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.
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.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Striedter, G. F. Principles of Brain Evolution (Sinauer, Sunderland, Massachusetts, 2005).
Northcutt, R. G. Evolution of the telencephalon in non-mammals. Ann. Rev. Neurosci. 4, 301–350 (1981).
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.
Preuss, T. M. in The Cognitive Neuroscience IV. (ed. Gazzaniga, M. S.) (The MIT Press, Cambridge, Massachusetts, 2009).
Goffinet, A. M. & Rakic, P. (eds) Mouse Brain Development. (Springer-Verlag, Berlin; New York, 2000).
Darwin, C. Descent of Man (J. Murray, London, UK, 1871).
Gould, S. J. Ontogeny and Phylogeny (Harvard University Press, Cambridge, Massachusetts, 1977).
Carroll, S. B. Evo-Devo and an expanding evolutionary synthesis: A genetic theory of morphological evolution. Cell 134, 25–36 (2008).
Mountcastle, V. B. The evolution of ideas concerning the function of the neocortex. Cereb. Cortex 5, 289–295 (1995).
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).
Brodmann, K. Beiträge zur histologischen Lokalisierung der Grosshirnrinde. Dritte Mitteilung: Die Rindenfelder niederer Affen. J. Psychol. Neurol. 9, 177–226 (1905) (in German).
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).
Rakic, P. Principles of neuronal cell migration. Experientia 46, 882–891 (1990).
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).
Molnár Z. et al. Comparative aspects of cerebral cortical development. Eur. J. Neurosci. 23, 921–934 (2006).
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).
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.
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).
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).
Kriegstein, A. R. & Noctor, S. C. Patterns of neuronal migration in the embryonic cortex. Trends Neurosci. 27, 392–399 (2004).
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).
Rakic, P. Neurons in the monkey visual cortex: systematic relation between time of origin and eventual disposition. Science l83, 425–427 (1974).
Zecevic, N. & Rakic, P. Development of layer I neurons in the primate cerebral cortex. J. Neurosci. 21, 5607–5619 (2001).
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).
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).
Gleeson, J. G. & Walsh, C. A. Neuronal migration disorders: from genetic diseases to developmental mechanisms. Trends Neurosci. 23, 352–359 (2000).
Hatten, M. E. New directions in neuronal migration. Science 297, 1660–1663 (2002).
Rakic, P., Ayoub, A. E., Breunig, J. J. & Dominguez, M. H. Decision by division: Making cortical maps. Trends Neurosci. 32, 291–301 (2009).
Rakic, P. Pre and post-developmental neurogenesis in primates. Clinical Neurosci. Res. 2, 29–39 (2002).
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.
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).
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.
Kuida, K. et al. Reduced apoptosis and cytochrome c-mediated caspase activation in mice lacking Caspase-9. Cell 94, 325–333 (1998).
Kuida, K. et al. Decreased apoptosis in the brain and premature lethality in CPP32-deficient mice. Nature 384, 368–372 (1996).
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).
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).
Dehay, C. & Kennedy, H. Cell-cycle control and cortical development. Nature Rev. Neurosci. 8, 438–450 (2007).
Chenn, A. & Walsh, C. A. Regulation of cerebral cortical size by control of cell cycle exit in neural precursors. Science 297, 365–369 (2002).
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).
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).
Richman, D. P., Steward, R. M., Hutchinson, J. W. & Caviness, V. S. Jr Mechanical model of brain convolutional development. Science 189, 18–21 (1975).
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).
Van Essen, D. C. A tension-based theory of morphogenesis and compact wiring in the central nervous system. Nature 385, 313–318 (1997).
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.
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).
Gal, J. S. et al. Molecular and morphological heterogeneity of neural precursors in the mouse neocortical proliferative zones. J. Neurosci. 26, 1045–1056 (2006).
Schmechel, D. E. & Rakic, P. Arrested proliferation of radial glial cells during midgestation in rhesus monkey. Nature 227, 303–305 (1979).
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).
Rakic, P. Elusive radial glial cells: Historical and evolutionary perspective. Glia 43, 19–32 (2003).
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).
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).
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).
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).
Zecevic, N. Specific characteristic of radial glia in the human fetal telencephalon. Glia 48, 27–35 (2004).
Howard, B. M. et al. Radial glia cells in the developing human brain. Neuroscientist 14, 459–473 (2008).
Felleman, D. J. & Van Essen, D. C. Distributed hierarchical processing in the primate cerebral cortex. Cereb. Cortex 1, 1–47 (1991).
Preuss, T. M. Do rats have prefrontal cortex? The Rose-Woolsey-Akert program reconsidered. J. Cogn. Neurosci. 7, 1–24 (1995).
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).
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).
Rakic, P. Prenatal genesis of connections subserving ocular dominance in the rhesus monkey. Nature 26l, 467–471 (1976).
Rakic, P. Development of visual centers in the primate brain depends on binocular competition before birth. Science 2l4, 928–993l (1981).
Shatz, C. J. Impulse activity and the patterning of connections during CNS development. Neuron 5, 745–756 (1990).
Kaas, J. H. & Preuss, T. M. eds. in The Evolution of Primate Nervous Systems Volume 4 (Elsevier, Oxford, UK, 2007).
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.
Mallamaci, A. & Stoykova, A. Gene networks controlling early cerebral cortex arealization. Eur. J. Neurosci. 23, 847–856 (2006).
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).
Rash, G. & Grove, E. A. Patterning the dorsal telencephalon: a role for sonic hedgehog? J. Neurosci. 27, 11595–11603 (2007).
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).
Breunig, J. J . et al. Primary cilia regulate hippocampal neurogenesis by mediating sonic hedgehog signaling. Proc. Natl Acad. Sci. USA 105, 13127–13132 (2008).
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).
Garel, S. et al. Molecular regionalization of the neocortex is disrupted in Fgf8 hypomorphic mutants. Development 130, 1903–1914 (2003).
Storm, E. E. et al. Dose-dependent functions of Fgf8 in regulating telencephalic patterning centers. Development 133, 1831–1844 (2006).
Armentano, M. et al. COUP-TFI regulates the balance of cortical patterning between frontal/motor and sensory areas. Nature Neurosci. 10, 1277–1286 (2007).
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).
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).
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).
Rubenstein, J. L. R. & Rakic, P. Genetic control of cortical development. Cereb. Cortex 9, 521–552 (1999).
Rakic, P. Neurocreationalism: making new cortical maps. Science 294, 1011–1012 (2001).
Krubitzer, L & Kaas, J. The evolution of the neocortex in mammals: how is phenotypic diversity generated? Curr. Opin. Neurobiol. 15, 444–453 (2005).
Changeux, J. P. & Danchin, A. Selective stabilisation of developing synapses as a mechanism for the specification of neuronal networks. Nature 264, 705–712 (1976).
Rakic, P. & Riley, K. P. Overproduction and elimination of retinal axons in the fetal rhesus monkey. Science 209, 1441–1444 (1983).
Rakic, P. & Riley, K. P. 1983 Regulation of axon numbers in the primate optic nerve by prenatal binocular competition. Nature 305, 135–137 (1983).
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).
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).
LaMantia, A. S. & Rakic, P. Axon overproduction and elimination in the corpus callosum of the developing rhesus monkey. J. Neurosci. 10, 2156–2175 (1990).
Shatz, C. J. Form from function in visual system development. Harvey Lect. 93, 17–34 (1997–1998).
Brun, A. The subpial granular layer of the foetal cerebral cortex in man. Acta. Pathol. Microbiol. Scand. Suppl. 179, 1–98 (1965).
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.
Rakic, P. & Zecevic, N. Emerging complexity of layer I in human cerebral cortex. Cereb. Cortex 13, 1072–1083 (2003).
Rakic, P. & Sidman, R. L. Telencephalic origin of pulvinar neurons in fetal human brain. Z. Anat. Entwickl.-Gersch. 129, 53–82 (1969).
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).
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).
Ramón y Cajal, S. Textura del sistema nervioso del hombre y vertebrados. Vol. 2, (Moya, Madrid, Spain, 1899) (in Spanish).
DeFelipe, J. Cortical interneurons: from Cajal to 2001. Progr. Brain Res. 136, 215–238 (2002).
Jones, E. G. . The origins of cortical interneurons: mouse versus monkey and human cerebral cortex. Cereb. Cortex 19, 1953–1956.
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).
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).
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).
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).
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).
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).
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).
Petanjek, Z., Berger, B. & Esclapez, M. Origins of cortical GABAergic neurons in the cynomolgus monkey. Cereb. Cortex 19, 249–262 (2009).
Rakic, S. & Zecevic N. Emerging complexity of cortical layer I in humans. Cereb. Cortex, 13, 1072–1083 (2003).
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).
Fertuzinhos, S. et al. Selective depletion of molecularly defined cortical interneurons in human holoprosencephaly with severe striatal hypoplasia. Cereb. Cortex 19, 2196–2207 (2009).
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).
Ramón y Cajal, S. Histologie du Système Nerveux de l'Homme et des Vertébrés, Volume II. Translated by L. Azoulay (Maloine, Paris, France, 1911).
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).
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).
Lewis, D. A. & Levitt, P. Schizophrenia as disorder of neurodevelopment. Ann. Rev. Neurosci. 25, 409–432 (2002).
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).
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).
Molyneaux, B. J. et al. Fezl is required for the birth and specification of corticospinal motor neurons. Neuron 47, 817–831 (2005).
Rilling, J. K. & Insel, T. R. The primate neocortex in comparative perspective using magnetic resonance imaging. J. Hum. Evol. 37, 191–223 (1999).
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).
Kostovic, I. Structural and histochemical reorganization of the human prefrontal neocortex during perinatal and postnatal life. Prog. Brain Res. 85, 223–239 (1990).
Zapala, A. et al. Adult mouse brain gene expression patterns bear an embryologic imprint. Proc. Natl Acad. Sci. USA 102, 10357–10362 (2005).
Semeralul, M. O. et al. Microarray analysis of the developing cortex. J. Neurobiol. 66, 1646–1658 (2006).
Roth, R. B. et al. Gene expression analyses reveal molecular relationships among 20 regions of the human CNS. Neurogenetics 7, 67–80 (2006).
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).
Mirnics, K. et al. Molecular characterization of schizophrenia viewed by microarray analysis of gene expression in prefrontal cortex. Neuron 28, 53–67 (2000).
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).
Mao, R. et al. Primary and secondary transcriptional effects in the developing human Down syndrome brain and heart. Genome Biol. 6, R107 (2005).
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.
Sun, T. et al. Early asymmetry of gene transcription in embryonic human left and right cerebral cortex. Science 308, 1794–1798 (2005).
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).
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).
Prabhakar, S. et al. Human-specific gain of function in a developmental enhancer. Science 321, 1346–1350 (2008).
Kudo, L. C. et al. Genetic analysis of anterior posterior expression gradients in the developing mammalian forebrain. Cereb. Cortex 17, 2108–2122 (2007).
Muhlfriedel, S. et al. Novel genes differentially expressed in cortical regions during late neurogenesis. Europ. J. Neurosci. 26, 33–50 (2007).
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).
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).
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).
Vernes, S. C. et al. A functional genetic link between distinct developmental language disorders. N. Engl. J. Med. 359, 2337–2345 (2008).
Abrahams, B. S. et al. Genome-wide analyses of human perisylvian cerebral cortical patterning. Proc. Natl Acad. Sci. USA 104, 17849–17854 (2007).
Levitt, P. Developmental neurobiology and clinical disorders: lost in translation? Neuron 46, 407–412 (2005).
King, M. C. & Wilson, A. C. Evolution at two levels in humans and chimpanzees. Science 188, 107–116 (1975).
Carroll, S. B. Evolution at two levels: on genes and form. PLoS Biol. 3, e245 (2005).
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).
Rockel, A. J., Hiorns, R. W. & Powell T. P. S. The basic uniformity in structure of the neocortex. Brain 103, 221–244 (1980).
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).
Rakic, P. Confusing cortical columns Proc. Natl Acad. Sci. USA 105, 12099–12100 (2008).
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).
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).
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).
Rakic, P. Less is more: progenitor death and cortical size. Nature Neurosci. 8, 981–982 (2005).
Sur, M. & Rubenstein, J. L. R. Patterning and plasticity of the cerebral cortex. Science 310, 805–810 (1973).
Wonders C. P. & Anderson S. A. The origin and specification of cortical interneurons. Nature Rev. Neurosci. 7, 687–696 (2006).
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.
The author declares no competing financial interests.
- 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.
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.
A short region of DNA to which proteins including transcription factors can bind to enhance transcription levels of genes in gene clusters.
About this article
Cite this article
Rakic, P. Evolution of the neocortex: a perspective from developmental biology. Nat Rev Neurosci 10, 724–735 (2009). https://doi.org/10.1038/nrn2719
Altered cortical thickness development in 22q11.2 deletion syndrome and association with psychotic symptoms
Molecular Psychiatry (2021)
Molecular Psychiatry (2021)
Transcription factor 4 controls positioning of cortical projection neurons through regulation of cell adhesion
Molecular Psychiatry (2021)
Distinct roles of Fto and Mettl3 in controlling development of the cerebral cortex through transcriptional and translational regulations
Cell Death & Disease (2021)
Neurochemical Research (2021)