Evolution of The Neocortex: A Perspective From Developmental Biology

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Evolution of the neocortex:

a perspective from
developmental biology
Pasko Rakic
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.
The neocortex, as the name implies, is the newest addi- the developing human brain have revealed quantitative
tion to our brain and is considered to be the crowning and qualitative differences in the gene composition and
achievement of evolution and the biological substrate expression between the neocortex of rodents and primates,
of human mental prowess. Although its origin can and we have only begun to explore the developmental and
be traced to reptiles1,2 in the Carboniferous Period, it evolutionary origin of these differences.
first appears as a uniform, six-layered sheet consisting As the excavated skulls of our common predecessors
of radially deployed neurons in small mammals that are empty, perhaps the only way to understand cortical
emerged during the transition from the Triassic period evolution at the cellular level is by comparison of the
to the Jurassic period. Increases in size and complexity of differential gene expression and developmental events
the cerebral cortex have culminated in the modern that occur during the embryonic development of living
human that separated from rodents between 90 and 100 mammals7. This approach, known as evo–devo8 (BOX 1)
million years ago and from the Old World monkeys, such reflects the realization that developmental neurobiol-
as macaques, 25 million years before the present time3,4 ogy can explain how the genetic information contained
(FIG.1). Given that the cerebral neocortex is the centre of within progenitor cells regulates the number, phenotype,
extraordinary human cognitive abilities, it is surprising migration and allocation of neurons in the developing
how little has been done to research its emergence. It brain, where they establish species-specific circuits.
seems that we are sometimes so seduced by similarities For obvious ethical and logistic reasons, experimen-
between species that we neglect the differences. tal manipulation is not possible in humans and thus,
There are several possible explanations for this ten- comparative analysis of the developmental events in
dency. First, the mouse is the best and most economical other mammalian species is used to reveal the origin of
experimental model system for studying the cerebral evolutionary novelties in the cerebral cortex.
cortex 5. Second, the concept, aptly advocated by Charles In this Review, I provide selective examples of what
Darwin, that the biological world is unified, and that evolutionary concepts can be deduced from evo–devo
Department of Neurobiology “there is no fundamental difference between man and studies that have been carried out in embryonic brains
and Kavli Institute for the higher mammals in their mental faculties”6 is still of rodents (mostly Mus musculus), non-human pri-
Neuroscience, Yale University engrained in our mind and we hope that human traits mates (mostly Macaca mulatta) and humans (Homo
School of Medicine, can be deduced from this commonality. Third, research sapiens). Although there is a large body of data on
New Haven, Connecticut
06510, USA.
on the development of the human brain has been mainly other mammalian species, I focus on only these three
e-mail: [email protected] descriptive. However, the recent application of the most species because of space limitations. These three pres-
doi:10.1038/nrn2719 advanced methods of molecular and cell biology to study ently living species effectively illustrate different levels
724 | O CTObeR 2009 | VOlume 10 www.nature.com/reviews/neuro
© 2009 Macmillan Publishers Limited. All rights reserved

f o c u S o n c n S E V o lo
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a Mouse b Macaque c Human share extrinsic connectivity 9–10. However, this apparent
cytoarchitectural uniformity exhibits different degrees
of variability in each area depending on their function.
This compartmentalization is particularly pronounced
in the large and convoluted human neocortex, with more
than 50 distinct cytoarchitectonic areas11.
Second, a remarkable feature of cortical development
in all mammalian species is that none of its constitu-
ent neurons is generated within the cortex itself. Rather,
they are generated in the proliferative transient embryonic
zones (such as the ventricular zone (VZ) and subven-
tricular zone (SVZ)), which are situated near the surface
of the cerebral lateral ventricles, and acquire their proper
areal and laminar positions through long-distance radial
and tangential migration across the intermediate zone
(reviewed in REFS 12–17). Neurons migrating radially
to the increasingly distant cortex follow the shafts of a
transient population of radial glial cells18–20. A detailed
description of the complex migratory process and its
underlying complex and multiple molecular mechanisms
cannot be described in this short Review. FIG. 2 conveys
the basic concepts and further details can be viewed
d Mus musculus in the Rakic laboratory animated video of a migrating
Macaca mulatta cortical neuron and animated video of radial migration.
Third, not only do the postmitotic neurons migrate
Homo sapiens
to the overlaying cortex, but also each generation
bypasses the previous one, a phenomenon known as the
–100 mya –25 mya 0 mya
‘inside-out gradient of neurogenesis’ (REFS 21,22) (see the
Figure 1 | Broad comparison of the brain of a mouse, a macaque monkey and a
animated video of radial migration). The sole excep-
human, and the phylogenetic divergence of these species. In the top panels of a, b
and c the cerebral hemispheres of a mouse, a macaque monkey Nature Reviews
and | Neuroscience
a human brain,
tion to the inside-out sequence of neurogenesis occurs
respectively, are drawn to approximately the same scale to convey the overall difference in the layer I of primates, in which, contrary to rodents,
that exits in the size and elaboration of the cerebral cortex in these three species. The neurogenesis continues throughout the entire period
prefrontal cortex, which has no counterpart in mouse, is shaded in blue in the macaque of corticogenesis23. The biological significance of the
and the human. In the bottom panels of a, b and c, diagrams of cerebral sections are inside-out sequence of settling of neurons in the cerebral
shown for these same species to illustrate that there has been a relative small increase in cortex is not clear 24, but if disturbed, by either genetic
the thickness of the cortex (dark purple outline) compared with the large increase in or environmental factors, neurons display abnormal
surface area (1: 100: 1000 X in mouse, macaque monkey and human, respectively). In part cortical function25. Only recently have methodological
d, the timescale of phylogenetic divergence of mouse (Mus musculus), macaque monkey advances given us an opportunity to study mechanisms
(Macaca mulatta) and human (Homo sapiens) is also shown based on the available DNA
involved in neuronal migration at the molecular and cel-
sequencing data (reviewed in REFS 3,4). mya, million years ago.
lular level (reviewed in REFS 14,26–28). In most mam-
mals, including humans, corticogenesis is completed
of neocortical expansion and elaboration (FIG. 1a,b,c), before or around the time of birth29.
and this is often taken, implicitly and erroneously, as an
indication of the lineage continuity between them with Human ascent through cortical expansion
Transient embryonic layers
the human species at the top; however, comparative ana- The first step in the evolutionary ascent of the human
Layers identified in the
embryonic brain, such as the tomical and DNA sequencing data clearly indicate that cerebral cortex is its enlargement, which occurs mainly
proliferative ventricular and these three species belong to different branches on the by expansion of the surface area without a compara-
subventricular zones (VZ/SVZ) phylogenetic tree (FIG. 1d). ble increase in its thickness (FIG. 1). The modest, only
or migratory intermediate zone about twofold, difference in cortical thickness between
that lack direct counterparts
in the adult brain, as defined
Peculiarities of the cerebral cortex rodents and primates is in part due to the enlargement of
by the Boulder Committee. The evolution of the cerebral neocortex cannot be fully neurons and neuropile in the extracellular space.
appreciated without understanding the way in which it is An explanation of the cellular mechanism that
Neuropile built. There are several features of cortical development underlies the enormous surface expansion of the cortex
The tissue situated between
that differ from the development of other organs of the without a comparable increase in its thickness has been
neuronal cell bodies,
composed of a complex body and even from the rest of the brain. offered by the radial unit hypothesis12 (FIG. 2). According
network of neuronal and glial First, the cerebral cortex in all mammalian spe- to this model, an increase in the number of neural stem
processes including dendrites, cies, including humans, is a cellular sheet composed cells by symmetrical divisions before the onset of neu-
dendritic spines, axonal of projection (or pyramidal) and local circuit neurons rogenesis would result in an exponential increase in
terminals and synapses, used
often to measure
(or interneurons) deployed in horizontal layers, inter- the number of founder cells that give rise to radial cor-
connectedness of a given sected by vertical (or radial) columns that are stere- tical columns (FIG. 2a). At later stages, the number of
structure. otypically interconnected in the vertical dimension and neurons increases linearly within each column, mostly
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by asymmetrical divisions of neural progenitors30. For Similarly, an even more dramatic increase in cor-
example, less than 7 extra rounds of cell divisions in tical surface occurs with an experimentally induced
the VZ at the early embryonic stages can account for increase in neuronal production. It is counterintuitive
the 1,000-fold difference in total cortical surface area that such a large increase in neocortical size is achieved
between mice and humans (FIGS 1,2a). The fact that the by a substantial prolongation, rather than reduction
forebrain primordium in humans is much bigger than in in duration of the cell cycle36–37. It is the changes in
mice and monkeys, even at embryonic stages before the pool size of the neural stem cells and the rate of the
onset of cortical neurogenesis19,31,32, supports this model. exit from the cell cycle that have a crucial role. For
Furthermore, this model predicts that neurons gener- example, the β-catenin-mediated signalling pathway
ated from the founder cells will follow adjacent shafts acts on the decision of the neuronal precursor cells to
of radial glial cells and thus, form more columns, which exit the cell cycle38 and, hence, has an influence on the
results in an expanded laminar rather than nuclear number of postmitotic neurons. Thus, transgenic mice
shaped structure. However, the radial unit hypothesis that express a stabilized form of β-catenin transgene in
does not imply homogeneity of radial units across the neural precursors develop an increased number of pre-
cortex within or between species. On the contrary, there cursor (founder) cells in the VZ, which in turn lead to a
is a large body of evidence to support that radial col- larger number of radial columns and consequently the
umns differ across the cerebral hemisphere and change formation of elaborate cerebral convolutions, contrast-
considerably in size and composition during cortical ing the smooth (lissencephalic) hemispheric surface of
evolution (BOX. 2). their wild type counterparts38,39 (FIG. 3b). Despite severe
additional brain abnormalities in these transgenic mice,
Experimental tests of the radial unit hypothesis. The many of the overproduced neurons migrate radially, set-
radial unit model has been tested by either diminish- tle into apparently normal laminar and radial positions
ing the rate of programmed cell death (apoptosis) or by and generate a much larger surface of the neocortex of
increasing the rate of neural stem cell proliferation in relative uniform thickness. by contrast, overexpression
the VZ. mice deficient in caspase 3 and 9, two impor- of cyclin-dependent kinase (CDK) inhibitor p27, which
tant components of programmed cell death (apop- acts on neuronal progenitors at later developmental
tosis) — an essential process during development 33,34 stages, decreases the production of neurons destined for
— have a larger number of neural stem (founder) cells the more superficial layers within the radial columns
and radial glial cells. These cells, in turn, produce more without increasing its surface40.
than the normal number of radial columns and, hence, Although, it is unlikely that mutation in caspase 9,
result in a larger cortical surface that forms incipient β-catenins, or CDK genes were involved in neocortical
convolutions35 (FIG. 3a). evolution, as mice that are deficient for these particu-
lar genes are not viable, these experiments can serve as
an example of the evo–devo approach to draw theories
on how a single gene mutation, that may have occurred
Box 1 | Evo–devo approach to reconstruct neocortical evolution
in our common, long-extinct ancestors, could have
The use of advanced methods to study embryonic brain development in living species increased the number of proliferative founder cells in
provides insights into possible cellular and molecular mechanisms that have enabled the VZ, which triggered a cascade of events that led to
the evolutionary expansion and elaboration of organs in common ancestors. The new an increase in the number of radial units and cortical
subfield of developmental biology called evo–devo, was created to elucidate how new
surface expansion, including formation of convolutions
features may have been created by gene mutation and, if inherited, propagated during
without an increase in cortical thickness.
evolution by natural selection7,8,139. The contemporary evo–devo approach should be
distinguished from Haeckle’s law of ontogenetic recapitulation of phylogeny that arose
in the ninteenth century (for historical reviews see REFS 1,2,7). The evo–devo approach Development of convolutions. It has been recognized as
embraces the concept of modularity or functional cellular units, such as segments, common sense that the increase in the initially smooth
somites, limb buds and cortical columns. Changes in these modules, if inheritable, often cortical surface must have led to its folding (FIG. 1).
result in lethality; but, if useful can enhance the survival and propagation of the species. However, understanding how these convolutions
The present Review is, by necessity, based on selected data on cortical development formed involves rather complicated logistical problems:
in humans, non-human primates and rodents, which are relevant for understanding one of them being that the pattern of convolutions is
neocortical evolution. For example, experimental inhibition or overexpression of highly reproducible within each species with relatively
specific genes in the embryo allows us to test their effect on development of the
small individual variations. To account for this stere-
cerebral cortex and to draw conclusions on their involvement in increasing
otypic pattern, a role of the long cortico-cortical axonal
evolutionary complexity35,38,74. In addition, it is possible to explore the timing of
expression of new genes and their modification directly in the embryonic human tracts in this process has been proposed 41–43. Indeed,
cortex128. Based on the available data we can propose models of how gene expression the formation of the convolutions in the human cer-
within the neural stem cells in the proliferative embryonic zones control the number of ebrum is associated with the formation of the volu-
columnar units, regulate neuronal migration and allocation into proper laminar and minous intermediate zone that eventually transforms
radial locations in the cortical plate, where they promote differentiation into into subcortical white matter, crisscrossed by the large
species-specific phenotypes, establish new patterns of synaptic connections and number of distinct fascicles of cortico–cortical connec-
determine particular neurotransmitters and receptors within the cytoarchitectonic tions. It has been speculated that the tension created by
areas subserving specific functions140. Thus, the evo–devo approach represents a these fascicles is responsible for the stereotyped shape
scientific way to unravel the events that led to the evolution of the neocortex, which
and orientation of the convolutions in gyrencephalic
we will never be able to verify in real time.
brains43.

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a b
Cortical
II column
Postmitotic
Cortical cell death ( ) CC 11 MZ
layers 1 2 3 4 5 6 7 8 9 10 E100
VI
CP
E40
Asymmetrical SP
division Pro-apoptotic
factors CC
RG
MN
Inhibitory factors TR
IZ
Symmetrical
Anti-apoptotic factors
division
Premitotic VZ
cell death ( ) Neural stem cell pool ( ) NB
Cortical founder pool ( ) MA VZ
1 2 3 4 5 6 7 8 9 10
Figure 2 | radial unit lineage model of cortical neurogenesis. a | Based on the radial unit hypothesis12,30, the model
illustrates how changes in the mode and the rates of cell proliferation and/or programmed cell death within the neural stem
cell pool (blue circles) in the ventricular zone (VZ) that divide symmetrically at early embryonic stages causes
Nature an exponential
Reviews | Neuroscience
increase in the number of radial columns, which, in turn, results in surface expansion of the cerebral cortex without changes in
its thickness. By contrast, similar changes in proliferation kinetics occurring in the founder cells (red circles), which divide
asymmetrically, cause a linear increase in the number of neurons within radial columns without a change in the cortical surface
area. b | The model of radial neuronal migration that underlies columnar organization based on REFS 12,30. The cohorts of
neurons generated in the VZ traverse the intermediate zone (IZ) and subplate zone (SP) containing ‘waiting’ afferents from
several sources (cortico-cortical connections (CC), thalamic radiation (TR), nucleus basalis (NB), monoamine subcortical
centers (MA)) and finally pass through the earlier generated deep layers before settling in at the interface between the cortical
plate (CP) and marginal zone (MZ). The timing of neurogenesis (E40–E100) refers to the embryonic age in the macaque
monkey12,22,32. The positional information of the neurons in the VZ and corresponding protomap within the SP and CP is
preserved during cortical expansion by transient radial glial scaffolding. Further details can be viewed in the Rakic laboratory
animated video of radial migration. RG, radial glia cell; MN, migrating neuron. Part a is modified with permission from REF. 147
 (2005) Macmillan Publishers Ltd. All rights reserved. Part b is reproduced, with permission, from REF. 140  (2007) Elsevier.
Evolutionary adaptation of radial glial cells. The tran- mature glial markers such as the glial fibrillary acidic
sient population of radial glial cells in the developing protein (GFAP) at the onset of corticogenesis, whereas
cerebral cortex serves both as neural stem cells and as a in rodents they are expressed only after birth48,50–55.
guide for the migration of their offspring and adjacent Therefore, even basic cell types such as the radial glial,
neuronal progenitors44–46. However, formation of con- have diversified during evolution to accommodate the
volutions requires long, curvilinear migratory pathways need to develop cerebral convolutions.
and durable radial glial shafts that serve as guides for
neuronal migration to the distant cerebral cortex at later Multiplication and elaboration of cortical maps
fetal stages. Thus, in the primate forebrain, many radial During evolution, functionally distinct cortical areas
glial cells transiently stop dividing while their fibres have expanded at individual rates and new areas have
span the entire cerebral wall, retaining their endfeet at been added, forming an elaborate mosaic56. For example,
the ventricular and pial surfaces47. A single radial glial broca and Wernicke language-related areas or the pre-
fibre in primates may serve as a guide for cohorts of up frontal granular cortex have not been, either anatomi-
to 30 simultaneously migrating neurons, including some cally or functionally, identified in rodents4,10,57 (FIG. 1).
of the interneurons that originate from the expanded Numerous ideas about the developmental mechanisms
SVZ48,49 and from the larger pool of progenitors with that could explain how this elaborate cortical parcella-
short radial processes in the VZ46,50,51. The greater stabil- tion occurred in evolution have been discussed. early
ity and longevity of the radial glial scaffolding may be an debates about whether structural differences between
Cortical parcellation evolutionary adaptation that enables proper allocation of areas are induced in the initially homogeneous popula-
Regionalization of the cerebral
neocortex into areas with
neurons to the expanded and convoluted cerebral cor- tion of cortical neurons by the patterned activity of the
distinct structural and tex32,49. Indeed, the radial glial in both human and non- inputs arriving from the periphery through the thala-
functional attributes. human primates differentiate precociously and express mus (the tabula rasa hypothesis) or, whether the cortical

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Patterning center progenitors themselves are targets of evolution (the pro- factors that are involved in neuronal production and
Group of cells in the embryonic tomap hypothesis) have been recently reviewed28,58,59 and phenotypic and areal specification65–69. However, this
brain that secrete molecules are not repeated here. In brief, the consensus that has FGF study shows dramatically that a change in expres-
(morphogens) that initiate emerged is that the species-specific diversity of the neo- sion of a single factor can result in a duplication of an
differential expression of
transcription factors that
cortical areas originates from differential gene expres- entire functional area.
specify formation of the sion in the neural stem cells in the embryonic VZ and
cortical areas. this information is transferred radially through migrat- Decisions in the proliferative centers. Numerous recent
ing postmitotic neurons to the overlying cortical plate. studies have demonstrated that the subdivisions and area
Thus, each area attracts appropriate inputs, rather than enlargements of the cortical areas in embryonic mice
being specified by them. Activity-dependent mecha- could be traced back to the proliferative VZ and SVZ
nisms have a significant role at subsequent stages that (reviewed in REFS 28,58,65). The generation of transgenic
refine the already formed synaptic connections12,60–62. mice in which the number of neurons and radial units is
increased serves as an example of how a larger-than-nor-
Duplication through morphogenetic factors. The evo- mal number of founder cells can create a cortex with an
lution of the cerebral cortex involves both an increase increased surface area and number of neurons that even-
in the number of new cytoarchitectonic areas, as well tually form new connections. For example, the expres-
as duplication of sensory representations63. It is gener- sion of FGF8 in the anterior parts of the telencephalon
ally accepted that the regionalization of the neocortex suppresses the posteriorly expressed chick ovalbumin
is initiated by patterning centres that secrete signalling that normally functions upstream of COuP transcrip-
molecules, such as the fibroblast growth factors (FGFs), tion factor 1 (COuP-TF1) and homeobox (emX2) in
wingless (WNTs) and bone morphogenetic protein the telencephalic neuroepithelial cells65,70–73, and this
(bmP), that regulate the position and size of cortical suppression results in a decrease in the anterior but an
areas (reviewed in REFS 28,64,65). For example, the increase in the posterior expression of these molecules.
mouse forebrain has an anterior patterning centre at The development of frontal and sensory subdivisions
the commissural plate that secretes FGF8 and FGF17. of the cortex is dependent on the graded action of FGF8
Perturbations of the patterning centre and expression (REF. 73) and FGF17 (REFS 74,75) and provides an elegant
of FGF8 can profoundly change the somatosensory example of how one area, such as the frontal cortex, can
map of the mouse cerebral cortex: overexpression of expand differentially and independently of the growth
FGF8 in the embryonic forebrain results in forma- rate of other areas75,76 (FIG. 4c). Furthermore, the size of an
tion of an additional barrel field, with a mirror image area can be regulated by the change in FGF17 expression
topographical representation of mouse whiskers64. The at early embryonic stages independent of the synaptic
cellular mechanism of this remarkable duplication is input from the periphery through the thalamus74 (FIG. 4).
unknown, but it is instructive that FGF8 expression The fact that it is now possible to enlarge and/or
is coordinated by distinct sets of transcription factors, duplicate distinct cytoarchitectonic areas in the neocor-
namely zinc-finger and sonic hedgehog transcription tex by genetic manipulation opens an unprecedented
opportunity to explore how these maps develop in each
individual, as well as how they may have been introduced
Box 2 | Evolutionary elaboration of radial columns during neocortical evolution. As a next step, it is impor-
tant to search for additional genes and morphoregulatory
During evolution, the neocortical surface expands by the addition of radial columns23,30
molecules that may be involved in cortical specification;
(FIG. 2), but the composition of the columns also undergoes changes. The notion of the
homogeneity of the columns141 has been abandoned in favour of their heterogeneity, and, to develop rodent and possibly non-human primate
both in different functional areas of an individual, as well as across species142,143. In all models, of cortical dysgenesis that mimic specific genetic
mammals, functional columns consist of an intermix of projection (excitatory, or acquired cortical disorders in human77. In the spirit of
glutaminergic) neurons and inhibitory (GABAergic) interneurons that are evo–devo reasoning, these studies illustrate how a single
stereotypically interconnected in the vertical dimension144 but receive diverse extrinsic mutation could have a sudden and profound effect dur-
input9,10,140. To achieve proper cellular composition, several neuronal clones move ing evolution on the pattern of cortical parcellation and
between their parental radial glial cells within the subventricular zone (SVZ) and the presents some insights into how it could have occurred
intermediate zone (IZ) of the embryonic cerebral wall145. The disturbance of this at the genetic and cellular level78.
intermixing, essential for proper cortical operations, may underlie disorders of selected
cognitive functions143. However, although this lateral shift of migrating neurons in the
More neurons, more connections. Obviously, an increase
SVZ–IZ was recognized 35 years ago based on reconstruction from serial electron
microscopic sections145, the molecular mechanisms that regulate this intermix of in the number of neurons, radial columns and cytoar-
neuronal clones has been elusive. chitectonic areas is not sufficient to explain the mul-
A recent study using a combination of the most advanced molecular technology titude of functional advances that evolved to generate
showed that, during radial neuronal migration, the lateral intermixing of neurons that the human cerebral cortex and which must also involve
belong to different clones within a given functional column depends on the expression the elaboration of neuronal connections2,62,79. There is a
levels of A-type Eph receptor tyrosine kinase and their ligands, ephrin-As146. large amount of comparative anatomical data showing
Eph/Ephrin-dependent intermixing in the SVZ and IZ may be only one of several that, in spite of considerable inter-individual variabil-
mechanisms for allocating proper composition of neuronal phenotypes that have been ity, the basic pattern of neuronal connection is species-
operating during mammalian evolution. However, it can serve as an example of how specific and highly reproducible. It is generally agreed
developmental studies in mice may provide an insight into mechanisms of evolutionary
that functional usefulness of evolutionarily new cortical
elaboration of columnar composition that may have happened in our extinct ancestors.
connections must be validated through the process of

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a Wild type Caspase 9 knockout between the formation of stereotypic, species-specific

connections that are established by surface mediated
attractions and innate, activity-dependent refinements,
from the experience-dependent synaptic plasticity that
shapes connections in cooperation with the outside
environment in each individual. These later-occurring,
experience-dependent changes are not inheritable and,
thus, cannot contribute to evolutionary advances, which
b Wild type ∆90β-catenin–GFP
require gene mutation in germinal cells.
New cell types and migratory pathways

Apart from an increase in the number of neurons and
their allocation into distinct cytoarchitectonic areas, the
evolution of the cerebral cortex has also been accompa-
nied by the introduction of new cell types that migrate
through old or new routes to appropriate, often distant
locations. During 100 million years of separation from a
common ancestor, the mouse and human cerebral cortex
have acquired a number of different features, only some of
which are briefly described in the following subsections.
c Lisencephalic cerebrum Convoluted cerebrum
The subpial granular layer. The subpial granular layer is
a prominent and voluminous transient cellular layer
situated below the pial surface of the fetal human cere-
brum that was first described by O. Ranke more than
a century ago. However, there are only a handful of
studies on its developmental history and function in
human and non-human primates19,23,87,88 and it has not
Increased number
yet been observed in rodents17. It appears around the
Founder cells
of founder cells eleventh gestational week in the human marginal zone,
peaks in size during mid-gestation and disappears by
Figure 3 | enlargement of cortical surface by decrease in programmed cell death
the time of birth17,31,89. Analysis of proliferative activity
or increase in proliferation. a | Brain sections of a wild type mouse
Nature and that
Reviews of a
| Neuroscience
in the developing cerebrum of cats and primates indi-
littermate in which both copies of caspase 9 were deleted are shown. Knockout of
caspase 9 leads to expansion of the progenitor pool, which in turn results in increased cates that the subpial granular layer produces neurons
number of radial columns and consequently a convoluted cortical surface. that may descend to the underlying cortical plate23,87.
c | Mid-coronal section through the forebrain (stained with cresyl violet) of an embryonic based on the uneven size and high incorporation of tri-
day 15.5 wild type mouse and of a transgenic mouse that expresses a Δ90β-catenin–GFP tiated thymidine in the subpial granular layer, which is
(green fluorescent protein) fusion protein in neural precursors. Expression of the fusion located above the developing cortical plate, it may con-
protein results in an increase of the precursor population and of the number of cortical tribute to the wealth of interneurons in certain cortical
columns. c | Diagrams showing how an increased number of progenitor cells can be areas, such as the primary visual cortex, which has an
distributed through radial glial scaffolding to form a sheet, rather than a lump of extraordinary large layer IV compared with rodents23.
postmitotic neurons. Parts a and c are reproduced, with permission, from REF. 35  (1999)
Thus, better characterization of the subpopulations of
Oxford University Press. Part b is reproduced, with permission, from REF. 38  (2002)
interneurons that originate in the subpial granular layer
American Association for the Advancement of Science.
may elucidate their function as well as their possible
involvement in human cortical disorders that do not
natural selection and, if proven to be advantageous, may occur or cannot be mimicked in mice.
contribute to the survival and propagation of the spe-
cies. However, as neurons are generated before they form Migration from the ganglionic eminence to the
axonal connections, an increase in neuronal number, thalamus. A human-specific migratory pathway formed
diversification of their types and attainment of their during mid-gestation by neurons streaming from the
positions will precede the establishment of new, useful ganglionic eminence of the ventral telencephalon
connections in cortical evolution. to the dorsal thalamus of the diencephalon, known
As reviewed in the next section, the new classes of as the corpus gangliothalamicum (CGT), was discovered
neurons allow the formation of new patterns of connec- four decades ago90. This voluminous, easily identifiable
tions. In this complex process, innate neuronal activity stream of migrating bipolar neurons in humans could
is essential for the validation and refinement of synap- not be found in any other species examined to date,
tic connections and leads to their selective stabilization including rodents, carnivores and New and Old World
and/or elimination through competitive interactions80–86. primates31,91. more recently, cell labelling in organotypic
This is a large research field that cannot be considered slice cultures of human embryonic brain tissue enabled
in sufficient detail in this Review. However, it is impor- tracing the migration of these cells directly from the
tant to mention that there should be a clear distinction ganglionic eminence to the dorsal thalamic association

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Homotypic–neurophilic nuclei92. These migratory cells, which rely on homotypic– derived almost exclusively from rodents as these are more
guidance neurophilic guidance and express distal-less homeobox 1 amenable to more advanced methods. Thus, tracing cell
Mode of neuronal migration (DlX1) and DlX2 proteins, which guide their tangential lineages using retroviral vectors in mice first showed that
along the surface of other migration, eventually form GAbAergic neurons in the interneurons and projection neurons originate from dif-
neurons that depends on
membrane-bound adhesion
dorsal thalamus, in particular, the pulvinar and medi- ferent progenitors96. Next, ingenious experiments in mice
molecules present on both odorsal nuclei, which are anatomically related to the demonstrated that the majority, if not all, of the cortical
migrating and guiding neurons association neocortex involved in higher cognitive func- interneurons in this species originate from the gangli-
as opposed to heterotypic tions, including symbolic reasoning or language92. Thus, onic eminence in the ventral pallium and then migrate
gliophilic migration that is
it seems that the human thalamus, to accommodate the tangentially to the dorsal telencephalon14,97–100 (FIG. 5).
guided by the shafts of radial
glial cells.
increased axonal input from the expanding association The suggestion that, in addition to those derived
neocortex, recruits an additional complement of neurons from the ganglionic eminence, a large number of
from the nearby, still mitotically active ganglionic emi- interneurons in humans originate from the volumi-
nence in the ventral telencephalon after the diencephalic nous SVZ was initially based on classical histological
proliferative VZ becomes exhausted92. observations31. However, more recently, several studies
that have succeeded to explore the origin of interneu-
Two origins of neocortical interneurons — a working rons in primates with more advanced methods, have
hypothesis. It was Ramón y Cajal93 who suggested that uniformly suggested that cortical GAbAergic neurons
extraordinary human mental abilities are closely related originate from the ganglionic eminence and the VZ
to the increase in the number and diversity of cortical and SVZ101–106 (FIG. 5b). This stands in contrast to the
interneurons, which he classified using the Golgi silver exclusive ganglionic eminence origin of interneurons
impregnation method. However, since then, many other in rodents. Importantly, fate-mapping experiments in
subclasses of primate-specific interneurons have been human mid-fetal slice cultures suggest that the percent-
characterized94,95. In spite of this, our knowledge of the age of cortical GAbAergic neurons that arise from the
origin and development of the interneurons has been dorsal pallium VZ and SVZ might be higher than those
arising from the ventral progenitors101. Furthermore, it
has been shown that proliferative cells (as identified by
a b bromodeoxyuridine incorporation) in slices of the dor-
Rostral Caudal
Cx FGF8 sal human VZ and SVZ during mid-gestation express
LGE M the ventral transcription factors (DlX1, DlX2 and
S NKX2.1)105. Finally, bipolar morphology and orientation
CP MGE
LT FGF18 of DlX-expressing cells also indicate their local origin
OC and radial migration89. These studies collectively sup-
HT port the idea that in primates, in addition to interneu-
FGF8 Eye
FGF17
rons born in the ganglionic eminence of the ventral
telencephalon, there is a population that originates in
the VZ and SVZ of the dorsal telencephalon (FIG. 5b).
Interneurons derived from the ganglionic eminence and
FGF15
the VZ and SVZ are GAbAergic, but their morphology
and molecular characteristics indicate that their func-
tion might be different and that the latter subclass may be
c Wild type Fgf17–/– Fgf8neo/neo Fgf15+/+ Fgf15–/– involved in human-specific higher cortical functions.
Support of the dual origin of interneurons in humans
comes from analysis of a congenital disorder named
holoprosencephaly (HPe) in which the ventral forebrain
structures, including the medial ganglionic eminence, in
some cases fail to develop. examination of the distribu-
Figure 4 | control of arealization of the frontal cortex by FGF expression.
Nature(which
a | Diagram of the forebrain depicting the rostral patterning centre Reviews Neuroscience
is |also known as tion of various classes of cortical GAbAergic interneu-
the commissural plate (CP)) of fibroblast growth factor 8 (FGF8). b | Coronal sections of the rons showed that the neocortex and hippocampus of
telencephalon of an embryonic day 12.5 mouse showing the expression of FGF isoforms in HPe specimens with severe ventral forebrain hypopla-
the rostral patterning centre. c | Coronal sections of the telencephalon of an embryonic sia lack specific subtypes of cortical GAbAergic neurons
day 12.5 mouse showing the regulation of COUP-TF1 (COUP transcription factor 1) that in mice are known to derive from the ganglionic
expression by different FGF isoforms. COUP-TF1 expression is increased in FGF17–/– null eminence106. by contrast, other subtypes of interneu-
mutant mice and FGF8 mutant mice (hypomorphic neo/neo mutant), which indicates that rons seem to be little or not affected by ventral midline
these factors repress COUP-TF1 expression in the wild type background. By contrast, defects, which suggests that they probably originate in
COUP-TF1 expression is decreased in FGF15–/– null mutants, which suggests that FGF15 the preserved dorsal pallium VZ and SVZ. The detailed
promotes COUP-TF1 expression. Cx, cortex; HT, hypothalamus; LGE, lateral ganglionic
analysis of the expression of various cell-specific mark-
eminence; LT, lamina terminalis; M, midbrain; MGE, medial ganglionic eminence; OC,
optic chiasm; S, septum. Part a is modified, with permission, from REF. 148  (1973) ers in the fetal and infant brains of HPe specimens with
American Association for the Advancement of Science. The panels in part b are courtesy mild and severe ventral forebrain defects revealed that
of J. L. Rubenstein and reproduced, with permission, from REF. 75  (2008) Wiley-Liss. The subclasses of GAbAergic cells, distinguished by co-
panels in part c are courtesy of J. L. Rubenstein and reproduced, with permission, from staining of nitric oxide synthase 1 (NOS1), neuropep-
REF. 76  (2008) Biomed central. tide Y (NPY), somatostatin (SST) and parvalbumin

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a Projection b The finding of evolutionarily novel origins that pro-

neuron duce different subtypes of interneurons in human and
non-human primates does not negate the significance
Interneuron
of the tangential migration of cortical GAbAergic cells
from the ganglionic eminence that were discovered in
CALR the mouse. In fact, studies in human101,102,106 and the
VZ/SVZ DF DF
cynomolgus monkey 103 indicate that the ganglionic
eminence produces a significant portion of interneu-
LGE rons that migrate to the neocortex through the tan-
VZ/SVZ
NOS1, NPY, SST, gential route. A better understanding of the underlying
CALR PVALB mechanisms that generate the greater diversity of inhibi-
NPY tory interneurons in human and non-human primates
SST MGE could uncover a possible role of these cells in human
VF PVALB GE psychiatric disorders95,111.
VF Predecessor neurons. The most recently discovered type

of neurons in human, the predecessor cell, has so far not
been observed in other species32. These large, bipolar
cells are the earliest generated neurons in the human
forebrain that emerge under the pial surface of the ven-
trolateral cerebral wall at the end of the first gestational
Figure 5 | rodent and human fetal forebrains at the peak of corticogenesis. month, before onset of neurogenesis in the VZ and SVZ
Diagrams of cross sections of half of a rodent (a) and a human (b) fetal
Nature forebrain
Reviews are
| Neuroscience of the dorsal telencephalon. They express Tu20 and
shown to scale (a zoom in of the rodent section is also provided for legibility). In rodents, T-box brain gene 1 (TbR1), have long horizontal proc-
the main source of interneurons is the ganglionic eminence (GE) — which is comprised esses and form an extensive network over the forebrain
of the lateral ganglionic eminence (LGE) and the medial ganglionic eminence (MGE) — of primordium32. my research team has proposed that
the ventral telencephalon. These neurons migrate tangentially to the neocortex in the predecessor cells may be a transient population, involved
dorsal telencephalon. By contrast, interneurons in the human forebrain originate both in
in determining the number of functional radial units in
the GE as well as locally in the ventricular and subventricular zones (VZ/SVZ) of the
dorsal telencephalon subjacent to the neocortex. Interneurons originating from the
the cerebral cortex. However, it is important to estab-
cortical VZ/SVZ and GE express a different set of markers, namely nitric oxide synthase 1 lish whether these cells exist in non-human primates to
(NOS1), neuropeptide Y (NPY), somatostatin (SST) and parvalbumin (PVALB) when experimentally determine their lineage, pattern of gene
originating from the GE, and calretinin (CALR) when originating from the VZ/SVZ. expression, function and fate.
DF, dorsal forebrain; VF, ventral forebrain. Data to generate part a was derived from The selected examples of human-specific develop-
REF. 149; data to generate part b was derived from REFS 101,106. mental features and cellular events described earlier are by
no means exclusive. Such evolutionary novelties are
probably the result of gene mutations and/or the intro-
(PVAlb) are consistently absent in both fetal and infant duction of new genes and/or the addition of the devel-
stages. by contrast, the number of calretinin-positive opmental mechanisms and cell–cell interactions that act
GAbAergic cells seem to be little or not affected in the during the progenitor’s exit from the mitotic cycle. They
HPe cases. Furthermore, the absence of cells express- generate a different outcome depending on the evolu-
ing NOS1, NPY, SST and PVAlb correlated with the tionary context. Recent studies indicate that even sub-
dramatic depletion of the thyroid transcription factor 1 types of the pyramidal cells destined for layer V, which
(NKZX-1/TITF1)-positive medial ganglionic eminence are the main efferent system that connects the cortex
progenitors, which are the main source of these sub- with subcortical structures, are determined at the time
types of interneurons in mice. Although not conclusive, of their last division in the VZ112–114. These experimental
the results strongly suggest that cells expressing NOS1, studies in mice indicate that evolutionary novelties,
NPY, SST and PVAlb originate in the ganglionic emi- including introduction of new neuronal types, may start
nence and migrate tangentially into the cortex, whereas with a mutation that regulates the fate of neuronal stem
the calretinin-positive cells could have arisen from the cells in the proliferative zones.
dorsal neuroepithelium of the lateral ventricular wall
and migrated to the cortex radially together with gluta- Small is big: genetic differences
matergic projection neurons. Admittedly, this study One frequently repeated statement, which has almost
cannot eliminate the possibility that the calretinin-posi- become a cliché, is the emphasis on how small the
Association areas
tive cells could have arisen from less affected ganglionic genetic differences are between humans and the rest
Areas of the neocortex that are
particularly large in the human eminence progenitors. However, it is noteworthy that of the animal kingdom. Indeed, only about 1% of the
cortex (for example, prefrontal the neurons expressing NOS1, NPY and SST are most genes are human specific and yet, their effect on tim-
granular cortex or numerous in the derivatives of the marginal zone and ing, sequence and level of gene expression has obviously
language-related Broca and subplate zone in monkeys107, whereas the calretinin- great functional significance. For example, the human
Wernicke areas) are considered
as analysers for integration of
expressing interneurons populate cortical layers II–VI, brain is characterized by expansion in size and complex-
information from various which include the double bouquet cells that are absent ity of the association areas of the neocortex, most notably
sensory and motor areas. from the rodent cortex 108,109,110 (reviewed in REF. 95). the prefrontal cortex, but also the perisylvian areas that

REVIEWS
are related to speech and language processing 115. During autism or schizophrenia. Although microarray analy-
human development these areas have a several-fold sis and other techniques have been available for more
larger subplate zone that consists of multipolar neurons than a decade and have been applied in mice118,119, so far
and incoming ‘waiting’ thalamic axons116 and mature at there have been only few genome-wide expression stud-
a slower pace than in other areas117. Furthermore, some, ies of the human brain. The most comprehensive studies
if not most, of the specific functional prefrontal cortex in terms of brain regions were done on aged brains120,121,
subdivisions do not exist in non-primate species and or on comparisons between diseased and healthy
their development, therefore, cannot be modelled easily brains122,123–124.
in mice4,10. Yet, it is precisely these areas that are probably
most significant for the unique human mental abilities, Region specific differential gene expression. A recent
as well as neuropsychiatric disorders such as dyslexia, study examined 13 brain regions from both cerebral
hemispheres of the fetal human brain125. using the most
advanced generation of microarrays, over one million
a known and predicted exons in nine distinct neocorti-
cal areas were profiled, including subdivisions of the
1–3,4 prefrontal cortex, as well as the temporal and parietal
association areas of the perisylvian cortex (FIG. 6a).
32 40 The data revealed a huge number of transcriptional
9
differences, including genes that were both differen-
44,45
41 tially expressed and alternatively spliced. For example,
13 22 although the greatest distinction within the neocortex
13 is between the prefrontal and non-frontal areas, there
are also expression patterns common to the perisylvian
Prefrontal cortex
areas (prospective broca’s, Geschwind’s and Wernicke’s
Perisylvian areas
area), which, although distributed across three lobes,
are functionally linked by their involvement in speech
and language125. The functions of these genes commonly
b Prefrontal cortex Perisylvian areas enriched in perisylvian areas might therefore hold some
PART1 CDH13 clues to the evolution of structure and connectivity that
ASAM HTR7
SLN LRP1B allowed for the development of language in our species.
AKR1B1 FARP1 In addition, the prospective broca’s area (and its right
FAM59A LPHN2
SDK1 AMIGO2 hemisphere homologue) is, on the basis of gene expres-
CACNA1A OPRK1
CBLN2 ZNF8048 sion patterns, more similar to the neighbouring motor
WBSCR17
C12orf38
ENC1
NGEF
cortex than to the prefrontal cortex 125. Interestingly, no
EXTL3 PTPNS statistically significant left–right transcriptional asym-
CPNE8
SLC5A8 LRRC2 metry at the population level was identified, suggesting
KCNJ6 PLXNA4B
DSCR1L1 CSMD2 that such asymmetries most likely occur earlier during
C20orf102 CDH3
SLITRK5
fetal gestation as previously suggested126; but, also not-
H2AFY2
CTNNBL1 UNC5C ing that more sensitive technologies, as well as greater
CYP20A1 FLJ20366
CA8 SYT13 sample sizes, may yet uncover such asymmetry at the
MEGF11
SULF1 CNTNAP5
late mid-fetal stage.
ABCA1 DKFZP564O0823 The application of weighted gene co-expression net-
FKBP9 CENTA1
ZIC3 KIAA0513 work analysis to microarray-derived expression data
PACSIN2 THY1 has previously provided unique insights into the genetic
MARCH3 TMEM28
mechanisms of human brain evolution and disease127.
Figure 6 | Gene expression patterns of neocortical
Applying this analysis to data from the developing
areas of the human fetal cerebral hemispheres.
a | The neocortical areas investigated included four distinct human brain led to the identification of networks of
Nature Reviews | Neuroscience genes that are linked both to brain regions, including
subdivisions of the prefrontal cortex (blue), namely orbital,
medial, dorsolateral and ventrolateral (Brodmann’s areas: the prefrontal cortex, and to biological processes such
9,13,32,44,45), and perisylvian areas (1–3,4,40,41,42) as alternative splicing 125. Genes with the highest degree
(yellow). In addition to the ventrolateral prefrontal cortex, of interaction within such networks, known as ‘hubs’,
which encompasses the prospective Broca’s area (44/45), may represent critical transcription or other regula-
Network of genes two other speech and language-related areas were tory factors, and are prime candidates for functional
A collection of genes that are assayed: parietal and temporal association cortices, which characterization.
co-regulated or interact with encompass the prospective Wernicke’s–Geschwind’s areas
each other. Several recent studies indicate that tissue- and cell
(22/39). b | Examples of different clusters of correlated
type-specific enhancers have crucial roles in neuronal
gene expression patterns in the perisylvian and cortical
Enhancers
areas. Selected highly correlated clusters of genes with the specification and development 128. For example, the tran-
A short region of DNA to which scription factor SOX5 (SRY (sex determining region Y)
proteins including transcription most restricted expression patterns are listed at the right
factors can bind to enhance side of columns. Red is higher level of expression, blue is -box 5) regulates connections of the neurons in the sub-
transcription levels of genes in lower expression. Part b is modified with permission from plate zone and cortical layer 6. Thus, subsets of such
gene clusters. REF. 125  (2009) Cell Press. transcription factors and their enhancers, may have

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led to the emergence of new gene expression patterns abilities, such as language, are also involved in disorders,
and neocortical areal phenotypes through recent evolu- such as autism, for which there is no accepted mouse
tionary modification129. These spatially comprehensive model137. Future analyses contrasting fetal human brain
expression data in the fetal neocortex have opened the gene networks with comparable data from mice (as has
door to the systematic investigation of the relationship been done for human and chimpanzee adult brains138
between recently evolved enhancers and transcriptional will provide new insights into the complex transcrip-
specificity. Genes that are differentially expressed in the tional and molecular underpinnings of cortical evolu-
developing human neocortex were associated with puta- tion and development of human specific neuronal and
tive recently evolved enhancers, providing a short list of synaptic organization.
candidate genes and regulatory elements for functional
characterization. The number of such associations was Conclusion
statistically disproportionate relative to the genome- The evo–devo approach might eventually elucidate the
wide frequency of such putative enhancers, providing advent of the human in the universe, achieved through
further evidence that the evolution of regulatory factors expansion and elaboration of the cerebral cortex. based
may have had an important role in the evolution of the on the recent findings from the descriptive and experi-
human cortex 125. mental embryonic studies of various mammalian species,
The recent data in humans125 have uncovered an we can develop realistic models of how gene mutations
order of magnitude of greater transcriptional differ- that influenced the fate of cell progenitors during evolu-
ences between neocortical areas than has been obtained tion affect neuron number, regulate their migration into
in comparable studies in rodents130,131. For example, the proper regions, promote formation of new phenotypes
gene CNTNAP2 (contactin associated protein-like 2), that establish new areas with new connections which
previously studied for its role in autism and specific lan- express particular sets of neurotransmitters and recep-
guage impairment132–135 is selectively and highly enriched tors. Neglecting or minimizing evolutionary differences
in the orbital prefrontal cortex, an area involved in regu- between the species may be among the reasons for the
lation of social behaviour in humans and has no com- failures of many clinical trials that were based exclusively
parable analogue in rodents124. The mouse homologue on the highly promising findings in rodents. However,
Cntnap2 has not been found to be expressed in any areal the evo–devo approach for the study of corticoneuro-
pattern or gradient in the mouse brain at any stage of genesis is not only important to the compelling problems
development 136 (m.b. Johnson and N. Sestan, personal of congenital disorders of higher cortical functions in
communication). This is an example of how unique humans, but also provides a hint about how we may have
structures and gene expression patterns that give rise to evolved to be masters of our destiny.
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Evolution of the neocortex:

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a Wild type Caspase 9 knockout between the formation of stereotypic, species-specific

New cell types and migratory pathways

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a Projection b The finding of evolutionarily novel origins that pro-

VF Predecessor neurons. The most recently discovered type

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