Nkx2-1. (b–f) Higher magnification of the boxed areas in (a) showing Nkx2-1+ cells in the neocortex (b), dLGE (c), MGE (d, e) and striatum (f). (g, h) The majority of Nkx2-1+ cells in the MGE expressed Ki67. (i, j) Nkx2-1+ cells in the neocortical VZ/SVZ did not express Ki67. Scale bars, 2 mm (a); 100 μm (b–f); 50 μm (g–j).

Supplementary Figure 6 Supplementary Figure 6. Gsx2 is expressed in the LGE and MGE but not in the neocortical VZ/SVZ of the human fetal brain at GW24.

(a) Ki67 and Sp8 double-immunostained GW24 human brain section. (b) An adjacent section immunostained with Gsx2. (c–e) Higher magnification of boxed areas in (b) showing that Gsx2+ cells were in the LGE and MGE, but not in the neocortical VZ/SVZ. Scale bars, 500 μm (a, b); 50 μm (c–e).

Supplementary Figure 7 COUP-TFII+/Sp8+ cells in the neocortical VZ/SVZ do not express Ki67, Tbr2 or Olig2.

(a–c) GW24 human brain sections triple-immunostained with COUP-TFII/Sp8/Ki67 (a), COUP-TFII/Sp8/Tbr2 (b) and COUP-TFII/Sp8/Olig2 (c).

Supplementary Figure 8 The subtypes of neocortical interneurons in the adult human brain express transcription factors Sox6, COUP-TFII and Sp8.

(a–n) Brain sections from the parietal lobe of the adult neocortex immunostained with interneuron markers and transcription factors. Note that the majority of PV+ (a), CB+ (c), SOM+ (e) and nNOS+ (g) cells expressed Sox6. Few, if any, PV+ (b), CB+ (d) and NPY+ (i) cells expressed COUP-TFII or Sp8. A small number of SOM+ (f) and nNOS+ (h) cells in deeper layers expressed COUP-TFII. The majority of CR+ (m), VIP+ (n) and strongly Reelin+ (j) cells expressed COUP-TFII and/or Sp8. Few, if any, CR+ (l) and strongly Reelin+ (k) cells expressed Sox6. (o–t) Some interneuron markers were co-expressed in a subpopulation of neocortical interneurons. Note that a wide range overlap of SOM+, nNOS+ and CB+ cells (o). The majority of NPY+ cells expressed SOM and nNOS (p). Nearly all VIP+ cells expressed CR (t). However, no CR+/SOM+ (q) or CR+/nNOS+ (r) cells were found. Scale bars, 100 μm (a–t); 50 μm (inserts).

Supplementary Figure 9 The proportions of Sox6+, COUP-TFII+ and Sp8+ neocortical interneurons in the frontal, temporal and occipital lobe of the adult human brain are different.

(a) Sox6/COUP-TFII/Sp8 triple-immunostained brain section from the parietal lobe of the adult neocortex (Brodmann areas 3, 1, 2). (b) Sox6/NeuN double-immunostained neocortical section showing Sox6+/NeuN+ interneurons. (c) Quantification data showed that there was a higher proportion of COUP-TFII+ and/or Sp8+ interneurons in the frontal lobe neocortex (Brodmann areas 9), while a higher proportion of Sox6+ interneurons were in the temporal (Brodmann areas 21) and occipital lobe neocortex (Brodmann areas 17).

Supplementary Figure 10 Identification of the MGE, LGE and CGE in E55 macaque monkey forebrain based on expression of Nkx2-1, COUP-TFII and Sp8.

(a–f) Nkx2-1 and COUP-TFII double-immunostained brain coronal sections spanning the rostral-caudal extent of E55 monkey brain. (g–i) Higher magnification of boxed areas in (c, d). Note that a small number of COUP–TFII+ cells in the dorsal MGE (g). (j–o) Sp8 and COUP-TFII double-immunostained E55 brain sections. Note that Sp8 was expressed in the cortical VZ in a high to low rostrodorsal to caudoventral gradient. (p–s) Higher magnification of boxed areas in (k, n, o). Note COUP-TFII+ cells in both the VZ and SVZ of the vCGE (s).

Supplementary Figure 11 Expression of Gsx2, Pax6 and Sp8 in E55 monkey forebrain.

(a–f) Gsx2 and Sp8 double-immunostaining was performed on E55 monkey brain sections. (g–j) Higher magnification of boxed areas in (a, c, f). Gsx2 was mainly expressed in the GE VZ, while Sp8 was mainly expressed in the LGE/CGE SVZ. Many Gsx2+/Sp8+ cells were found in the SVZ. (k–p) Pax6 and Sp8 double-immunostaining was performed on E55 monkey brain sections. (q–t) Higher magnification of boxed areas in (l–n). Note that all Sp8+ cells in the medial cortical VZ expressed Pax6 (i), suggesting that they are primary progenitors of excitatory glutamatergic projection neurons.

Supplementary Figure 12 The proportions of Sox6+, COUP-TFII+ and Sp8+ interneurons in the monkey frontal, temporal and occipital lobe are different.

(a) In 6-month-old and 17-month-old monkey brains, a higher proportion of COUP-TFII+ and/or Sp8+ interneurons was found in the frontal lobe neocortex (prefrontal cortex), while a higher proportion of Sox6+ interneurons was found in the neocortex of the temporal (lateral temporal cortex) and occipital lobe (primary visual cortex). (b–d) The percentage of different subtypes of interneurons that expressed transcription factors in the 6-month-old monkey prefrontal cortex. (e–g) The percentage of different transcription factors that expressed interneuron markers in the 6-month-old monkey prefrontal cortex. (h–j) The percentage of different transcription factors that expressed interneuron markers in the 17-month-old monkey prefrontal cortex. (k) Schematic diagram showing the origin and classification of monkey and human neocortical interneurons. We propose that the majority of neocortical interneurons in the monkey and human brain originate from the MGE, dLGE and CGE of the ventral telencephalon (see quantitative data in Fig. 5 and Fig. 6). MGE-derived neocortical interneurons (Sox6+) mainly includes PV+, SOM+, nNOS+, CB+ and NPY+ interneurons. PV+ interneurons represent a distinct subpopulation of MGE-derived neocortical interneurons, whereas SOM+, nNOS+ and CB+ interneurons largely overlap. The vast majority of NPY+ interneurons express SOM and nNOS but not CB. NPY+ interneurons strongly express SOM and nNOS, representing type I nNOS+ interneurons that have large somata. Weakly Reelin (W-Reelin)+ interneurons are derived from the MGE, which we only analyzed in the monkey neocortex. W-Reelin+ interneurons express SOM, nNOS and CB, but not NPY. A small subset of COUP-TFII+ interneurons is derived from the dorsal/caudal MGE (Sox6+). These interneurons express SOM and nNOS, but not CB or NPY. A small fraction of MGE-derived CR+/Sox6+ interneurons are present in the monkey but not human neocortex. These interneurons express SOM and nNOS, but not CB, NPY or COUP-TFII. Dorsal LGE and CGE (dLGE/CGE)-derived neocortical interneurons (COUP-TFII+ and/or Sp8+) mainly includes CR+, VIP+ and strongly Reelin (S-Reelin)+ interneurons. The vast majority of CR+ interneurons expresses COUP-TFII and/or Sp8, contributing to the largest population of dLGE/CGE-derived interneurons. Nearly all VIP+ and S-Reelin+ interneurons that express COUP-TFII and/or Sp8 but not Sox6 are derived from the dLGE/CGE. A subpopulation of S-Reelin+ interneurons and the majority of VIP+ interneurons also express CR.

Supplementary Figure 13 Ascl1 expression in E80 monkey neocortical and subcortical progenitor cells.

(a) Triple-immunostaining for Ascl1/Pax6/Tbr2 in E13.5 mouse brain section. (b) Immunostaining for Ascl1 in E80 monkey coronal brain section. (c) Double-immunostaining for Ascl1/Pax6 in E80 monkey coronal brain section showing that the majority of Ascl1+ cells expressed Pax6. (d–g) Higher magnification of boxed areas in (b) showing Ascl1+ cells in the neocortical VZ/SVZ (d, e), dorsal PSB (f) and ventral PSB (g). Note that many Ascl1+ cells in the neocortical VZ/SVZ expressed Tbr2 (d, e).

Supplementary Figure 14 Ascl1+ cells and Tbr2+ cells in the fetal human CGE and neocortex at GW18.

(a) Double-immunostaining for Ascl1 and Tbr2 in GW18 human coronal brain section. (b) Higher magnification of the boxed area in (a). (c–e) Higher magnification of the boxed area in (a) showing that most Ascl1+ cells in the cortical VZ/SVZ expressed Tbr2. (f, g) Ascl1+ cells in the neocortical SVZ did not express GAD65/67 or GABA.

Supplementary Figure 15 Ascl1 expression in GW24 human neocortical and subcortical progenitor cells.

(a) Immunostaining for Ascl1 in GW24 human coronal brain section. (b–e) Higher magnification of boxed areas in (a) showing Ascl1+ cells in the neocortical SVZ (b), LGE (c), MGE (d), and ventral PSB (e). (f–h) Higher magnification of the boxed area in (b) showing that the majority of Ascl1+ cells expressed Pax6, suggesting that Ascl1+ cells in the neocortical SVZ are progenitors of neocortical projection neurons. Scale bars, 1 mm (a), 400 μm (b–e); 100 μm (f–h).

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Supplementary Figures 1–15, Supplementary Tables 1–3, and Supplementary Movies 1–4 (PDF 21782 kb)

This movie shows an example of one mitotic MGE cell migrating tangentially to the LGE.

GFP-expressing adenovirus (adenoGFP) was microinjected into the MGE of an E55 monkey brain slice. Time-lapse images were captured by Perkin Elmer UltraView live cell imaging system. The recording was started around 24 hours after virus injection. The recording time lasted approximately 120 hours (5 days) and the recording interval was 25 minutes. Twenty-four after virus injection, we found many GFP-labeled cells in the VZ/SVZ of the MGE and LGE. A very small number of GFP+ cells were also observed in the neocortex at this stage. Forty-nine hours after virus injection, a mitotic cell (arrows) in the MGE migrating into the LGE was observed. (MPG 13758 kb)

MGE cells migrate towards the LGE.

Twenty-five hours after virus injection, a mitotic cell (arrows) and a postmitotic cell (arrowhead) migrated tangentially from the MGE towards the LGE. Note that the postmitotic cell (arrowhead) had a leading process oriented away from the MGE. (MPG 18260 kb)

This movie shows an example of one mitotic cell migrating from the LGE towards the neocortex.

Forty-four hours after virus injection, a mitotic cell (arrows) in the LGE migrated towards the neocortex. This cell divided twice while migrating. (MPG 11086 kb)

This movie shows a mitotic cell migrating from the LGE towards the neocortex.

Fifty-eight hours after virus injection, a mitotic cell (arrows) in the LGE migrated towards the neocortex. (MPG 13386 kb)

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Ma, T., Wang, C., Wang, L. et al. Subcortical origins of human and monkey neocortical interneurons. Nat Neurosci 16, 1588–1597 (2013). https://doi.org/10.1038/nn.3536

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