Review

Neuronal subtype specification in the cerebral cortex

Published online:

Abstract

In recent years, tremendous progress has been made in understanding the mechanisms underlying the specification of projection neurons within the mammalian neocortex. New experimental approaches have made it possible to identify progenitors and study the lineage relationships of different neocortical projection neurons. An expanding set of genes with layer and neuronal subtype specificity have been identified within the neocortex, and their function during projection neuron development is starting to be elucidated. Here, we assess recent data regarding the nature of neocortical progenitors, review the roles of individual genes in projection neuron specification and discuss the implications for progenitor plasticity.

  • Subscribe to Nature Reviews Neuroscience for full access:

    $59

    Subscribe

Additional access options:

Already a subscriber?  Log in  now or  Register  for online access.

References

  1. 1.

    & Cellular Components of the Cerebral Cortex (Plenum, New York, 1984).

  2. 2.

    Histology of the Nervous System of Man and Vertebrates (Oxford Univ. Press, New York, 1995).

  3. 3.

    & Linked regularities in the development and evolution of mammalian brains. Science 268, 1578–1584 (1995).

  4. 4.

    , , , & Distinct origins of neocortical projection neurons and interneurons in vivo. Cereb. Cortex 12, 702–709 (2002).

  5. 5.

    et al. Cortical excitatory neurons and glia, but not GABAergic neurons, are produced in the Emx1-expressing lineage. J. Neurosci. 22, 6309–6314 (2002).

  6. 6.

    Mode of cell migration to the superficial layers of fetal monkey neocortex. J. Comp. Neurol. 145, 61–83 (1972).

  7. 7.

    et al. Separate progenitors for radial and tangential cell dispersion during development of the cerebral neocortex. Neuron 21, 295–304 (1998).

  8. 8.

    , , & Coexistence of widespread clones and large radial clones in early embryonic ferret cortex. Cereb. Cortex 9, 636–645 (1999).

  9. 9.

    & The origin and specification of cortical interneurons. Nature Rev. Neurosci. 7, 687–696 (2006).

  10. 10.

    & An integrated approach to classifying neuronal phenotypes. Nature Rev. Neurosci. 6, 810–818 (2005).

  11. 11.

    Neuronal specification in the spinal cord: inductive signals and transcriptional codes. Nature Rev. Genet. 1, 20–29 (2000).

  12. 12.

    & Vertebrate neural cell-fate determination: lessons from the retina. Nature Rev. Neurosci. 2, 109–118 (2001).

  13. 13.

    , & Proneural genes and the specification of neural cell types. Nature Rev. Neurosci. 3, 517–530 (2002).

  14. 14.

    Cellular and molecular control of neurogenesis in the mammalian telencephalon. Curr. Opin. Cell Biol. 17, 639–647 (2005).

  15. 15.

    & Cell migration in the forebrain. Annu. Rev. Neurosci. 26, 441–483 (2003).

  16. 16.

    Embryonic vertebrate central nervous system: revised terminology. The Boulder Committee. Anat. Rec. 166, 257–261 (1970).

  17. 17.

    & (eds) in Neocortical Development 255 (Raven, New York, 1991).

  18. 18.

    & Autoradiographic study of cell migration during histogenesis of cerebral cortex in mouse. Nature 192, 766–768 (1961).

  19. 19.

    & Proliferative events in the cerebral ventricular zone. Brain Dev. 17, 159–163 (1995).

  20. 20.

    Neurons in rhesus monkey visual cortex: systematic relation between time of origin and eventual disposition. Science 183, 425–427 (1974).

  21. 21.

    et al. A novel mode of tangential migration of cortical projection neurons. Dev. Biol. 298, 299–311 (2006).

  22. 22.

    , , , & Neurons derived from radial glial cells establish radial units in neocortex. Nature 409, 714–720 (2001).

  23. 23.

    Developmental and evolutionary adaptations of cortical radial glia. Cereb. Cortex 13, 541–549 (2003).

  24. 24.

    & Evidence of common progenitors and patterns of dispersion in rat striatum and cerebral cortex. J. Neurosci. 22, 4002–4014 (2002).

  25. 25.

    & Cell cycle dependence of laminar determination in developing neocortex. Science 254, 282–285 (1991).

  26. 26.

    & Restriction of late cerebral cortical progenitors to an upper-layer fate. Neuron 17, 55–61 (1996). One paper from a series of experiments by McConnell and colleagues investigating the fate potential of neocortical progenitors at different stages of cortical neurogenesis. Here, the authors demonstrate that late progenitors are unable to generate deep-layer neurons when transplanted into the niche that normally generates deep-layer neurons.

  27. 27.

    & Progenitors resume generating neurons after temporary inhibition of neurogenesis by Notch activation in the mammalian cerebral cortex. Development 132, 1295–1304 (2005).

  28. 28.

    et al. Brain-derived neurotrophic factor participates in determination of neuronal laminar fate in the developing mouse cerebral cortex. J. Neurosci. 26, 13218–13230 (2006).

  29. 29.

    , , , & Fezl is required for the birth and specification of corticospinal motor neurons. Neuron 47, 817–831 (2005). Fezl was the first transcription factor found to be necessary for the generation of one neuronal population (subcerebral projection neurons) within the cortex.

  30. 30.

    & The cell biology of neurogenesis. Nature Rev. Mol. Cell Biol. 6, 777–788 (2005).

  31. 31.

    & Cleavage orientation and the asymmetric inheritance of Notch1 immunoreactivity in mammalian neurogenesis. Cell 82, 631–641 (1995).

  32. 32.

    Proliferative characteristics of the ependymal layer during the early development of the mouse neocortex: a pilot study based on recording the number, location and plane of cleavage of mitotic figures. J. Anat. 116, 67–91 (1973).

  33. 33.

    , , & Characterization of CNS precursor subtypes and radial glia. Dev. Biol. 229, 15–30 (2001).

  34. 34.

    et al. Neuronal or glial progeny: regional differences in radial glia fate. Neuron 37, 751–764 (2003).

  35. 35.

    , , & Radial glia serve as neuronal progenitors in all regions of the central nervous system. Neuron 41, 881–890 (2004).

  36. 36.

    et al. Glial cells generate neurons: the role of the transcription factor Pax6. Nature Neurosci. 5, 308–315 (2002).

  37. 37.

    , & Isolation of radial glial cells by fluorescent-activated cell sorting reveals a neuronal lineage. Development 127, 5253–5263 (2000).

  38. 38.

    et al. Human cortical neurons originate from radial glia and neuron-restricted progenitors. J. Neurosci. 27, 4132–4145 (2007).

  39. 39.

    , , & Cortical neurons arise in symmetric and asymmetric division zones and migrate through specific phases. Nature Neurosci. 7, 136–144 (2004). Using low-titre retroviral infection and in vitro time-lapse imaging, the authors demonstrate that radial glia give rise to neurons through two different mechanisms: either by an asymmetric cell division in the VZ that produces a neuron and a radial glia cell or through the generation of an intermediate progenitor that migrates into the SVZ before dividing symmetrically to produce two neurons.

  40. 40.

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

  41. 41.

    & Cell proliferation in the neural tube: an electron microscopic and golgi analysis in the mouse cerebral vesicle. Z. Zellforsch. Mikrosk. Anat. 115, 226–264 (1971).

  42. 42.

    & Growth patterns in the lateral wall of the mouse telencephalon. II. Histological changes during and subsequent to the period of isocortical neuron production. J. Anat. 134, 415–442 (1982).

  43. 43.

    , & . Early ontogeny of the secondary proliferative population of the embryonic murine cerebral wall. J. Neurosci. 15, 6058–6068 (1995).

  44. 44.

    et al. Asymmetric production of surface-dividing and non-surface-dividing cortical progenitor cells. Development 131, 3133–3145 (2004).

  45. 45.

    , , & Neurons arise in the basal neuroepithelium of the early mammalian telencephalon: a major site of neurogenesis. Proc. Natl Acad. Sci. USA 101, 3196–3201 (2004).

  46. 46.

    et al. Expression of Cux-1 and Cux-2 in the subventricular zone and upper layers II–IV of the cerebral cortex. J. Comp. Neurol. 479, 168–180 (2004).

  47. 47.

    , , & Cortical upper layer neurons derive from the subventricular zone as indicated by Svet1 gene expression. Development 128, 1983–1993 (2001).

  48. 48.

    , , & Dynamics of Cux2 expression suggests that an early pool of SVZ precursors is fated to become upper cortical layer neurons. Cereb. Cortex 14, 1408–1420 (2004).

  49. 49.

    et al. Pyramidal neurons of upper cortical layers generated by NEX-positive progenitor cells in the subventricular zone. Proc. Natl Acad. Sci. USA 102, 17172–17177 (2005).

  50. 50.

    , & The evolutionary origin of the mammalian isocortex: towards an integrated developmental and functional approach. Behav. Brain Sci. 26, 535–552; discussion 552–585 (2003).

  51. 51.

    Ontogenesis of the pyramidal cell of the mammalian neocortex and developmental cytoarchitectonics: a unifying theory. J. Comp. Neurol. 321, 223–240 (1992).

  52. 52.

    A comparison of neurotransmitter-specific and neuropeptide-specific neuronal cell types present in the dorsal cortex in turtles with those present in the isocortex in mammals: implications for the evolution of isocortex. Brain Behav. Evol. 38, 53–91 (1991).

  53. 53.

    , & Patterns of neural stem and progenitor cell division may underlie evolutionary cortical expansion. Nature Rev. Neurosci. 7, 883–890 (2006).

  54. 54.

    , , , & Unique morphological features of the proliferative zones and postmitotic compartments of the neural epithelium giving rise to striate and extrastriate cortex in the monkey. Cereb. Cortex 12, 37–53 (2002).

  55. 55.

    , & Induction of deep layer cortical neurons in vitro. Development 124, 915–923 (1997).

  56. 56.

    , , , & Regionalization and fate specification in neurospheres: the role of Olig2 and Pax6. Mol. Cell. Neurosci. 25, 664–678 (2004).

  57. 57.

    et al. The timing of cortical neurogenesis is encoded within lineages of individual progenitor cells. Nature Neurosci. 9, 743–751 (2006).

  58. 58.

    , , & Coupling cell cycle exit, neuronal differentiation and migration in cortical neurogenesis. Cell Cycle 5, 2314–2318 (2006).

  59. 59.

    , & Parsing the prosencephalon. Nature Rev. Neurosci. 3, 943–951 (2002).

  60. 60.

    , , & LIM-homeodomain gene Lhx2 regulates the formation of the cortical hem. Mech. Dev. 100, 165–175 (2001). The authors report that Lhx2 is required for the formation of the neocortical progenitor domain, and find that the neocortex of Lhx2-mutant mice is almost entirely replaced by an expanded cortical hem.

  61. 61.

    , & Patterning of the dorsal telencephalon and cerebral cortex by a roof plate–lhx2 pathway. Neuron 32, 591–604 (2001). The authors find that Lhx2 expression is partly regulated by bone morphogenetic protein signalling from the roof plate at the dorsal midline. Like reference 60, this paper reports that Lhx2 is required for the formation of the neocortical progenitor domain and that the neocortex of Lhx2-mutant mice is almost entirely replaced by an expanded cortical hem and choroid plexus.

  62. 62.

    , , & Paleocortex is specified in mice in which dorsal telencephalic patterning is severely disrupted. J. Comp. Neurol. 466, 545–553 (2003).

  63. 63.

    , & Dual role of brain factor-1 in regulating growth and patterning of the cerebral hemispheres. Cereb. Cortex 9, 543–550 (1999).

  64. 64.

    & Foxg1 confines Cajal–Retzius neuronogenesis and hippocampal morphogenesis to the dorsomedial pallium. J. Neurosci. 25, 4435–4441 (2005). The authors demonstrate that Foxg1 is required for the specification of neocortical progenitors. In its absence, the neocortex is replaced by an expanded cortical hem and an expanded archicortex.

  65. 65.

    , , , & Foxg1 suppresses early cortical cell fate. Science 303, 56–59 (2004). The authors find that the absence of Foxg1 results in the generation of increased numbers of Cajal–Retzius cells instead of neocortical projection neurons. Remarkably, inactivation of Foxg1 midway through the generation of projection neurons results in the production of additional Cajal–Retzius cells.

  66. 66.

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

  67. 67.

    et al. Conversion of cerebral cortex into basal ganglia in Emx2−/−/Pax6Sey/Sey double-mutant mice. Nature Neurosci. 5, 737–745 (2002). The authors find that without at least one allele of Emx2 or Pax6, no neocortex is generated.

  68. 68.

    et al. Sequential phases of cortical specification involve Neurogenin-dependent and independent pathways. EMBO J. 23, 2892–2902 (2004).

  69. 69.

    , , & Pax6 modulates the dorsoventral patterning of the mammalian telencephalon. J. Neurosci. 20, 8042–8050 (2000).

  70. 70.

    , & Genetic control of dorsal–ventral identity in the telencephalon: opposing roles for Pax6 and Gsh2. Development 127, 4361–4371 (2000).

  71. 71.

    , & Gsh2 and Pax6 play complementary roles in dorsoventral patterning of the mammalian telencephalon. Development 128, 193–205 (2001).

  72. 72.

    & Ventralized dorsal telencephalic progenitors in Pax6 mutant mice generate GABA interneurons of a lateral ganglionic eminence fate. Proc. Natl Acad. Sci. USA 102, 7374–7379 (2005).

  73. 73.

    et al. Pax6 controls cerebral cortical cell number by regulating exit from the cell cycle and specifies cortical cell identity by a cell autonomous mechanism. Dev. Biol. 302, 50–65 (2007).

  74. 74.

    , , , & Determination of the migratory capacity of embryonic cortical cells lacking the transcription factor Pax-6. Development 124, 5087–5096 (1997).

  75. 75.

    & Expression of the transcription factor, tailless, is required for formation of superficial cortical layers. Cereb. Cortex 13, 921–931 (2003).

  76. 76.

    et al. The Tlx gene regulates the timing of neurogenesis in the cortex. J. Neurosci. 24, 8333–8345 (2004).

  77. 77.

    , , , & Pax6 is required to regulate the cell cycle and the rate of progression from symmetrical to asymmetrical division in mammalian cortical progenitors. Development 129, 455–466 (2002).

  78. 78.

    et al. Pax6, Tbr2, and Tbr1 are expressed sequentially by radial glia, intermediate progenitor cells, and postmitotic neurons in developing neocortex. J. Neurosci. 25, 247–251 (2005).

  79. 79.

    et al. Mouse brain organization revealed through direct genome-scale TF expression analysis. Science 306, 2255–2257 (2004).

  80. 80.

    et al. Genome-wide atlas of gene expression in the adult mouse brain. Nature 445, 168–176 (2007).

  81. 81.

    et al. BGEM: an in situ hybridization database of gene expression in the embryonic and adult mouse nervous system. PLoS Biol. 4, e86 (2006).

  82. 82.

    , & GenePaint.org: an atlas of gene expression patterns in the mouse embryo. Nucleic Acids Res. 32, D552–D556 (2004).

  83. 83.

    et al. A gene expression atlas of the central nervous system based on bacterial artificial chromosomes. Nature 425, 917–925 (2003).

  84. 84.

    , & Differential expression of COUP-TFI, CHL1, and two novel genes in developing neocortex identified by differential display PCR. J. Neurosci. 20, 7682–7690 (2000).

  85. 85.

    et al. Identification of the genes that are expressed in the upper layers of the neocortex. Cereb. Cortex 14, 1144–1152 (2004).

  86. 86.

    et al. Neuronal subtype-specific genes that control corticospinal motor neuron development in vivo. Neuron 45, 207–221 (2005). The first paper reporting on the identification of genes that are specific to corticospinal motor neurons and that in combination identify and control development of this neuron type in vivo.

  87. 87.

    et al. Molecular taxonomy of major neuronal classes in the adult mouse forebrain. Nature Neurosci. 9, 99–107 (2006). The authors define the global expression profile of 12 neuronal populations chosen from different regions of the adult forebrain and use the gene expression data to propose a taxonomic classification of neuron types on the basis of their molecular similarities.

  88. 88.

    , & Dynamic spatiotemporal expression of LIM genes and cofactors in the embryonic and postnatal cerebral cortex. Dev. Dyn. 226, 460–469 (2003).

  89. 89.

    , & Graded and areal expression patterns of regulatory genes and cadherins in embryonic neocortex independent of thalamocortical input. J. Neurosci. 19, 10877–10885 (1999).

  90. 90.

    , , , & Transcriptional regulation of cortical neuron migration by POU domain factors. Science 295, 1528–1532 (2002). The authors show that Brn1 and Brn2 are necessary for proper cortical lamination, such that in the absence of both these genes neurons of upper layers II/III and layer V fail to migrate and position below the subplate, whereas layer VI neurons are unaffected, resulting in an inverted cortex.

  91. 91.

    et al. Brn-1 and Brn-2 share crucial roles in the production and positioning of mouse neocortical neurons. Genes Dev. 16, 1760–1765 (2002).

  92. 92.

    , , & The expression pattern of the orphan nuclear receptor RORβ in the developing and adult rat nervous system suggests a role in the processing of sensory information and in circadian rhythm. Eur. J. Neurosci. 9, 2687–2701 (1997).

  93. 93.

    , , , & Characterization of Foxp2 and Foxp1 mRNA and protein in the developing and mature brain. J. Comp. Neurol. 460, 266–279 (2003).

  94. 94.

    , , & Regulation of the POU domain gene SCIP during cerebral cortical development. J. Neurosci. 14, 472–485 (1994).

  95. 95.

    et al. Cortical neurons require Otx1 for the refinement of exuberant axonal projections to subcortical targets. Neuron 24, 819–831 (1999).

  96. 96.

    et al. Beyond laminar fate: toward a molecular classification of cortical projection/pyramidal neurons. Dev. Neurosci. 25, 139–151 (2003).

  97. 97.

    et al. Selective neurofilament (SMI-32, FNP-7 and N200) expression in subpopulations of layer V pyramidal neurons in vivo and in vitro. Cereb. Cortex 14, 1276–1286 (2004).

  98. 98.

    , & Model of forebrain regionalization based on spatiotemporal patterns of POU-III homeobox gene expression, birthdates, and morphological features. J. Comp. Neurol. 355, 237–295 (1995).

  99. 99.

    et al. T-brain-1: a homolog of Brachyury whose expression defines molecularly distinct domains within the cerebral cortex. Neuron 15, 63–78 (1995).

  100. 100.

    et al. Tbr1 regulates differentiation of the preplate and layer 6. Neuron 29, 353–366 (2001). The authors report that the transcription factor Tbr1 is necessary for proper development of Cajal–Retzius cells, subplate neurons and layer VI neurons. In the absence of Tbr1, the preplate does not split properly, deep-layer VI neurons are located below the subplate, with disruption of cortical lamination, as well as abnormal corticothalamic, thalamocortical and cortico-cortical connectivity.

  101. 101.

    , , & Molecular mechanisms of cortical differentiation. Eur. J. Neurosci. 23, 857–868 (2006).

  102. 102.

    et al. A role for neural determination genes in specifying the dorsoventral identity of telencephalic neurons. Genes Dev. 14, 67–80 (2000).

  103. 103.

    & Radial migration of superficial layer cortical neurons controlled by novel Ig cell adhesion molecule MDGA1. J. Neurosci. 26, 4460–4464 (2006).

  104. 104.

    , , & Laminar and areal differences in the origin of the subcortical projection neurons of the rat somatosensory cortex. J. Comp. Neurol. 282, 428–445 (1989).

  105. 105.

    , & Corticopontine projection in the rat: the distribution of labelled cortical cells after large injections of horseradish peroxidase in the pontine nuclei. J. Comp. Neurol. 286, 427–441 (1989).

  106. 106.

    & Towards the classification of subpopulations of layer V pyramidal projection neurons. Neurosci. Res. 55, 105–115 (2006).

  107. 107.

    & Development of projection neuron types, axon pathways, and patterned connections of the mammalian cortex. Neuron 10, 991–1006 (1993).

  108. 108.

    & Cells of origin and terminal distribution of descending projections of the rat somatic sensory cortex. J. Comp. Neurol. 175, 129–157 (1977).

  109. 109.

    & Cortical axons branch to multiple subcortical targets by interstitial axon budding: implications for target recognition and 'waiting periods'. Neuron 1, 901–910 (1988).

  110. 110.

    & Axon elimination in the developing corticospinal tract of the rat. Brain Res. 466, 103–119 (1988).

  111. 111.

    , & 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). Similarly to reference 29, this reports that Fez2f regulates the differentiation of layer V neurons and their subcerebral projections.

  112. 112.

    , , & 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). The authors knocked down Fez2f expression in cortical neurons via small interfering RNA and showed that reduced levels of this transcription factor results in abnormal connectivity by layer V and VI neurons to subcortical targets and in abnormal neuronal subtype-specific dendritic differentiation.

  113. 113.

    , , & Fez1 is layer-specifically expressed in the adult mouse neocortex. Eur. J. Neurosci. 20, 2909–2916 (2004).

  114. 114.

    et al. Zinc finger gene fez-like functions in the formation of subplate neurons and thalamocortical axons. Dev. Dyn. 230, 546–556 (2004).

  115. 115.

    , , & Otx1 and Otx2 define layers and regions in developing cerebral cortex and cerebellum. J. Neurosci. 14, 5725–5740 (1994).

  116. 116.

    & Can regenerating axons recapitulate developmental guidance during recovery from spinal cord injury? Nature Rev. Neurosci. 7, 603–616 (2006).

  117. 117.

    et al. Ryk-mediated Wnt repulsion regulates posterior-directed growth of corticospinal tract. Nature Neurosci. 8, 1151–1159 (2005).

  118. 118.

    & IGF-I specifically enhances axon outgrowth of corticospinal motor neurons. Nature Neurosci. 9, 1371–1381 (2006).

  119. 119.

    , , & Drosophila neuroblasts sequentially express transcription factors which specify the temporal identity of their neuronal progeny. Cell 106, 511–521 (2001).

  120. 120.

    & Regulation of neuroblast competence in Drosophila. Nature 425, 624–628 (2003).

  121. 121.

    , & Neurogenesis of corticospinal motor neurons extending spinal projections in adult mice. Proc. Natl Acad. Sci. USA 101, 16357–16362 (2004).

  122. 122.

    , & Induction of neurogenesis in the neocortex of adult mice. Nature 405, 951–955 (2000).

  123. 123.

    et al. The temporal and spatial origins of cortical interneurons predict their physiological subtype. Neuron 48, 591–604 (2005).

  124. 124.

    et al. Preferential origin and layer destination of GAD65–GFP cortical interneurons. Cereb. Cortex 14, 1122–1133 (2004).

  125. 125.

    , , , & In utero fate mapping reveals distinct migratory pathways and fates of neurons born in the mammalian basal forebrain. Development 128, 3759–3771 (2001).

  126. 126.

    , , & Expression of p73 and reelin in the developing human cortex. J. Neurosci. 22, 4973–4986 (2002).

  127. 127.

    et al. Generation of reelin-positive marginal zone cells from the caudomedial wall of telencephalic vesicles. J. Neurosci. 24, 2286–2295 (2004).

  128. 128.

    , , & Massive loss of Cajal–Retzius cells does not disrupt neocortical layer order. Development 133, 537–545 (2006).

  129. 129.

    et al. Multiple origins of Cajal–Retzius cells at the borders of the developing pallium. Nature Neurosci. 8, 1002–1012 (2005).

  130. 130.

    , & Origin of GABAergic neurons in the human neocortex. Nature 417, 645–649 (2002).

  131. 131.

    & Patterning centers, regulatory genes and extrinsic mechanisms controlling arealization of the neocortex. Curr. Opin. Neurobiol. 12, 14–25 (2002).

  132. 132.

    et al. Emx2 and Pax6 function in cooperation with Otx2 and Otx1 to develop caudal forebrain primordium that includes future archipallium. J. Neurosci. 25, 5097–5108 (2005).

  133. 133.

    & Emx1, Emx2 and Pax6 in specification, regionalization and arealization of the cerebral cortex. Cereb. Cortex 13, 641–647 (2003).

Download references

Acknowledgements

This work was partially supported by grants from the National Institutes of Health (NS45523, NS49553, NS41590), the Harvard Stem Cell Institute, the Spastic Paraplegia Foundation and the ALS Association to J.D.M. P.A. was partially supported by a Claflin Distinguished Scholar Award, the Harvard Stem Cell Institute, the Spastic Paraplegia Foundation and a grant from the ALS Association. B.J.M. was supported by the Harvard M.S.T.P. and the United Sydney Association.

Author information

Author notes

    • Paola Arlotta

    Current address: Center for Regenerative Medicine, Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.

    • Bradley J. Molyneaux
    •  & Paola Arlotta

    These authors contributed equally to this work.

Affiliations

  1. MGH-HMS Center for Nervous System Repair, Departments of Neurosurgery and Neurology, Program in Neuroscience, Harvard Medical School, Massachusetts General Hospital; and Harvard Stem Cell Institute, Harvard University, Boston, Massachusetts 02114, USA.

    • Bradley J. Molyneaux
    • , Paola Arlotta
    • , Joao R. L. Menezes
    •  & Jeffrey D. Macklis
  2. Laboratório de Neuroanatomia Celular, Departamento de Anatomia, Instituto de Ciências Biomédicas, Programa em Ciências Morfológicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.

    • Joao R. L. Menezes

Authors

  1. Search for Bradley J. Molyneaux in:

  2. Search for Paola Arlotta in:

  3. Search for Joao R. L. Menezes in:

  4. Search for Jeffrey D. Macklis in:

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Jeffrey D. Macklis.

Supplementary information

PDF files

  1. 1.

    Supplementary information S1 (table)

    Names and Entrez Gene ID numbers of the genes

Glossary

Subcortical targets

Structures located ventral to the cortex, including the thalamus, brainstem and spinal cord.

Subcerebral targets

Structures located ventral to the cerebrum (telencephalon/diencephalon), including the brainstem and spinal cord.

Cajal–Retzius cells

Early-born neurons of cortical layer I that express reelin.

Competence state

The intrinsic molecular state of a cell that determines its differentiation potential.

Niche

Specific anatomical, cellular and molecular environment of a cell or population of cells.

Symmetric cell division

A mode of cell division that gives rise to two daughter cells of the same type.

Asymmetric cell division

A mode of cell division that gives rise to two different daughter cells.

Associative projection neurons

Neurons that extend axonal projections within a single cerebral hemisphere.

Commissural projection neurons

Neurons that extend axonal projections within the cortex to the opposite hemisphere via the corpus callosum or the anterior commissure.

Corticofugal projection neurons

Neurons that extend axonal projections 'away' from the cortex. These include subcerebral projection neurons and corticothalamic neurons.