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Evolution of the neocortex: a perspective from developmental biology

Key Points

  • In spite of its stereotypic laminar and columnar organization, the cerebral neocortex displays numerous species-specific adaptations of old and acquired new traits that subserve specific functions introduced during 100 million years of mammalian evolution.

  • The human neocortex, a substrate of our unique cognitive abilities, has many distinct traits in addition to a larger surface, including different places of neuronal origin, distinct migratory pathways and acquisition of new cell types that were traditionally studied by comparative anatomists.

  • The contemporary, evo–devo approach uses developmental principles and mechanisms uncovered by experiments in embryos of living species to obtain a glimpse into how the human neocortex may have developed at the cellular and molecular level in extinct common ancestors.

  • The radial unit model of cortical evolution provides insight into how mutation of genes that control the transition from the symmetric to asymmetric mode of cell division in the proliferative ventricular zone subjected to radial constraint during migration can generate neocortical expansion in surface rather than in thickness.

  • The protomap hypothesis of differential enlargement of the existing and introduction of new cytoarchitectonic areas has been tested in mouse embryos by mutation and/or changes of gene expression and transcriptional factors in the neural stem cells of the proliferative ventricular and subventricular zones.

  • Understanding of the species-specific difference in tempo and sequence of cortical development as well as genesis of new cell subtypes, functional columns and synaptic connectivity is essential for design of therapies for trauma, congenital malformations, neurodegenerative disorders and ageing of the human cerebral neocortex.

Abstract

The enlargement and species-specific elaboration of the cerebral neocortex during evolution holds the secret to the mental abilities of humans; however, the genetic origin and cellular mechanisms that generated the distinct evolutionary advancements are not well understood. This article describes how novelties that make us human may have been introduced during evolution, based on findings in the embryonic cerebral cortex in different mammalian species. The data on the differences in gene expression, new molecular pathways and novel cellular interactions that have led to these evolutionary advances may also provide insight into the pathogenesis and therapies for human-specific neuropsychiatric disorders.

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Figure 1: Broad comparison of the brain of a mouse, a macaque monkey and a human, and the phylogenetic divergence of these species.
Figure 2: Radial unit lineage model of cortical neurogenesis.
Figure 3: Enlargement of cortical surface by decrease in programmed cell death or increase in proliferation.
Figure 4: Control of arealization of the frontal cortex by FGF expression.
Figure 5: Rodent and human fetal forebrains at the peak of corticogenesis.
Figure 6: Gene expression patterns of neocortical areas of the human fetal cerebral hemispheres.

References

  1. 1

    Striedter, G. F. Principles of Brain Evolution (Sinauer, Sunderland, Massachusetts, 2005).

    Google Scholar 

  2. 2

    Northcutt, R. G. Evolution of the telencephalon in non-mammals. Ann. Rev. Neurosci. 4, 301–350 (1981).

    CAS  PubMed  Google Scholar 

  3. 3

    Murphy, W. J, Pevzner, P. A. & O'Brian, S. J. Mammalian phylogenomic comes of age. Trends Genet. 20, 631–639 (2004). A concise and informative review of the DNA sequencing-based time-scale of phylogenetic divergence of various mammalian species.

    CAS  PubMed  Google Scholar 

  4. 4

    Preuss, T. M. in The Cognitive Neuroscience IV. (ed. Gazzaniga, M. S.) (The MIT Press, Cambridge, Massachusetts, 2009).

    Google Scholar 

  5. 5

    Goffinet, A. M. & Rakic, P. (eds) Mouse Brain Development. (Springer-Verlag, Berlin; New York, 2000).

    Google Scholar 

  6. 6

    Darwin, C. Descent of Man (J. Murray, London, UK, 1871).

    Google Scholar 

  7. 7

    Gould, S. J. Ontogeny and Phylogeny (Harvard University Press, Cambridge, Massachusetts, 1977).

    Google Scholar 

  8. 8

    Carroll, S. B. Evo-Devo and an expanding evolutionary synthesis: A genetic theory of morphological evolution. Cell 134, 25–36 (2008).

    CAS  Google Scholar 

  9. 9

    Mountcastle, V. B. The evolution of ideas concerning the function of the neocortex. Cereb. Cortex 5, 289–295 (1995).

    CAS  PubMed  Google Scholar 

  10. 10

    Goldman-Rakic, P. S. in Handbook of Physiology, The Nervous System, Higher Functions of the Brain Vol. V., Part 1, Ch. 9 (ed. F. Plum) 373–417 (Bethesda, Md Am. Physiol. Soc., Section I, Vol. V., Part 1 1987).

    Google Scholar 

  11. 11

    Brodmann, K. Beiträge zur histologischen Lokalisierung der Grosshirnrinde. Dritte Mitteilung: Die Rindenfelder niederer Affen. J. Psychol. Neurol. 9, 177–226 (1905) (in German).

    Google Scholar 

  12. 12

    Rakic, P. Specification of cerebral cortical areas. Science 241, 170–176 (1988). A review of the initial evidence that phenotype, and laminar and areal position of cortical neurons are specified at the proliferative zones and are only later influenced by the incoming axonal input (protomap hypothesis). The article also proposes the radial unit hypothesis of cortical development and evolution that has recently been supported by genetic and cell biological methods (see also references 38, 39, 65, 74 and 75).

    CAS  Google Scholar 

  13. 13

    Rakic, P. Principles of neuronal cell migration. Experientia 46, 882–891 (1990).

    CAS  PubMed  Google Scholar 

  14. 14

    Marin, O. & Rubenstein, J. L. A long, remarkable journey: tangential migration in the telencephalon. Nature Rev. Neurosci. 2, 780–790 (2001). A comprehensive and highly informative review on the pattern of neuronal migration to the cerebral cortex with a particular emphasis on the tangential migration of GABAergic interneurons from the ganglionic eminence of the ventral telencephalon (see references 98 and 99).

    CAS  Google Scholar 

  15. 15

    Molnár Z. et al. Comparative aspects of cerebral cortical development. Eur. J. Neurosci. 23, 921–934 (2006).

    PubMed Central  PubMed  Google Scholar 

  16. 16

    Anderson, S. A., Marín, O., Horn, C., Jennings, K. & Rubenstein, J. L. Distinct cortical migrations from the medial and lateral ganglionic eminences. Development 128, 353–363 (2001).

    CAS  PubMed  Google Scholar 

  17. 17

    Bystron, I., Blakemore, C. & Rakic, P. Development of human cerebral cortex. Boulder Committee revisited. Nature Rev. Neurosci. 9, 110–122 (2008). A historical review of the discoveries of the transient embryonic zones and with an update of their nomenclature.

    CAS  Google Scholar 

  18. 18

    Rakic, P. Mode of cell migration to the superficial layers of fetal monkey neocortex. J. Comp. Neurol. 145, 6l–84 (1972). This paper presents evidence from a combination of the Golgi method and serial electron microscopy that postmitotic neurons in the large and convoluted primate cerebrum follow the increasingly elongated and curvilinear shafts of the radial glial cells, some of which do not divide while serving transiently as migratory guides (see reference 47).

    Google Scholar 

  19. 19

    Sidman, R. L. & Rakic, P. Neuronal migration with special reference to developing human brain: a review. Brain Res. 62, 1–35 (1973). This is the first and the most comprehensive review of the modes and patterns of neuronal migration in the embryonic and fetal human brain with a special emphasis on the cerebral and cerebellar cortices (see reference 33).

    CAS  PubMed  Google Scholar 

  20. 20

    Kriegstein, A. R. & Noctor, S. C. Patterns of neuronal migration in the embryonic cortex. Trends Neurosci. 27, 392–399 (2004).

    CAS  PubMed  Google Scholar 

  21. 21

    Angevine, J. B. Jr & Sidman, R. L. Autoradiographic study of cell migration during histogenesis of cerebral cortex in the mouse. Nature 192, 766–768 (1961).

    PubMed Central  PubMed  Google Scholar 

  22. 22

    Rakic, P. Neurons in the monkey visual cortex: systematic relation between time of origin and eventual disposition. Science l83, 425–427 (1974).

    Google Scholar 

  23. 23

    Zecevic, N. & Rakic, P. Development of layer I neurons in the primate cerebral cortex. J. Neurosci. 21, 5607–5619 (2001).

    CAS  PubMed Central  PubMed  Google Scholar 

  24. 24

    Aboitiz, F., Montiel, J. & López, J. An hypothesis on the early evolution of the development of the isocortex. Brain Res. Bull. 57, 481–483 (2002).

    PubMed  Google Scholar 

  25. 25

    Caviness, V. S. Jr & Rakic, P. Mechanisms of cortical development: a view from mutations in mice. Ann. Rev. Neurosci. 1, 297–326 (1978). A review of the early evidence of the data from spontaneous mutation in mice showing that the basic neuronal phenotype reflects the time of neuron origin irrespective of their subsequent laminar positions. This finding led to the conclusion that neurons attract appropriate thalamic input rather than being initially equipotent and specified by the type of input as previously assumed (see references 74 and 137).

    PubMed  Google Scholar 

  26. 26

    Gleeson, J. G. & Walsh, C. A. Neuronal migration disorders: from genetic diseases to developmental mechanisms. Trends Neurosci. 23, 352–359 (2000).

    CAS  PubMed Central  PubMed  Google Scholar 

  27. 27

    Hatten, M. E. New directions in neuronal migration. Science 297, 1660–1663 (2002).

    CAS  PubMed  Google Scholar 

  28. 28

    Rakic, P., Ayoub, A. E., Breunig, J. J. & Dominguez, M. H. Decision by division: Making cortical maps. Trends Neurosci. 32, 291–301 (2009).

    CAS  PubMed Central  PubMed  Google Scholar 

  29. 29

    Rakic, P. Pre and post-developmental neurogenesis in primates. Clinical Neurosci. Res. 2, 29–39 (2002).

    CAS  Google Scholar 

  30. 30

    Rakic, P. A small step for the cell — a giant leap for mankind: a hypothesis of neocortical expansion during evolution. Trends Neurosci. 18, 383–388 (1995). A review of the mechanisms of neocortical expansion with a suggestion on how a single or only few genes can shift the timing from symmetric to asymmetric mode of cell division in the embryonic VZ and can suddenly and exponentially change the surface area of the neocortex.

    CAS  PubMed  Google Scholar 

  31. 31

    Sidman, R. L. & Rakic, P. in Histology and Histopathology of the Nervous System. (eds. Haymaker W. & Adams, R. D.) 3–145 (C. C. Thomas, 1982).

    Google Scholar 

  32. 32

    Bystron, I., Rakic, P., Molnar, Z. & Blakemore, C. The first neurons of the human cerebral cortex. Nature Neurosci. 9, 880–885 (2006). The authors use the newest immunocytochemical methods on fresh tissues from the early stages of the embryonic human telencephalon to discover a previously unrecognized cell class, termed 'predecessor neuron'. Both the evolutionary implication and medical significance of this finding in the human cortical primordium are discussed.

    CAS  PubMed Central  PubMed  Google Scholar 

  33. 33

    Kuida, K. et al. Reduced apoptosis and cytochrome c-mediated caspase activation in mice lacking Caspase-9. Cell 94, 325–333 (1998).

    CAS  PubMed  Google Scholar 

  34. 34

    Kuida, K. et al. Decreased apoptosis in the brain and premature lethality in CPP32-deficient mice. Nature 384, 368–372 (1996).

    CAS  Google Scholar 

  35. 35

    Haydar, T. F., Kuan, C.-Y., Flavell, R. A. & Rakic, P. The role of cell death in regulating the size and shape of the mammalian forebrain. Cereb. Cortex 9, 621–626 (1999).

    CAS  PubMed Central  Google Scholar 

  36. 36

    Kornack, D. R. & Rakic, P. Changes in cell cycle kinetics during the development and evolution of primate neocortex. Proc. Natl Acad. Sci. USA 95, 1242–1246 (1998).

    CAS  PubMed Central  PubMed  Google Scholar 

  37. 37

    Dehay, C. & Kennedy, H. Cell-cycle control and cortical development. Nature Rev. Neurosci. 8, 438–450 (2007).

    CAS  Google Scholar 

  38. 38

    Chenn, A. & Walsh, C. A. Regulation of cerebral cortical size by control of cell cycle exit in neural precursors. Science 297, 365–369 (2002).

    CAS  Google Scholar 

  39. 39

    Chenn, A. & Walsh, C. A. Increased neuronal production, enlarged forebrains and cytoarchitectural distortions in beta-catenin overexpressing transgenic mice. Cereb. Cortex 13, 599–606 (2003).

    PubMed  Google Scholar 

  40. 40

    Tarui T. et al. Overexpression of p27(Kip1), probability of cell cycle exit, and laminar destination of neocortical neurons. Cereb. Cortex, 15, 1343–1355 (2005).

    CAS  PubMed  Google Scholar 

  41. 41

    Richman, D. P., Steward, R. M., Hutchinson, J. W. & Caviness, V. S. Jr Mechanical model of brain convolutional development. Science 189, 18–21 (1975).

    CAS  PubMed  Google Scholar 

  42. 42

    Goldman-Rakic, P. S. & Rakic, P. in Cerebral Dominance, The Biological Foundation (eds Geschwind, N. & Galaburda, A. M.) 179–192 (Harvard University Press, Cambridge, MA, 1984).

    Google Scholar 

  43. 43

    Van Essen, D. C. A tension-based theory of morphogenesis and compact wiring in the central nervous system. Nature 385, 313–318 (1997).

    CAS  PubMed  Google Scholar 

  44. 44

    Noctor, S. C., Flint, A. C., Weissman, T. A., Dammerman, R. S. & Kriegstein, A. R. Neurons derived from radial glial cells establish radial units in neocortex. Nature 409, 714–720 (2001). The experimental evidence, obtained from the live images of retrovirally labelled cells in the slices of the embryonic mouse cerebral wall, that radial glial cells can produce neurons that directly or after additional mitotic divisions, migrate and form radial columns in the overlaying cortical plate.

    CAS  PubMed Central  Google Scholar 

  45. 45

    Fishell, G. & Kriegstein, A. R. Neurons from radial glia: the consequences of asymmetric inheritance. Curr. Opin. Neurobiol. 13, 34–41 (2003). Review of the evidence that radial glial cells can produce neurons (see reference 44).

    CAS  PubMed Central  PubMed  Google Scholar 

  46. 46

    Gal, J. S. et al. Molecular and morphological heterogeneity of neural precursors in the mouse neocortical proliferative zones. J. Neurosci. 26, 1045–1056 (2006).

    CAS  PubMed Central  PubMed  Google Scholar 

  47. 47

    Schmechel, D. E. & Rakic, P. Arrested proliferation of radial glial cells during midgestation in rhesus monkey. Nature 227, 303–305 (1979).

    Google Scholar 

  48. 48

    Schmechel, D. E. & Rakic, P. A Golgi study of radial glial cells in developing monkey telencephalon: Morphogenesis and transformation into astrocytes. Anat. Embryol. 156, 115–152 (1979).

    CAS  PubMed  Google Scholar 

  49. 49

    Rakic, P. Elusive radial glial cells: Historical and evolutionary perspective. Glia 43, 19–32 (2003).

    PubMed  Google Scholar 

  50. 50

    Levitt, P., Cooper, M. L. & Rakic, P. Coexistence of neuronal and glial precursor cells in the cerebral ventricular zone of the fetal monkey: an ultrastructural immunoperoxidase analysis. J. Neurosci. 1, 27–39 (1981). The first evidence that neuronal and glial cell lines can be distinguished at the initial stages of corticoneurogenesis in primates, the finding that has been confirmed in human post-mortem material (see references 54 and 55).

    CAS  PubMed Central  PubMed  Google Scholar 

  51. 51

    Levitt, P., Cooper, M. L. & Rakic, P. Early divergence and changing proportions of neuronal and glial precursor cells in the primate cerebral ventricular zone. Dev. Biology 96, 472–484 (1983).

    CAS  Google Scholar 

  52. 52

    Levitt, P. & Rakic, P. Immunoperoxidase localization of glial fibrillary acid protein in radial glial cells and astrocytes of the developing rhesus monkey brain. Comp. Neurol. l93, 8l5–840 (1980).

    Google Scholar 

  53. 53

    Kadhim, H. J., Gadisseux, J.-F. & Evrard, P. Topographical and cytological evolution of the glial phase during prenatal development of the human brain: Histochemical and electron microscopic study. J. Neuropath. Exp. Neurol. 47, 166–188 (1988).

    CAS  PubMed  Google Scholar 

  54. 54

    Zecevic, N. Specific characteristic of radial glia in the human fetal telencephalon. Glia 48, 27–35 (2004).

    PubMed Central  PubMed  Google Scholar 

  55. 55

    Howard, B. M. et al. Radial glia cells in the developing human brain. Neuroscientist 14, 459–473 (2008).

    PubMed Central  PubMed  Google Scholar 

  56. 56

    Felleman, D. J. & Van Essen, D. C. Distributed hierarchical processing in the primate cerebral cortex. Cereb. Cortex 1, 1–47 (1991).

    CAS  PubMed Central  Google Scholar 

  57. 57

    Preuss, T. M. Do rats have prefrontal cortex? The Rose-Woolsey-Akert program reconsidered. J. Cogn. Neurosci. 7, 1–24 (1995).

    CAS  Google Scholar 

  58. 58

    O'Leary, D. D. M. & Borngasser, D. Cortical ventricular zone progenitors and their progeny maintain spatial relationships and radial patterning during preplate development indicating an early protomap. Cereb. Cortex 16 (Suppl. 1), i46–i56 (2006). This article reviews the evidence that the initial neuronal phenotypes for the prospective species-specific pattern and size of cytoarchitectonic areas are indicated early in the proliferative zones (see the protomap hypotheses in references 13 and 65) as well as recent experimental evidence (see references 74 and 75).

    PubMed  Google Scholar 

  59. 59

    Lukaszewicz, A. C. et al., The concerted modulation of proliferation and migration contributes to the specification of the cytoarchitecture and dimensions of cortical areas. Cereb. Cortex 16 (Suppl. 1), i26–i34 (2006).

    PubMed  Google Scholar 

  60. 60

    Rakic, P. Prenatal genesis of connections subserving ocular dominance in the rhesus monkey. Nature 26l, 467–471 (1976).

    Google Scholar 

  61. 61

    Rakic, P. Development of visual centers in the primate brain depends on binocular competition before birth. Science 2l4, 928–993l (1981).

    Google Scholar 

  62. 62

    Shatz, C. J. Impulse activity and the patterning of connections during CNS development. Neuron 5, 745–756 (1990).

    CAS  PubMed  Google Scholar 

  63. 63

    Kaas, J. H. & Preuss, T. M. eds. in The Evolution of Primate Nervous Systems Volume 4 (Elsevier, Oxford, UK, 2007).

    Google Scholar 

  64. 64

    Fukuchi-Shimogori, T. & Grove, E. A. Neocortex patterning by the secreted signaling molecule FGF8. Science 294, 1071–1074 (2001). The authors use in utero microelectroporation-mediated gene transfer to introduce an extra source of FGF8 into the occipital pole which results in an extra somato-sensory (barrel) cytoarchitectonic field with a nearly perfect duplication of the topographic map.

    CAS  PubMed Central  PubMed  Google Scholar 

  65. 65

    Mallamaci, A. & Stoykova, A. Gene networks controlling early cerebral cortex arealization. Eur. J. Neurosci. 23, 847–856 (2006).

    PubMed  Google Scholar 

  66. 66

    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).

    PubMed Central  PubMed  Google Scholar 

  67. 67

    Rash, G. & Grove, E. A. Patterning the dorsal telencephalon: a role for sonic hedgehog? J. Neurosci. 27, 11595–11603 (2007).

    CAS  PubMed  Google Scholar 

  68. 68

    Crossley, P. H., Martinez, S., Ohkubo, Y. & Rubenstein, J. L. Coordinate expression of Fgf8, Otx2, Bmp4, and Shh in the rostral prosencephalon during development of the telencephalic and optic vesicles. Neuroscience 108, 183–206 (2001).

    CAS  PubMed  Google Scholar 

  69. 69

    Breunig, J. J . et al. Primary cilia regulate hippocampal neurogenesis by mediating sonic hedgehog signaling. Proc. Natl Acad. Sci. USA 105, 13127–13132 (2008).

    CAS  PubMed  Google Scholar 

  70. 70

    Bishop, K. M., Goudreau, G. & O'Leary, D. D. Regulation of area identity in the mammalian neocortex by Emx2 and Pax6. Science 288, 344–349 (2000).

    CAS  PubMed Central  PubMed  Google Scholar 

  71. 71

    Garel, S. et al. Molecular regionalization of the neocortex is disrupted in Fgf8 hypomorphic mutants. Development 130, 1903–1914 (2003).

    CAS  PubMed Central  PubMed  Google Scholar 

  72. 72

    Storm, E. E. et al. Dose-dependent functions of Fgf8 in regulating telencephalic patterning centers. Development 133, 1831–1844 (2006).

    CAS  PubMed  Google Scholar 

  73. 73

    Armentano, M. et al. COUP-TFI regulates the balance of cortical patterning between frontal/motor and sensory areas. Nature Neurosci. 10, 1277–1286 (2007).

    CAS  PubMed  Google Scholar 

  74. 74

    Cholfin, J. A. & Rubenstein, J. L. Patterning of frontal cortex subdivisions by Fgf17. Proc. Natl Acad. Sci. USA 104, 7652–7657 (2007). The experimental evidence that prospective cytoarchitectonic areas are specified in the proliferative zones, as predicted by the protomap hypothesis (see reference 12). The authors also show that the manipulation of cell proliferation rate in the ventricular zone can independently change the size of a selected cortical area (see reference 64).

    CAS  PubMed Central  PubMed  Google Scholar 

  75. 75

    Cholfin, J. A. & Rubenstein, J. L. Frontal cortex subdivision patterning is coordinately regulated by Fgf8, Fgf17, and Emx2. J. Comp. Neurol. 509, 144–155 (2008).

    PubMed Central  PubMed  Google Scholar 

  76. 76

    Borello, U., Cobos, I., Long, J. E., Murre, C. & Rubenstein, J. L. R. FGF15 promotes neurogenesis and opposes FGF8 function during neocortical development. Neural Dev. 3, 17 (2008).

    PubMed Central  PubMed  Google Scholar 

  77. 77

    Rubenstein, J. L. R. & Rakic, P. Genetic control of cortical development. Cereb. Cortex 9, 521–552 (1999).

    CAS  PubMed Central  PubMed  Google Scholar 

  78. 78

    Rakic, P. Neurocreationalism: making new cortical maps. Science 294, 1011–1012 (2001).

    CAS  PubMed  Google Scholar 

  79. 79

    Krubitzer, L & Kaas, J. The evolution of the neocortex in mammals: how is phenotypic diversity generated? Curr. Opin. Neurobiol. 15, 444–453 (2005).

    CAS  PubMed Central  PubMed  Google Scholar 

  80. 80

    Changeux, J. P. & Danchin, A. Selective stabilisation of developing synapses as a mechanism for the specification of neuronal networks. Nature 264, 705–712 (1976).

    CAS  PubMed  Google Scholar 

  81. 81

    Rakic, P. & Riley, K. P. Overproduction and elimination of retinal axons in the fetal rhesus monkey. Science 209, 1441–1444 (1983).

    Google Scholar 

  82. 82

    Rakic, P. & Riley, K. P. 1983 Regulation of axon numbers in the primate optic nerve by prenatal binocular competition. Nature 305, 135–137 (1983).

    CAS  PubMed  Google Scholar 

  83. 83

    Huttenlocher, P. R., de Courten, C., Gare, L. J. & Van der Loos, H. Synaptogenesis in human visual cortex—evidence for synapse elimination during normal development. Neurosci. Lett. 33, 247–252 (1982).

    CAS  PubMed Central  Google Scholar 

  84. 84

    Rakic, P., Bourgeois, J.-P., Eckenhoff, M. E., Zecevic, N., & Goldman-Rakic, P. S. Concurrent overproduction of synapses in diverse regions of the primate cerebral cortex. Science 232, 232–235 (1986).

    CAS  PubMed Central  PubMed  Google Scholar 

  85. 85

    LaMantia, A. S. & Rakic, P. Axon overproduction and elimination in the corpus callosum of the developing rhesus monkey. J. Neurosci. 10, 2156–2175 (1990).

    CAS  PubMed  Google Scholar 

  86. 86

    Shatz, C. J. Form from function in visual system development. Harvey Lect. 93, 17–34 (1997–1998).

    PubMed  Google Scholar 

  87. 87

    Brun, A. The subpial granular layer of the foetal cerebral cortex in man. Acta. Pathol. Microbiol. Scand. Suppl. 179, 1–98 (1965).

    Google Scholar 

  88. 88

    Gadisseux, J-F, Goffinet, A. M. Lyon, G. & Evrard, P. The human transient subpial granular layer: An optical, immunohistochemical, and ultrastructural analysis. J. Comp. Neurol. 324, 94–114 (2004). The detailed study of the subpial granular layers in the developing human cerebral cortex that, in spite of its large size in human (see reference 87) is neglected in the literature because of its absence in rodents.

    Google Scholar 

  89. 89

    Rakic, P. & Zecevic, N. Emerging complexity of layer I in human cerebral cortex. Cereb. Cortex 13, 1072–1083 (2003).

    PubMed Central  PubMed  Google Scholar 

  90. 90

    Rakic, P. & Sidman, R. L. Telencephalic origin of pulvinar neurons in fetal human brain. Z. Anat. Entwickl.-Gersch. 129, 53–82 (1969).

    CAS  Google Scholar 

  91. 91

    Letinic, K. & Kostovic, I. Transient fetal structure, the gangliothalamic body, connects telencephalic germinal zone with all thalamic regions in the developing human brain. J. Comp. Neurol. 384, 373–395 (1997).

    CAS  PubMed  Google Scholar 

  92. 92

    Letinic, K. & Rakic, P. Telencephalic origin of human thalamic GABAergic neurons. Nature Neurosci. 4, 931–936 (2001). The use of contemporary methods, including retroviral labelling in the slices of embryonic human brain tissue, to follow the migratory pathway of a class of thalamic interneurons from their origin in the telencephalic ganglionic eminence to the diencephalons, to settle in the thalamic association nuclei. This uniquely human migratory stream was initially observed by classical histological methods (see reference 90).

    CAS  PubMed  Google Scholar 

  93. 93

    Ramón y Cajal, S. Textura del sistema nervioso del hombre y vertebrados. Vol. 2, (Moya, Madrid, Spain, 1899) (in Spanish).

    Google Scholar 

  94. 94

    DeFelipe, J. Cortical interneurons: from Cajal to 2001. Progr. Brain Res. 136, 215–238 (2002).

    Google Scholar 

  95. 95

    Jones, E. G. . The origins of cortical interneurons: mouse versus monkey and human cerebral cortex. Cereb. Cortex 19, 1953–1956.

    PubMed  Google Scholar 

  96. 96

    Parnavelas, J. G., Barfield, J. A., Franke, E. & Luskin, M. B. Separate progenitor cells give rise to pyramidal and nonpyramidal neurons in the rat telencephalon. Cereb. Cortex 1, 463–491 (1991).

    CAS  PubMed  Google Scholar 

  97. 97

    de Carlos, J. A., López-Mascaraque, L. & Valverde, F. Dynamics of cell migration from the lateral ganglionic eminence in the rat. J. Neurosci. 16, 6146–6156 (1996).

    CAS  PubMed  Google Scholar 

  98. 98

    Anderson, S., Mione, M., Yun, K. & Rubenstein, J. L. R. Differential origins of neocortical projection and local circuit neurons: Role of Dlx genes in neocortical interneurogenesis. Cereb. Cortex 9, 646–654 (1999).

    CAS  PubMed  Google Scholar 

  99. 99

    Lavdas, A. A., Grigoriou, M., Pachnis, V. & Parnavelas, J. G. The medial ganglionic eminence gives rise to a population of early neurons in the developing cerebral cortex. J. Neurosci. 19, 7881–7888 (1999). A study of the origin and tangential migration of early generated GABAergic interneurons from the medial portion of the ganglionic eminence of the ventral telencephalon to the cerebral cortex (see also references 14 and 98 for a comprehensive review on this subject).

    CAS  PubMed Central  PubMed  Google Scholar 

  100. 100

    Batista-Brito, R., Machold, R., Klein, C. & Fishell, G. Gene expression in cortical interneuron precursors is prescient of their mature function. Cereb. Cortex 18, 2306–2317 (2008).

    PubMed Central  PubMed  Google Scholar 

  101. 101

    Letinic, K., Zoncu, R. & Rakic, P. Origin of GABAegic neurons in the human neocortex. Nature 417, 645–649 (2002). The evidence obtained by using retroviral labelling in the supravital slices of the embryonic human forebrain, showing that a large proportion of interneurons in the primates are generated in the local SVZ and migrate radially to the suprajacent cortex (see references 102, 103 and 106). The evolutionary and medical implication for human-specific psychiatric disorders is discussed (see reference 111).

    CAS  PubMed  Google Scholar 

  102. 102

    Petanjek, Z., Dujmovic´, A., Kostovic´, I. & Esclapez, M. Distinct origin of GABA-ergic neurons in forebrain of man, nonhuman primates and lower mammals. Coll. Antropol. 32, (Suppl 1), 9–17 (2008).

    PubMed  Google Scholar 

  103. 103

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

    PubMed  Google Scholar 

  104. 104

    Rakic, S. & Zecevic N. Emerging complexity of cortical layer I in humans. Cereb. Cortex, 13, 1072–1083 (2003).

    Google Scholar 

  105. 105

    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).

    PubMed Central  PubMed  Google Scholar 

  106. 106

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

    PubMed Central  PubMed  Google Scholar 

  107. 107

    Hendry, S. H. C., Jones, E. G. & Emson, P. C. Morphology, distribution and synaptic relations of somatostatin and neuropeptide Y-immunoreactive neurons in rat and monkey neocortex. J. Neurosci. 4, 2497–2517 (1984).

    CAS  PubMed  Google Scholar 

  108. 108

    Ramón y Cajal, S. Histologie du Système Nerveux de l'Homme et des Vertébrés, Volume II. Translated by L. Azoulay (Maloine, Paris, France, 1911).

    Google Scholar 

  109. 109

    DeFelipe, J. González-Albo, M. C., Del Río, M. R. & Elston, G. N. Distribution and patterns of connectivity of interneurons containing calbindin, calretinin, and parvalbumin in visual areas of the occipital and temporal lobes of the macaque monkey. J. Comp. Neurol. 412, 515–526 (1999).

    CAS  PubMed  Google Scholar 

  110. 110

    Hendry, S. H. C. et al. Two classes of cortical GABA neurons defined by differential calcium binding protein immunoreactivities. Exp. Brain Res. 76, 467–472 (1989).

    CAS  PubMed  Google Scholar 

  111. 111

    Lewis, D. A. & Levitt, P. Schizophrenia as disorder of neurodevelopment. Ann. Rev. Neurosci. 25, 409–432 (2002).

    CAS  PubMed  Google Scholar 

  112. 112

    Chen, J. G. et al. Zfp312 is required for subcortical axonal projections and dendritic morphology of deep-layer pyramidal neurons of the cerebral cortex. Proc. Natl Acad. Sci. USA 102, 17792–17797 (2005).

    CAS  PubMed  Google Scholar 

  113. 113

    Chen, B., Schaevitz,. R. & McConnell, S. K. Fezl regulates the differentiation and axon targeting of layer 5 subcortical projection neurons in cerebral cortex. Proc. Natl Acad. Sci. USA 102, 17184–17189 (2005).

    CAS  PubMed  Google Scholar 

  114. 114

    Molyneaux, B. J. et al. Fezl is required for the birth and specification of corticospinal motor neurons. Neuron 47, 817–831 (2005).

    CAS  PubMed  Google Scholar 

  115. 115

    Rilling, J. K. & Insel, T. R. The primate neocortex in comparative perspective using magnetic resonance imaging. J. Hum. Evol. 37, 191–223 (1999).

    CAS  PubMed  Google Scholar 

  116. 116

    Kostovic, I. & Rakic, P. Developmental history of the transient subplate zone in the visual and somatosensory cortex of the macaque monkey and human brain. J. Comp. Neurol. 297, 441–470 (1990). The detailed temporal and regional description of the subplate zone in developing human and non-human primate cerebrum which shows its enlargements subjacent to the prospective association areas (see reference 117).

    CAS  PubMed Central  PubMed  Google Scholar 

  117. 117

    Kostovic, I. Structural and histochemical reorganization of the human prefrontal neocortex during perinatal and postnatal life. Prog. Brain Res. 85, 223–239 (1990).

    CAS  PubMed  Google Scholar 

  118. 118

    Zapala, A. et al. Adult mouse brain gene expression patterns bear an embryologic imprint. Proc. Natl Acad. Sci. USA 102, 10357–10362 (2005).

    CAS  PubMed Central  PubMed  Google Scholar 

  119. 119

    Semeralul, M. O. et al. Microarray analysis of the developing cortex. J. Neurobiol. 66, 1646–1658 (2006).

    CAS  PubMed  Google Scholar 

  120. 120

    Roth, R. B. et al. Gene expression analyses reveal molecular relationships among 20 regions of the human CNS. Neurogenetics 7, 67–80 (2006).

    CAS  PubMed  Google Scholar 

  121. 121

    Haroutunian, V., Katsel, P., Dracheva, S. & Davis, K. L. The human homolog of the QKI gene affected in the severe dysmyelination “quaking” mouse phenotype: downregulated in multiple brain regions in schizophrenia. Am. J. Psychiatry 163, 1834–1837 (2006).

    PubMed  Google Scholar 

  122. 122

    Mirnics, K. et al. Molecular characterization of schizophrenia viewed by microarray analysis of gene expression in prefrontal cortex. Neuron 28, 53–67 (2000).

    CAS  PubMed  Google Scholar 

  123. 123

    Ryan, M. M. et al. Gene expression analysis of bipolar disorder reveals downregulation of the ubiquitin cycle and alterations in synaptic genes. Mol. Psychiatry 11, 965–978 (2006).

    CAS  PubMed  Google Scholar 

  124. 124

    Mao, R. et al. Primary and secondary transcriptional effects in the developing human Down syndrome brain and heart. Genome Biol. 6, R107 (2005).

    PubMed Central  PubMed  Google Scholar 

  125. 125

    Johnson, M. B. et al. Functional and evolutionary insights into human brain development through global transcriptome analysis. Neuron 62, 494–509 (2009). A whole-genome, exon-level expression analysis of fetal human cortex that reveals a large number of human specific gene expression, alternative splicing patterns and co-expression networks in the prefrontal and parietal association neocortex.

    CAS  PubMed Central  PubMed  Google Scholar 

  126. 126

    Sun, T. et al. Early asymmetry of gene transcription in embryonic human left and right cerebral cortex. Science 308, 1794–1798 (2005).

    CAS  PubMed Central  PubMed  Google Scholar 

  127. 127

    Oldham, M. C., Horvath, S. & Geschwind, D. H. Conservation and evolution of gene coexpression networks in human and chimpanzee brains. Proc. Natl Acad. Sci. USA 103, 17973–17978 (2006).

    CAS  Google Scholar 

  128. 128

    Kwan, K. Y. et al. SOX5 postmitotically regulates migration, postmigratory differentiation, and projections of subplate and deep-layer neocortical neurons. Proc. Natl Acad. Sci. USA 105, 16021–16026 (2008).

    CAS  PubMed  Google Scholar 

  129. 129

    Prabhakar, S. et al. Human-specific gain of function in a developmental enhancer. Science 321, 1346–1350 (2008).

    CAS  PubMed Central  PubMed  Google Scholar 

  130. 130

    Kudo, L. C. et al. Genetic analysis of anterior posterior expression gradients in the developing mammalian forebrain. Cereb. Cortex 17, 2108–2122 (2007).

    PubMed  Google Scholar 

  131. 131

    Muhlfriedel, S. et al. Novel genes differentially expressed in cortical regions during late neurogenesis. Europ. J. Neurosci. 26, 33–50 (2007).

    Google Scholar 

  132. 132

    Arking, D. E. et al. A common genetic variant in the neurexin superfamily member CNTNAP2 increases familial risk of Autism. Am. J. Hum. Genet. 82, 160–164 (2008).

    CAS  PubMed Central  PubMed  Google Scholar 

  133. 133

    Alarcón, M. et al. Linkage, association and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene. Am. J. Hum. Genet. 82, 150–159 (2008).

    PubMed Central  PubMed  Google Scholar 

  134. 134

    Bakkaloglu, B. et al. Molecular cytogenetic analysis and resequencing of contactin associated protein-like 2 in autism spectrum disorders. Am. J. Hum. Genet. 82, 165–173 (2008).

    CAS  PubMed Central  PubMed  Google Scholar 

  135. 135

    Vernes, S. C. et al. A functional genetic link between distinct developmental language disorders. N. Engl. J. Med. 359, 2337–2345 (2008).

    CAS  PubMed Central  PubMed  Google Scholar 

  136. 136

    Abrahams, B. S. et al. Genome-wide analyses of human perisylvian cerebral cortical patterning. Proc. Natl Acad. Sci. USA 104, 17849–17854 (2007).

    CAS  Google Scholar 

  137. 137

    Levitt, P. Developmental neurobiology and clinical disorders: lost in translation? Neuron 46, 407–412 (2005).

    CAS  PubMed  Google Scholar 

  138. 138

    King, M. C. & Wilson, A. C. Evolution at two levels in humans and chimpanzees. Science 188, 107–116 (1975).

    CAS  Google Scholar 

  139. 139

    Carroll, S. B. Evolution at two levels: on genes and form. PLoS Biol. 3, e245 (2005).

    PubMed Central  PubMed  Google Scholar 

  140. 140

    Rakic, P. The radial edifice of cortical architecture: from neuronal silhouettes to genetic engineering. Special Issue on: Centenery of Neuroscience Discovery: Reflecting on the Nobel Prize to Golgi and Cajal in 1906. Brain Res. Rev. 55, 204–219 (2007).

    PubMed Central  PubMed  Google Scholar 

  141. 141

    Rockel, A. J., Hiorns, R. W. & Powell T. P. S. The basic uniformity in structure of the neocortex. Brain 103, 221–244 (1980).

    CAS  PubMed Central  PubMed  Google Scholar 

  142. 142

    Herculano-Housel. S., Collins, C. E., Wang, P. & Kaas J. The basic non-uniformity of the cerebral cortex. Proc. Natl Acad. Sci. USA 105, 12593–12598 (2008).

    Google Scholar 

  143. 143

    Rakic, P. Confusing cortical columns Proc. Natl Acad. Sci. USA 105, 12099–12100 (2008).

    CAS  PubMed  Google Scholar 

  144. 144

    Yu, Y. C., Bultje, R. S., Wang, X. & Shi, S. H. Specific synapses develop preferentially among sister excitatory neurons in the neocortex. Nature 458, 501–504 (2009).

    CAS  PubMed Central  PubMed  Google Scholar 

  145. 145

    Rakic, P., Stensaas, L. J., Sayre, E. P. & Sidman, R. L. Computer-aided three-dimensional reconstruction and quantitative analysis of cells from serial electronmicroscopic montages of fetal monkey brain. Nature 250, 3l–34 (1974).

  146. 146

    Torii, M., Hashimoto-Torii, K., Levitt, P. & Rakic, P. Integration of neuronal clones in the radial cortical columns by EphA/ephrin-A signaling. Nature (2009) (in the press).

  147. 147

    Rakic, P. Less is more: progenitor death and cortical size. Nature Neurosci. 8, 981–982 (2005).

    CAS  PubMed Central  PubMed  Google Scholar 

  148. 148

    Sur, M. & Rubenstein, J. L. R. Patterning and plasticity of the cerebral cortex. Science 310, 805–810 (1973).

    Google Scholar 

  149. 149

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

    CAS  Google Scholar 

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Acknowledgements

I am grateful to the former and present members of my laboratory whose skills, wisdom, hard work and insightful discussions made this article possible. I am also grateful to the U.S. Public Health Service and private philanthropic organizations that provided funding over the past four decades including NINDS, NEI, NIMH, NIDA, March of Dimes, NARSAD, NAAR and MOD Foundations and the Kavli Institute for Neuroscience at Yale.

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Video of a migrating cortical neuron

Video of radial migration

Glossary

Transient embryonic layers

Layers identified in the embryonic brain, such as the proliferative ventricular and subventricular zones (VZ/SVZ) or migratory intermediate zone that lack direct counterparts in the adult brain, as defined by the Boulder Committee.

Neuropile

The tissue situated between neuronal cell bodies, composed of a complex network of neuronal and glial processes including dendrites, dendritic spines, axonal terminals and synapses, used often to measure connectedness of a given structure.

Cortical parcellation

Regionalization of the cerebral neocortex into areas with distinct structural and functional attributes.

Patterning center

Group of cells in the embryonic brain that secrete molecules (morphogens) that initiate differential expression of transcription factors that specify formation of the cortical areas.

Homotypic–neurophilic guidance

Mode of neuronal migration along the surface of other neurons that depends on membrane-bound adhesion molecules present on both migrating and guiding neurons as opposed to heterotypic gliophilic migration that is guided by the shafts of radial glial cells.

Association areas

Areas of the neocortex that are particularly large in the human cortex (for example, prefrontal granular cortex or language-related Broca and Wernicke areas) are considered as analysers for integration of information from various sensory and motor areas.

Network of genes

A collection of genes that are co-regulated or interact with each other.

Enhancers

A short region of DNA to which proteins including transcription factors can bind to enhance transcription levels of genes in gene clusters.

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Rakic, P. Evolution of the neocortex: a perspective from developmental biology. Nat Rev Neurosci 10, 724–735 (2009). https://doi.org/10.1038/nrn2719

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