REVIEW
Renewed focus on the developing human neocortexGavin Clowry,1 Zoltan Molnar2 and Pasko Rakic3
1Institute of Neuroscience, Newcastle University, Newcastle upon Tyne, UK2Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK3Department of Neurobiology, Kavli Institute of Neuroscience, Yale University School of Medicine, New Haven, CT, USA
Abstract
Many specifically human psychiatric and neurological conditions have developmental origins. Rodent models
are extremely valuable for the investigation of brain development, but cannot provide insight into aspects that
are specifically human. The human brain, and particularly the cerebral cortex, has some unique genetic, molecu-
lar, cellular and anatomical features, and these need to be further explored. Cortical expansion in human is not
just quantitative; there are some novel types of neurons and cytoarchitectonic areas identified by their gene
expression, connectivity and functions that do not exist in rodents. Recent research into human brain develop-
ment has revealed more elaborated neurogenetic compartments, radial and tangential migration, transient cell
layers in the subplate, and a greater diversity of early-generated neurons, including predecessor neurons.
Recently there has been a renaissance of the study of human brain development because of these unique dif-
ferences, made possible by the availability of new techniques. This review gives a flavour of the recent studies
stemming from this renewed focus on the developing human brain.
Key words development; embryonic gene expression; human cerebral cortex; interstitial neurons; magnetic
resonance imaging; neurogenesis; neuronal migration; plasticity; prenatal and perinatal brain lesions; regenera-
tion; subplate.
Introduction
The initial discoveries of the basic cellular events and funda-
mental principles of the development of the vertebrate cen-
tral nervous system came from the classical histological
studies of postmortem human embryonic and fetal brains
at the turn of the 19th ⁄ 20th century (e.g. His, 1904; Hoch-
stetter, 1919). Although even today most neuroscientists
carry out research with the implicit intention of providing
insight into the development and workings of our own
brain and the hope of finding ways to treat human neuro-
logical and neuro-psychiatric diseases, by necessity the vast
majority of studies are carried out on animal models. The
reasons for this are obvious: one simply cannot contemplate
employing invasive techniques such as intracellular record-
ing, tract tracing, experimental anatomical manipulations
or in-vivo microdialysis and gene manipulations in humans.
Even where non-invasive techniques have been developed,
e.g. functional magnetic resonance imaging (MRI) or posi-
tron emission tomography scanning, they have considerable
limitations and are not easily adapted for babies, or for
in-utero examination. As a result, our understanding of the
mechanisms of cellular and pathological brain development
depends almost exclusively on information obtained from
animal models.
Enormous progress has been made by animal-based
research, but it is imperative to study, in addition, the devel-
opment of the brain directly on human tissue for several
powerful reasons. First, the human brain, and particularly
cerebral cortex, has some unique genetic, molecular, cellu-
lar and anatomical features. Second, many specifically
human psychiatric and neurological conditions have devel-
opmental origins. Third, it is very difficult to interpret and
extrapolate with certainty the data obtained in rodents to
understand aspects of human brain development including
evolutionarily novel traits. Fourth, it has been realized that
cortical expansion in primates is not just quantitative and
that there are some novel types of neurons and cytoarchi-
tectonic areas identified by their gene expression, connec-
tivity and functions that do not exist in rodents (Fig. 1).
Advances in molecular genetics and stem cell biology that
Correspondence
Gavin Clowry, Institute of Neuroscience, Newcastle University, Fram-
lington Place, Newcastle upon Tyne NE2 4HH, UK. E: g.j.clowry@
ncl.ac.uk;
Zoltan Molnar, Department of Physiology, Anatomy and Genetics, Le
Gros Clark Building, University of Oxford, South Parks Road, Oxford
OX1 3QX, UK. E: [email protected]
Accepted for publication 12 July 2010
ªª 2010 The AuthorsJournal of Anatomy ªª 2010 Anatomical Society of Great Britain and Ireland
J. Anat. (2010) 217, pp276–288 doi: 10.1111/j.1469-7580.2010.01281.x
Journal of Anatomy
enable the study of gene expression and the activity of
transcription factors directly on the tissue and cells of inter-
est have facilitated direct investigation of the developing
human brain. Furthermore, techniques for non-invasively
studying the immature human brain are improving rapidly
in both sophistication and resolution, allowing observations
that were not even contemplated a few years ago.
Recent progress in our understandingof human cortical development
In spite of all the obstacles and difficulties, there have been
considerable advances in our knowledge of the basic pat-
tern of human cortical development since the Committee
of the American Associations of Anatomists met in Boulder,
Colorado in 1970 to propose a unified nomenclature for
vertebrate brain development based on the human fetal
cerebrum (Boulder Committee, 1970; reviewed in Bystron
et al. 2008). New proliferative and transient cellular com-
partments in the developing cerebrum have been described
and characterized. Furthermore, our understanding of corti-
cal regionalization into cytoarchitectonic fields has
increased dramatically. For instance, the mechanisms lead-
ing to cortical arealization and its elaboration during evolu-
tion have been extensively studied. This is an important
conceptual and biomedical issue, as it addresses the ques-
tion of how the human cerebral cortex has acquired some
cognitive functions such as abstract thinking and language.
Principles of cortical arealization in human
The protomap hypothesis, originally proposed by Rakic
(1988), states that the proliferative ventricular zone of the
forebrain, by virtue of differential patterns of gene expres-
sion, maps out the prospective areal, laminar and columnar
organization of the cerebral cortex. According to this
hypothesis, postmitotic neurons at their birth close to the
cerebral ventricle potentially contain the genetic instruc-
tions essential for finding their final place of residence in
the cortex, where they form a basic species-specific pattern
of subcortical and cortico-cortical connection. Although
these connections can be refined by spontaneous and
extrinsic activity after their formation and modified in
response to injury, they are remarkably stereotyped in each
species (Brodmann, 1908; Rakic et al. 1991, 2009). This con-
cept stands in opposition to the protocortex hypothesis that
A B C
D
G
E F
~100 mya ~25 mya 0
Homo sapiens
Maccaqua mulata
Mus musculus
1 cm
Fig. 1 Cerebral hemispheres of the mouse (A), macaque monkey (B) and human (C) drawn at approximately the same scale to convey the overall
difference in the size and elaboration of the cerebral cortex. The pink overlay indicates the area of the prefrontal cortex that has no counterpart in
mouse. The coronal sections of the cerebral hemispheres of the same species (D–F) illustrate the relatively small increase in the thickness of the
neocortex compared with a large difference in surface of approximately 1 : 100 : 1000 in mouse, macaque monkey and human, respectively.
(G) The time-scale of phylogenetic divergence of Mus musculus, Maccaca mulata and Homo sapiens based on the DNA sequencing data. Modified
from Rakic (2009). Original panels are from the Comparative Mammalian Brain Collection: http://www.mirrorservice.org/sites/brainmuseum.org/
index.html.
ªª 2010 The AuthorsJournal of Anatomy ªª 2010 Anatomical Society of Great Britain and Ireland
Renewed focus on the developing human neocortex, G. Clowry et al. 277
states that all cortical neurons, at least at the onset of corti-
cal development, have the same potential, and that their
cell fate is driven entirely by external forces such as the
inputs from the specific thalamic nuclei (O’Leary, 1989). In
the past two decades the results of many studies, including
some from the initial proponents of the protocortex
hypothesis, have increasingly supported the validity of the
protomap model. For example, patterning centres in the
developing forebrain that secrete diffusible morphogenetic
proteins such as fibroblast growth factors, Wnts, sonic
hedgehog or bone morphogenetic proteins create gradi-
ents that can control gene expression even before the
formation of connections (Fukuchi-Shimogori & Grove,
2003; Cholfin & Rubenstein, 2007; O’Leary & Borngasser,
2006; O’Leary & Sahara, 2008). Even the final position and
phenotype of GABAergic interneurons, which were tradi-
tionally considered to be randomly dispersed, appear to be
determined at the time of their last cell division in the spe-
cific segments of the ganglionic eminence (Merkle et al.
2007; Batista-Brito et al. 2008). However, it is also evident
that, as complex areas are not fully mapped-out in the
germinal zone, environmental influences must also play an
important modulatory role during development (Rakic
et al. 2009).
Susan Lindsay and colleagues are investigating the origins
and location of patterning centres in the human forebrain
and have found differences between human and animal
models (Kerwin et al. 2010 in this issue). It has been shown
in mice that gene expression controlled by morphogenetic
gradients includes the expression of transcription factors
that in turn control the expression of cell–cell recognition
molecules and other markers that determine the phenotype
of neural cells (e.g. O’Leary & Borngasser, 2006; O’Leary &
Sahara, 2008; Rakic, 2009; Rakic et al. 2009). However,
Susan Lindsay has shown how an online atlas of the
developing human brain (The HUDSEN Atlas, http://
www.ncl.ac.uk/ihg/EADHB/; Wang et al. 2010b) can aug-
ment this concept and provide the essential information on
gene expression and interactive computer-based 3D models
that may be key to understanding the origin of many cogni-
tive disorders that cannot be obtained in any other way
(Johnson et al. 2009; Kerwin et al. 2010) (Fig. 2).
Nadhim Bayatti and colleagues have demonstrated how
patterns of gene expression that may represent protomaps
in the human neocortex show similarities with animal mod-
els but also important differences (Bayatti et al. 2008b; Ip
et al. 2010 in this issue), which need to be understood, con-
sidering the more complex pattern of arealization observed
in humans, and the large plasticity in arealization some-
times observed following a lesion early in human brain
development (Basu et al. 2010). Fruitful studies have been
made on the development of those regions of the cortex
Fig. 2 Subdivisions of the developing human
brain in a 3D virtual model of an embryo at
Carnegie Stage 22 (approximately 7–8
gestational weeks). Different regions have
been defined and presented in different
colours: pallium, red; subpallium, orange;
hypothalamus, brown; diencephalon, shades
of green; mesencephalon, blue;
metencephalon, shades of purple;
myelencephalon, magenta; spinal cord, dark
red; dorsal root ganglia, blue. For reference
the eye has been painted dark blue, and the
inner ear yellow. Figure provided by Dr Janet
Kerwin, Newcastle University (http://
www.HUDSEN.org).
ªª 2010 The AuthorsJournal of Anatomy ªª 2010 Anatomical Society of Great Britain and Ireland
Renewed focus on the developing human neocortex, G. Clowry et al.278
that show the greatest differences with other species in the
mature human brain, namely the frontal ⁄ prefrontal cortex,
perisylvian cortex and in particular Broca’s area, the site of
speech generation (Abrahams et al. 2007; Judas & Cepanec,
2007). A recent effort to profile gene expression in the
developing human cerebral cortex has revealed a human-
specific pattern and modifications, particularly in the areas
related to language, such as Broca and Wernicke (Johnson
et al. 2009). Pierre Vanderhaeghen and colleagues and
other groups have undertaken a transcriptome analysis of
these rapidly evolving brain regions (Pollard et al. 2006; see
also Konopka et al. 2009). The changes in developmental
gene expression patterns and their regulatory networks are
of particular importance for understanding the evolution-
ary processes involved in generating these cortical areas.
It is becoming increasingly clear that many psychiatric ill-
nesses may have developmental origins in the earliest
stages of formation of the neocortex. Not only autism, but
also schizophrenia and possibly even Alzheimer’s disease,
could be caused by interactions between genetic suscepti-
bility and environmental factors such as viral infection or
toxin exposure during pregnancy (Ben-Ari, 2008). Renzo
Guerrini has been involved in work identifying the genes
underlying abnormalities of the cortex leading to epilepsy,
including genes expressed at different stages of the devel-
opmental process, i.e. proliferation, migration and connec-
tion formation (Guerrini et al. 2008; Chioza et al. 2009). It is
also clear, however, that external events can interfere with
the timetable of development leading to brain malforma-
tion. Waney Squier and Anne Jansen have investigated
how stroke and brain injury in utero, during sensitive peri-
ods of development, as well as genetic malformations, lead
to epilepsy caused by the erroneous migration of inhibitory
interneurons (Hannan et al. 1999; Squier et al. 2003; Squier
& Jansen, 2010 in this issue). Alcohol, radiation, diet and
infection could all have an impact on cortical development.
Some very rare cases of brain injuries are associated with
diagnostic procedures (Squier et al. 2000). Pasko Rakic has
even suggested that ultrasound examination may impede
the migration of developing neurons in embryonic mouse
cortex (Ang et al. 2006) and work on this subject in non-
human primates is underway. Laurence Garey has presented
data suggesting that a specific loss of synaptic connectivity
in restricted regions of the cortex in schizophrenics has a
neurodevelopmental origin (Lynch et al. 2002; Garey, 2010
in this issue); but is the trigger genetic, or environmental, or
both?
The limitations of studies on non-humancortical development
One of the challenges for the future is to map developmen-
tal events precisely in the human in terms of the timing and
location of both gene expression and significant events
such as neurogenesis, migration and axon pathway forma-
tion. Currently, such studies are being performed in animal
models, particularly mice, because of the availability of
transgenic techniques, and stunning progress is being made
[Caviness & Rakic, 1978; Goffinet & Rakic, 2000; Bult et al.
2008; Mouse Genome Informatics (MGI) resource at the
Jackson Laboratory: http://www.informatics.jax.org]. How-
ever, we need to find detailed and precise species-specific
differences in the other cortical areas during mouse and
human development in order to safely interpret the results
of mouse studies with regard to understanding human
brain development, and to be aware when mouse–human
extrapolations are not appropriate (Manger et al. 2008).
Irina Bystron has shown that in human forebrain, unlike
rodent, predecessor cells migrate into the cortical primor-
dium from the subpallium even before local neurogenesis
has begun (Bystron et al. 2005, 2006; Carney et al. 2007).
Predecessor neurons, which migrate tangentially from
lower segments of the neuraxis, might initiate the onset of
local neurogenesis via pial contacts with stem cells (Fig. 3A).
However, there are also other human-specific cell types that
migrate tangentially between different brain subdivisions,
most of which emerge during later stages of prenatal devel-
opment (reviewed by Bystron et al., 2008). One of these is
tangential migration of GABAergic inerneurons from the
ganglionic eminence situated in the ventral telencephalon
to the pulvinar and lateral posterior nucleus of the thala-
mus in the diencephalon (Rakic & Sidman, 1969; Letinic &
Rakic, 2001). These neurons stream through an easily
detectable transient structure – the corpus gangliothalami-
cus – that is located beneath the surface of the pulvinar
adjacent to the telo-diencephalic sulcus in human fetuses
between 18 and 34 weeks of gestational age (GA)
(Fig. 4A–C) (Rakic & Sidman, 1969). More recent studies
using immunohistochemistry, DiI (1,1¢-dioctadecyl-3,3,3¢,3¢-tetramethylindocarbocyanine perchlorate) labelling and
organotypic culture assays indicate that these migrating
neurons are glutamate decarboxylase- and distal-less gene-
positive and guided by homotypic–neurophilic cues
(Fig. 4C–F) (Letinic & Rakic, 2001). The corpus gangliotha-
lamicus and the migrating cells could not be identified in
any non-human species so far examined including rodents,
carnivores and even non-human primates. Although the
human corpus gangliothalamicus contains more cells than
the entire mouse ganglionic eminence, and was discovered
over 40 years ago (Rakic & Sidman, 1969), only two addi-
tional studies (Letinic & Kostovic, 1997; Letinic & Rakic,
2001) have so far been devoted to it, in spite of the fact
that it is probably functionally and biomedically very impor-
tant. For example, the human pulvinar is reciprocally con-
nected to the Broca and Wernicke areas and, based on
stimulation studies, it has been proposed that it is involved
in the processing of language and in specific forms of ano-
mias (Ojemann et al. 1968; Ojeman, 1984). These observa-
tions all suggest that cortical evolution must be viewed
together with the evolution of the thalamus.
ªª 2010 The AuthorsJournal of Anatomy ªª 2010 Anatomical Society of Great Britain and Ireland
Renewed focus on the developing human neocortex, G. Clowry et al. 279
The difference in the size and composition of the subven-
tricular zone in human and non-human species may be
equally important. Studies of embryonic forebrain at a ser-
ies of stages reveal that the subventricular zone in human is
not only much larger than that of other species (Sidman &
Rakic 1973, 1982; Rakic & Sidman, 1968) but that it also
appears earlier in development and contains displaced
radial glial cells that enhance cortical evolutionary expan-
MZ
CP
SP
IZ
OSVZ
VZ
ISVZ
G
B
C
CP
H3/4A
4
H3/4A
4SPIZ
SVZ
VZ
VZ
A
D E F
TBR2
SATB2
Fig. 3 Cerebral cortical germinal zone during neurogenesis and the first postmitotic neurons of the human brain. (A) The first postmitotic neurons,
the predecessor neurons in the primordial plexiform layer (PPL) of the human cerebral cortex, were revealed with TU-20 immunostaining (orange)
in a coronal section of a Carnegie Stage 13 (4–4.5 gestational weeks) dorsal cortex. The predecessor cells and their tangentially oriented processes
populate the PPL in the telencephalon, with a clear basal-to-dorsal density gradient prior to local cortical neurogenesis. They are not
immunoreactive to reelin. Reelin-expressing Cajal-Retzius cells in mouse embryo cortex at embryonic day 14 (B) and in human fetus cortex at 21
gestational weeks (C). Cajal-Retzius cells increase in numbers and morphological complexity in mammals. Scale bars: 40 lm (B), 20 lm (C). (D–F)
At 11 gestational weeks, the human cortical germinal zone consists of the ventricular and subventricular zones (VZ and SVZ, respectively). The
intermediate zone (IZ), subplate (SP), cortical plate (CP) and marginal zone (MZ) were also present in the developing cortical wall as revealed by
bisbenzimide (blue). H3+ cells were prominent in the VZ and extraventricular compartments. Expression of H3 and 4A4 was studied with double
immunohistochemistry (E) and co-expression in these cells was confirmed by confocal microscopy (F), H3 (red) and 4A4 (green). 4A4
immunoreactivity was primarily restricted to the VZ ⁄ SVZ although double-positive cells were present in the apical portion of the IZ. The arrowhead
indicates a single-labelled pH3-immunorective profile in the SVZ; the small arrow depicts a similar profile in the IZ. A pial-directed process
originating from a radial glia in the VZ is indicated by a thick arrow. (G) Further compartmentalization of the germinal zone to internal SVZ (ISVZ)
and outer SVZ (OSVZ) is apparent at 12 gestational weeks on a TBR2- and SATB2-immunostained cerebral cortical slice. TBR2, expressed by
intermediate neuronal progenitor cells, marks out the proliferative zones, whereas SATB2, expressed by some postmitotic neurons, marks out the
IZ, SP, CP and MZ. All parts of this figure are reproduced with permission: A is from Bystron et al. (2006); B,C from Molnar et al. (2006); D–F
from Carney et al. (2007); and G was kindly provided by Bui Kar Ip (Newcastle University).
ªª 2010 The AuthorsJournal of Anatomy ªª 2010 Anatomical Society of Great Britain and Ireland
Renewed focus on the developing human neocortex, G. Clowry et al.280
sion and elaboration (Schmechel & Rakic, 1979; Carney
et al., 2007; Molnar et al. 2006; Bayatti et al. 2008a; Bystron
et al. 2008; Fish et al. 2008; Hansen et al. 2010; Fietz et al.
2010). Furthermore, it contains a distinct outer and inner
sublayer that is also present in non-human primates but not
in rodents (Smart et al. 2002; Lukaszewicz et al. 2006; Han-
sen et al. 2010; Fietz et al. 2010) (Fig. 3D–G).
Human-specific aspects of the earliest stagesof cortical development
Gundela Meyer has shown that the earliest cortical struc-
ture, the preplate, has a more complex structure in humans
than in rodents (Meyer, 2007, 2010 in this issue) (Fig. 3B,C).
It includes the Cajal-Retzius cells, important in guiding cell
migration, and pioneer neurons that form the first axons to
leave the cortex (Suarez-Sola et al. 2009). The role of both
of these early-generated cell populations may be a good
deal more complicated in human than in rodent. In addi-
tion, layer I in the fetal cerebral cortex of human and non-
human primates contains a large subpial granular layer that
does not exist in rodents and other animals (Brun, 1965;
Gadisseux et al. 1992; Zecevic and Rakic, 2001). This tran-
sient proliferative layer may produce interneurons that are
involved in human-specific psychiatric disorders. Pierre
Vanderhaeghen and colleagues have identified an RNA
gene that is rapidly evolving in humans and is expressed by
Cajal-Retzius cells (Pollard et al. 2006). Milos Judas has
described a population of nitrinergic interstitial neurons
that transiently populate the fetal white matter and are dis-
tinct from subplate neurons. Re-examination of the original
publications and material has revealed that interstitial neu-
rons, subplate neurons and the subplate zone were first
observed and variously described in large brains of gyrence-
phalic mammals (including human), characterized by an
abundant white matter and slow and protracted prenatal
and postnatal development (Judas et al. 2010a,b, both in
this issue). These fetal interstitial neurons are poorly deve-
GE CGT
0.1 mm
P
E
DA B
F
CGT
P
C
Fig. 4 A transient, human-specific structure, the corpus gangliothalamicus (CGT), is situated close to the telo-diencephalic junction, between the
telecephalic ganglionic eminence (GE) and dorsal thalamus (DT) in human fetal cerebrum. Semi-diagrammatic drawings of the human thalamus at
10 (A) and 24 (B) gestational weeks showing early genesis of thalamic neurons from the local proliferative ependyma, now called ventricular zone
and their migration from the GE via the corpus gargliothalamises (CGT) to the pulvinar (P) at early and late fetal stages, respectively. (C) CGT at
the surface of the pulvinar (P) in a human 18 gestational week fetus stained with Cresyl violet. (D) Drawing of the Golgi-impregnated images of
migrating neurons in the CGT and transitional forms to neurons beneath. (E) Neurons in the CGT double-immunostained with GE-specific marker
Dlx 1 ⁄ 2 and Tuj1 and GABA are indicated with arrows and asterisks, respectively. (F) Use of organotypic cultures to assay the attractive effect of
the human DT and the repellent effect of the mouse and human choroid plexus (CP) and mouse subthalamic nucleus (S) on neurons migrating
from the explants of the human GE. A–D from Rakic & Sidman (1969); E,F from Letinic & Rakic (2001). 3v, third ventricle; C, caudate nucleus; Cl,
clausfrum; CM, centrum medianum; GE, ganglionic eminence; GP, globus pallidus; LV, lateral ventricle; H, hippocampus.
ªª 2010 The AuthorsJournal of Anatomy ªª 2010 Anatomical Society of Great Britain and Ireland
Renewed focus on the developing human neocortex, G. Clowry et al. 281
loped or absent in the brains of rodents but they represent
a prominent feature of the significantly enlarged white
matter of human and non-human primate brains (Kostovic
& Rakic, 1980; Suarez-Sola et al. 2009). The number of inter-
stitial neurons subjacent to some cortical areas is larger than
the number of the thalamic neurons that project into these
areas, yet their function and possible role in human mental
disorder is completely unknown.
The cortical subplate shows important differences
between human and rodents (reviewed by Ayoub & Kosto-
vic, 2009; Kanold & Luhmann, 2010; Wang et al. 2010b in
this issue). This transient, developmental structure is the first
site of synapse formation in the cortex and the first region
to receive inputs from the thalamus and other regions; its
functioning is crucial to establishing the correct wiring and
functional maturation of the cerebral cortex. For example,
the subplate zone reaches its largest size and survives lon-
gest in the regions subjacent to the association cortices that
contain transient cortico-cortical and callosal connections
before they enter the cortical plate (Kostovic & Rakic, 1990).
More recently, Ivica Kostovic and Mary Rutherford have car-
ried out extensive research comparing MRI data with histo-
logical sections to demonstrate how vastly larger and more
elaborate the human subplate is compared with that of
other species (Kostovic et al. 2002; Kostovic & Vasung, 2009;
Perkins et al. 2008; Wang et al. 2010b in this issue). Donna
Ferriero has demonstrated the vulnerability of the subplate
in premature babies with in-vivo imaging (McQuillen &
Ferriero, 2005; Ferriero & Miller, 2010 in this issue). We have
presented data showing the evolution and changes in gene
expression and complexity of the subplate between species
(Hoerder-Suabedissen et al. 2009; Wang et al. 2009; Bayatti
et al. 2008a; Wang et al. 2010b in this issue). Recently it has
been shown that during human fetal brain development in
some of the prospective association areas, such as the pre-
frontal cortex, sets of genes are expressed that are not
expressed in rodents (Johnson et al. 2009).
Another significant rodent ⁄ primate species difference is
in the manner of origin of inhibitory interneurons in the
neocortex. A remarkable discovery made in rodents was
that these interneurons are born almost entirely outside
the dorsal telencephalon, in the subpallium, from which
they migrate tangentially into the cortex (reviewed in
Marin & Rubenstein, 2001). However, it has also been
shown by Rakic and colleagues, using immunohistochemis-
try and retroviral labelling of slice preparations, that at later
stages of human fetal development in some areas, e.g. pro-
spective visual cortex, the majority of interneurons are actu-
ally generated within the cortical progenitor zones (Letinic
et al. 2002). This interpretation was supported by the use of
double-label immunohistochemistry (Zecevic et al. 2005;
Mo & Zecevic, 2008) and in the analysis of malformations
that involve deletion of the ganglionic eminence (Fertuzin-
hos et al. 2009). Studies carried out in non-human primates
have confirmed this to be the case at least in the macaque
monkey (Petanjek et al. 2009). However, the most recent
immunohistochemical study of the 15 GA human did not
reveal double GABA-labelled postmitotic cells in the sub-
ventricular zone (Hansen et al. 2010), whereas they were
detected in 20 GA fetus (Zecevic et al. 2010). Clearly, this
field needs more work to delineate the specific areas and
stages of prolonged human development at which the
appropriate complement of distinct inerneuronal subtypes
is received. This is an important issue as failures in prolifera-
tion and migration of the specific classes of inhibitory inter-
neurons have been implicated in diverse conditions
including autism, epilepsy and schizophrenia, and we must
question whether our mouse models are appropriate for
the study of these diseases (Levitt, 2005; Lewis & Hashimoto,
2007; Jones, 2009; Hannan et al. 1999) (Fig. 5E).
Brain development cannot be understood without con-
templating the associated vascular development. Several
interactions have been described recently between the
developing nervous system and its vasculature (Javaherian
& Kriegstein, 2009; Stubbs et al. 2009; Nie et al. 2010). Some
of the signalling molecules involved in vascular develop-
ment are also involved in the formation of the blood–brain
barrier (Daneman et al. 2009). Kjeld Møllgard and col-
leagues have highlighted the differences between the
development of the blood–brain barrier and other inter-
faces between blood, cerebrospinal fluid and extracellular
fluid in the brain in humans and other species, and the
importance of these barriers in controlling the access of
morphogenetic molecules to receptors on brain cells (Saun-
ders et al. 1991, 2008).
The impact of imaging techniques inmapping human brain development
The rapid advancement of MRI is allowing important pro-
gress in the understanding of normal and pathological
human brain development. Structural MRI data from scan-
ning in vivo, in utero and postmortem, combined with
diffusion tensor imaging, are allowing us to map develop-
ment of the human brain. The growth of axon pathways
and the relative rates of growth of different regions of the
cortex in terms of relative grey and white matter volumes,
and the duration of transient structures such as the sub-
ventricular zone and subplate, may now all be examined in
this way. Ivica Kostovic, who made the original discovery
of the subplate zone (see Kostovic & Rakic, 1990), has more
recently compared diffusion tensor imaging studies with
histological sections to illustrate axon pathway formation
in the forebrain (Kostovic & Vasung, 2009; Vasung et al.
2010) (Fig. 5). Petra Huppi and Mary Rutherford have com-
pared data obtained from the perinatal imaging of both
healthy babies and babies with potential neonatal brain
injury in the hope that scanning can be used confidently
to predict the outcome of perinatal strokes or hypoxic epi-
sodes in premature babies (Ment et al. 2009; Rutherford
ªª 2010 The AuthorsJournal of Anatomy ªª 2010 Anatomical Society of Great Britain and Ireland
Renewed focus on the developing human neocortex, G. Clowry et al.282
et al. 2010). 3D MRI has been employed to measure brain
tissue volumes (cerebral cortical grey matter, white matter),
surface area and the sulcation index and has shown cortical
phenotypes associated with early behavioural development
measured with neurobehavioral assessment at term and
later in development. There is a close relationship between
the cortical surface at birth and neurobehavioral scores
(Dubois et al. 2008). Huppi and colleagues have mapped
E
A CB
D
Fig. 5 Magnetic resonance imaging (MRI) and histological investigations on subplate neurons in human and development of early human cortical
circuits. (A) In-utero MRI of the fetal subplate. The layers of the hemisphere are clearly seen on the T2-weighted single-shot images in the coronal
plane acquired in a fetus at 23 gestational weeks using a 1.5 T scanner. The subplate is seen as high signal intensity, reflecting its hydrophilic
extracellular matrix. At this stage of development the subplate is thicker than the cortex. The developing white matter has a low signal intensity
band reflecting increased cellular content (reproduced with permission from Wang et al. 2010b this issue). Low-power view of T1-weighted MRI
(B) and Periodic acid-Schiff (PAS)-stained coronal sections (C) through the brains of premature newborns at 36 gestational weeks demonstrating
the gradual dissolution of the subplate zone. Reproduced with permission from Kostovic et al. (2002). (D) Schematic summary of the neuronal
elements involved in early human cortical circuits superimposed on a Nissl-stained section of a 34 gestational week preterm human infant. This
period is characterized by the co-existence of transient circuitry in the subplate zone and elaboration of permanent (sensory-driven) circuitry in the
cortical plate. Note the initial six layers (I–VI) and the increase in GABAergic neurons (white circles) in the cortical plate. GABAergic neurons, black
circles; glutamatergic neurons, red diamond; cortical plate neurons, violet. Afferents from the basal forebrain (bf, blue), monoaminergic brain stem
nuclei (tegm, green) and thalamus (th, red). call, callosal fibers; wm, white matter; svz, subventricular zone; vz, ventricular zone. Reproduced with
permission from Kostovic & Judas (2007). (E) Neuronal heterotopias are seen in various pathologies and are associated with intractable epilepsy.
Studies using histological and carbocyanine dye (1,1¢-dioctadecyl-3,3,3¢,3¢-tetramethylindocarbocyanine perchlorate) tracing techniques in selected
cases of subcortical or periventricular nodular heterotopia revealed abnormally differentiated neurons with altered connectivity. Bisbenzimide
labelling (blue) reveals the cells and boundaries of the nodules and DiI labelling (orange) demonstrates the vast majority of labelled fibres coursing
around but not within the nodules. Some fibres are extending across the margin of the nodule and have punctate termini close to cell bodies
within the nodules. Reproduced with permission from Hannan et al. (1999).
ªª 2010 The AuthorsJournal of Anatomy ªª 2010 Anatomical Society of Great Britain and Ireland
Renewed focus on the developing human neocortex, G. Clowry et al. 283
the development of early asymmetries over the immature
cortex, and voxel-based analyses of cortical and white mat-
ter masks were performed over a group of newborns from
26 to 36 gestational weeks (Dubois et al. 2010). Interindi-
vidual variations were first detected in large cerebral
regions and the right and left hemispheres were compared
(Fig. 6). The first asymmetric cortical areas were in the left
perisylvian regions. This suggests the emergence of ana-
tomical lateralization in language processing prior to lan-
guage exposure (Dubois et al. 2010).
The outcome of injury in the developingbrain differs from effects in the adult
Donna Ferreiro and colleagues have imaged the biochemis-
try of hypoxia in the developing human brain (Vigneron,
a: Increases b: Decreases c: Superimposedin cortex
a: Asymmetriesin cortex
in white matter
in white matter
Cortex
6
L
R
L
R
T
0
6
T
0
White matterBoth
Cortex
White matterBoth
Most significant clusters
clusters
c: Superimposedb: Asymmetriesclusters
Fig. 6 Age-associated interindividual variations in cortical development have been studied with non-invasive magnetic resonance imaging.
Postprocessing of high-quality T1- and T2-weighted images enabled the segmentation of the cortex in large regions across both hemispheres of
the brain. Dedicated postprocessing tools enabled the quantitative study of the variations with increases in the cortex (a) and decreases in white
matter (b) for the left (L, up) and right (R, down) hemispheres in the preterm newborn. The first two rows show statistical T-maps (colour coded
blue to red) that are superposed to the 3D averaged cortical surface. Significant clusters showing ‘apparent increases’ in cortex (a) and ‘apparent
decreases’ in white matter (b). (c) The clusters for the cortex (blue) and white matter (red) had considerable overlay (black). Note that the right
hemisphere shows larger regions of age-associated variations in comparison with the left. In the third row, statistical T-maps are presented with
the most significant clusters along the horizontal, coronal and parasagittal planes. In the lower two rows interhemispherical asymmetries are
shown in the preterm group; statistical T-maps are superposed to the 3D averaged cortical surface in the significant clusters showing asymmetries
in cortex (a) and white matter (b), for the left (L, up) and right (R, down) hemispheres. The clusters (c) for cortex (blue) and white matter (red) are
mainly overlying (black). Reproduced with permission from Dubois et al. (2010).
ªª 2010 The AuthorsJournal of Anatomy ªª 2010 Anatomical Society of Great Britain and Ireland
Renewed focus on the developing human neocortex, G. Clowry et al.284
2006) and shown the delayed development of myelination
of the affected axon tracts (McQuillen & Ferriero, 2005;
Miller & Ferriero, 2009; Ferriero & Miller, 2010 in this issue).
Catherine Verney and Mary Rutherford have described how
microglia colonize the developing human telencephalon
and the role that they play in white matter injury (Monier
et al. 2007; Verney et al. 2010 in this issue).
Injury to the cortex and to subcortical white matter tracts
leads to conditions such as cerebral palsy that can involve
functional reorganization of cortical areas and projections.
James Bourne has described how multiple cortical visual
areas develop in the primate brain (Bourne & Rosa, 2006;
Burman et al. 2007; Bourne, 2010 in this issue) and has
shown that focal lesions in the immature brain lead to reor-
ganization of the cortex in different ways to lesions in the
adult brain, an issue that has been addressed in various
model systems (Huffman et al. 1999). Similarly, Janet Eyre
and colleagues and Martin Staudt and colleagues have used
a battery of techniques, including MRI and neurophysiolog-
ical recordings in human subjects, to investigate different
types of reorganization of the sensorimotor cortex and cort-
icospinal tract in response to developmental lesions as com-
pared with the effects of lesions in the adult (Basu et al.
2010; Eyre et al. 2007; Walther et al. 2009; Staudt, 2010 in
this issue). Martin Staudt and colleagues showed that when
a lesion prevents formation of a direct pathway from the
origin to the appropriate target the axonal tracts extend
around the lesion and nevertheless reach appropriate tar-
gets, directly supporting the principle of the protomap
hypothesis (Rakic, 1988) in the human brain. Older concepts
of plasticity regarded the immature brain as inherently
more plastic and able to overcome lesions; however, we
now understand that aberrant plasticity in response to
lesions can lead to the symptoms of cerebral palsy and
related conditions (Clowry, 2007; Eyre, 2007). With improve-
ments in imaging now allowing us to predict more accu-
rately the outcome of neurodevelopmental lesions, could
we, in the future, intervene to guide plasticity along a
reparative course?
It is inevitable that further developments in this field will
require national and international coordination of research.
Recent developments in human embryonic brain banking in
the UK (Lindsay & Copp, 2005), the on-line encyclopedia-
type project MOCA (Museum of Comparative Anthropoge-
ny), the emerging mouse and human gene expression
databases [Allen Brain Institute; Jones et al. 2009; Gensat,
International Coordinating Facility (INCF) for Informatics]
and clinical image libraries now provide excellent opportu-
nities for accelerated progress in understanding develop-
ment of the human neocortex. The next generation of
sequencing methods and developments in bioinformatics
will enable us to lift the platform of our analysis to a much
higher level, with global transcriptome analysis during
development and in disease (Johnson et al. 2009). It is
imperative that the knowledge and the implications of the
fundamental observations are transferred to the clinic in a
timely fashion. We hope that the reviews presented in this
issue will facilitate and enhance the dialogue between basic
researchers and clinicians.
Acknowledgements
We are grateful to members of our laboratories and to Gillian
Morriss-Kay for critically reading various versions of this manu-
script.
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