Abstract
We describe a distinctive, widespread population of neurons situated beneath the pial surface of the human embryonic forebrain even before complete closure of the neural tube. These 'predecessor' cells include the first neurons seen in the primordium of the cerebral cortex, before the onset of local neurogenesis. Morphological analysis, combined with the study of centrosome location, regional transcription factors and patterns of mitosis and neurogenesis, indicates that predecessor cells invade the cortical primordium by tangential migration from the subpallium. These neurons, described here for the first time, precede all other known cell types of the developing cortex.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Muller, F. & O'Rahilly, R. Olfactory structures in staged human embryos. Cells Tissues Organs 178, 93–116 (2004).
Sidman, R.L. & Rakic, P. Neuronal migration, with special reference to developing human brain: a review. Brain Res. 62, 1–35 (1973).
Marin-Padilla, M. Cajal-Retzius cells and the development of the neocortex. Trends Neurosci. 21, 64–71 (1998).
Boulder Committee. Embryonic vertebrate central nervous system: revised terminology. Anat. Rec. 166, 257–261 (1970).
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).
Meyer, G., Perez-Garcia, C.G., Abraham, H. & Caput, D. Expression of p73 and Reelin in the developing human cortex. J. Neurosci. 22, 4973–4986 (2002).
Bielle, F. et al. Multiple origins of Cajal-Retzius cells at the borders of the developing pallium. Nat. Neurosci. 8, 1002–1012 (2005).
Rakic, S. & Zecevic, N. Emerging complexity of layer I in human cerebral cortex. Cereb. Cortex 13, 1072–1083 (2003).
Letinic, K., Zoncu, R. & Rakic, P. Origin of GABAergic neurons in the human neocortex. Nature 417, 645–649 (2002).
Ang, E.S., Jr., Haydar, T.F., Gluncic, V. & Rakic, P. Four-dimensional migratory coordinates of GABAergic interneurons in the developing mouse cortex. J. Neurosci. 23, 5805–5815 (2003).
Metin, C., Baudoin, J.P., Rakic, S. & Parnavelas, J.G. Cell and molecular mechanisms involved in the migration of cortical interneurons. Eur. J. Neurosci. 23, 894–900 (2006).
Anderson, S.A., Eisenstat, D.D., Shi, L. & Rubenstein, J.L. Interneuron migration from basal forebrain to neocortex: dependence on Dlx genes. Science 278, 474–476 (1997).
Kohtz, J.D., Baker, D.P., Corte, G. & Fishell, G. Regionalization within the mammalian telencephalon is mediated by changes in responsiveness to Sonic Hedgehog. Development 125, 5079–5089 (1998).
Eisenstat, D.D. et al. DLX-1, DLX-2, and DLX-5 expression define distinct stages of basal forebrain differentiation. J. Comp. Neurol. 414, 217–237 (1999).
Corbin, J.G., Nery, S. & Fishell, G. Telencephalic cells take a tangent: non-radial migration in the mammalian forebrain. Nat. Neurosci. 4 Suppl, 1177–1182 (2001).
Meyer, G., Soria, J.M., Martinez-Galan, J.R., Martin-Clemente, B. & Fairen, A. Different origins and developmental histories of transient neurons in the marginal zone of the fetal and neonatal rat cortex. J. Comp. Neurol. 397, 493–518 (1998).
O'Rahilly, R.M.F. The Embryonic Human Brain: An Atlas of Developmental Stages (Wiley-Liss, New York, 1999).
Calof, A.L. et al. Progenitor cells of the olfactory receptor neuron lineage. Microsc. Res. Tech. 58, 176–188 (2002).
Whitlock, K.E. A new model for olfactory placode development. Brain Behav. Evol. 64, 126–140 (2004).
Iacopetti, P. et al. Expression of the antiproliferative gene TIS21 at the onset of neurogenesis identifies single neuroepithelial cells that switch from proliferative to neuron-generating division. Proc. Natl. Acad. Sci. USA 96, 4639–4644 (1999).
Weissman, T., Noctor, S.C., Clinton, B.K., Honig, L.S. & Kriegstein, A.R. Neurogenic radial glial cells in reptile, rodent and human: from mitosis to migration. Cereb. Cortex 13, 550–559 (2003).
Tsai, L.H. & Gleeson, J.G. Nucleokinesis in neuronal migration. Neuron 46, 383–388 (2005).
Solecki, D.J., Model, L., Gaetz, J., Kapoor, T.M. & Hatten, M.E. Par6α signaling controls glial-guided neuronal migration. Nat. Neurosci. 7, 1195–1203 (2004).
Bellion, A., Baudoin, J.P., Alvarez, C., Bornens, M. & Metin, C. Nucleokinesis in tangentially migrating neurons comprises two alternating phases: forward migration of the Golgi/centrosome associated with centrosome splitting and myosin contraction at the rear. J. Neurosci. 25, 5691–5699 (2005).
Zhu, C. et al. Functional analysis of human microtubule-based motor proteins, the kinesins and dyneins, in mitosis/cytokinesis using RNA interference. Mol. Biol. Cell 16, 3187–3199 (2005).
Meyer, G., Goffinet, A.M. & Fairen, A. What is a Cajal-Retzius cell? A reassessment of a classical cell type based on recent observations in the developing neocortex. Cereb. Cortex 9, 765–775 (1999).
Hevner, R.F., Neogi, T., Englund, C., Daza, R.A. & Fink, A. Cajal-Retzius cells in the mouse: transcription factors, neurotransmitters, and birthdays suggest a pallial origin. Brain Res. Dev. Brain Res. 141, 39–53 (2003).
Meyer, G., Schaaps, J.P., Moreau, L. & Goffinet, A.M. Embryonic and early fetal development of the human neocortex. J. Neurosci. 20, 1858–1868 (2000).
Kohtz, J.D. et al. N-terminal fatty-acylation of sonic hedgehog enhances the induction of rodent ventral forebrain neurons. Development 128, 2351–2363 (2001).
Anderson, S.A., Marin, O., Horn, C., Jennings, K. & Rubenstein, J.L. Distinct cortical migrations from the medial and lateral ganglionic eminences. Development 128, 353–363 (2001).
Bulfone, A. et al. T-brain-1: a homolog of Brachyury whose expression defines molecularly distinct domains within the cerebral cortex. Neuron 15, 63–78 (1995).
Hevner, R.F. et al. Tbr1 regulates differentiation of the preplate and layer 6. Neuron 29, 353–366 (2001).
Whitlock, K.E. & Westerfield, M. A transient population of neurons pioneers the olfactory pathway in the zebrafish. J. Neurosci. 18, 8919–8927 (1998).
Haubensak, W., Attardo, A., Denk, W. & Huttner, W.B. 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).
Noctor, S.C., Martinez-Cerdeno, V., Ivic, L. & Kriegstein, A.R. Cortical neurons arise in symmetric and asymmetric division zones and migrate through specific phases. Nat. Neurosci. 7, 136–144 (2004).
Englund, C. 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).
Kennedy, H. & Dehay, C. Cortical specification of mice and men. Cereb. Cortex 3, 171–186 (1993).
Valverde, F., De Carlos, J.A. & Lopez-Mascaraque, L. Time of origin and early fate of preplate cells in the cerebral cortex of the rat. Cereb. Cortex 5, 483–493 (1995).
Rakic, P. & Sidman, R.L. Supravital DNA synthesis in the developing human and mouse brain. J. Neuropathol. Exp. Neurol. 27, 246–276 (1968).
Carney, R.S.E., Bystron, I., Blakemore, C., Molnár, Z. & López-Bendito, G. Radial glial cell proliferation outside the proliferative zone: A quantitative study in fetal rat and human cortex. FENS Forum Abstr. 2, 145.4 (2004).
Jimenez, D., Lopez-Mascaraque, L.M., Valverde, F. & De Carlos, J.A. Tangential migration in neocortical development. Dev. Biol. 244, 155–169 (2002).
Marin, O. & Rubenstein, J.L. Cell migration in the forebrain. Annu. Rev. Neurosci. 26, 441–483 (2003).
Nadarajah, B., Brunstrom, J.E., Grutzendler, J., Wong, R.O. & Pearlman, A.L. Two modes of radial migration in early development of the cerebral cortex. Nat. Neurosci. 4, 143–150 (2001).
Whitlock, K.E. & Westerfield, M. The olfactory placodes of the zebrafish form by convergence of cellular fields at the edge of the neural plate. Development 127, 3645–3653 (2000).
Bystron, I., Molnar, Z., Otellin, V. & Blakemore, C. Tangential networks of precocious neurons and early axonal outgrowth in the embryonic human forebrain. J. Neurosci. 25, 2781–2792 (2005).
Committee to Review the Guidance on the Research Use of Fetuses and Fetal Material. Review of the guidance on the research use of fetuses and fetal material (Her Majesty's Stationery Office, London 1989).
Acknowledgements
We are grateful to L.H. Tsai and Z. Xie for discussion about centrosomal function. We thank A. Goffinet, J. Kohtz and R. Hevner for generous gifts of reelin, Dlx and Tbr1 antibodies, respectively. This work was supported by grants from the UK Medical Research Council (C.B. and Z.M.), the US Public Health Service and the Kavli Institute for Neuroscience at Yale (P.R.), the Russian Foundation for Basic Research and Leading Scientific Schools in Russia (I.B.).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Rights and permissions
About this article
Cite this article
Bystron, I., Rakic, P., Molnár, Z. et al. The first neurons of the human cerebral cortex. Nat Neurosci 9, 880–886 (2006). https://doi.org/10.1038/nn1726
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nn1726
This article is cited by
-
Single-cell atlas of early human brain development highlights heterogeneity of human neuroepithelial cells and early radial glia
Nature Neuroscience (2021)
-
Efficient Generation of Corticofugal Projection Neurons from Human Embryonic Stem Cells
Scientific Reports (2016)
-
Schizophrenia: a tale of two critical periods for prefrontal cortical development
Translational Psychiatry (2015)
-
Retinoic acid signaling and neuronal differentiation
Cellular and Molecular Life Sciences (2015)