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: zoltan.molnar@dpag.ox.ac.uk

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.

References

Abrahams BS, Tentler D, Perederiy JV, et al. (2007) Genome

wide analyses of human perisylvian cerebral cortical

patterning. Proc Natl Acad Sci USA 104, 17849–17854.

Ang ES Jr, Gluncic V, Duque A, et al. (2006) Prenatal exposure

to ultrasound waves impacts neuronal migration in mice. Proc

Natl Acad Sci USA 103, 12903–12910.

Ayoub AE, Kostovic I (2009) New horizons for the subplate zone

and its pioneering neurons. Cereb Cortex 19, 1705–1707.

Basu A, Graziadio S, Smith M, et al. (2010) Developmental

plasticity connects visual cortex to motoneurons after stroke.

Ann Neurol 67, 132–136.

Batista-Brito R, Machold R, Klein C, et al. (2008) Gene

expression in cortical interneuron precursors is prescient of

their mature function. Cereb Cortex 18, 2306–2317.

Bayatti N, Moss JA, Sun L, et al. (2008a) A molecular

neuroanatomical study of the developing human neocortex

from 8 to 17 postconceptional weeks revealing the early

differentiation of the subplate and subventricular zone. Cereb

Cortex 18, 1536–1548.

Bayatti N, Sarma S, Shaw C, et al. (2008b) Progressive loss of

PAX6, TBR2, NEUROD and TBR1 mRNA gradients correlates

with translocation of EMX2 to the cortical plate during

human cortical development. Eur J Neurosci 28, 1449–1456.

Ben-Ari Y (2008) Neuro-archaeology: pre-symptomatic archi-

tecture and signature of neurological disorders. Trends

Neurosci 31, 626–636.

Boulder Committee (1970) Embryonic vertebrate central nervous

system: revised terminology. Anat Rec 166, 257–261.

Bourne JA (2010) Unravelling the development of the visual cor-

tex: implications for plasticity and repair. J Anat 217, 449–468.

Bourne JA, Rosa MG (2006) Hierarchical development of the

primate visual cortex, as revealed by neurofilament

immunoreactivity: early maturation of the middle temporal

area (MT). Cereb Cortex 16, 405–414.

Brodmann K (1908) Beitraege zur histologischen Lokalisation

der Grosshirnrinde. VI. Mitteilung: Die Cortexgliederung des

Menschen. J Psychol Neurol 10, 231–246.

Brun A (1965) The subpial granular layer of the foetal cerebral

cortex in man. Its ontogeny and significance in congenital

cortical malformations. Acta Pathol Microbiol Scand 179(Suppl),

3–98.

Bult CJ, Eppig JT, Kadin JA, et al. (2008) The Mouse Genome

Database (MGD): mouse biology and model systems. Nucleic

Acids Res 36(Database issue), D724–D728.

Burman KJ, Lui LL, Rosa MG, et al. (2007) Development of non-

phosphorylated neurofilament protein expression in neurones

of the New World monkey dorsolateral frontal cortex. Eur J

Neurosci 25, 1767–1779.

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. 285

Bystron I, Molnar Z, Otellin V, et al. (2005) Tangential networks

of precocious neurons and early axonal outgrowth in the

embryonic human forebrain. J Neurosci 25, 2781–2792.

Bystron I, Rakic P, Molnar Z, et al. (2006) The first neurons of

the human cerebral cortex. Nat Neurosci 9, 880–886.

Bystron I, Blakemore C, Rakic P (2008) Development of the

human cerebral cortex: Boulder Committee revisited. Nat Rev

Neurosci 9, 110–122.

Carney RSE, Bystron I, Lopez-Bendito G, et al. (2007)

Developmental changes in pre- and post-cortical plate

formation patterns of abventricular mitoses in rodent and

human cortex. Brain Struct Funct 212, 37–54.

Caviness VS Jr, Rakic P (1978) Mechanisms of cortical

development: a view from mutations in mice. Ann Rev

Neurosci 1, 297–326.

Chioza BA, Aicardi J, Aschauer H, et al. (2009) Genome wide

high density SNP-based linkage analysis of childhood absence

epilepsy identifies a susceptibility locus on chromosome 3p23-

p14. Epilepsy Res 87, 247–255.

Cholfin JA, Rubenstein JL (2007) Patterning of frontal cortex

subdivisions by Fgf17. Proc Natl Acad Sci USA 104, 7652–7657.

Clowry GJ (2007) The dependence of spinal cord development

on corticospinal input and its significance in understanding

and treating spastic cerebral palsy. Neurosci Biobehav Rev 31,

1114–1124.

Daneman R, Agalliu D, Zhou L, et al. (2009) Wnt ⁄ beta-catenin

signaling is required for CNS, but not non-CNS, angiogenesis.

Proc Natl Acad Sci USA 106, 641–646.

Dubois J, Benders M, Borradori-Tolsa C, et al. (2008) Primary

cortical folding in the human newborn: an early marker of

later functional development. Brain 131, 2028–2041.

Dubois J, Benders M, Lazeyras F, et al. (2010) Structural

asymmetries of perisylvian regions in the preterm newborn.

Neuroimage 52, 32–42.

Eyre JA (2007) Corticospinal tract development and its

plasticity after perinatal injury. Neurosci Biobehav Rev 31,

1136–1149.

Eyre JA, Smith M, Dabydeen L, et al. (2007) Is hemiplegic

cerebral palsy equivalent to amblyopia of the corticospinal

system? Ann Neurol 62, 493–503.

Ferriero DM, Miller SP (2010) Imaging selective vulnerability in

the developing nervous system. J Anat 217, 429–435.

Fertuzinhos S, Krsnik Z, Kawasawa YI, et al. (2009) Selective

depletion of molecularly defined cortical interneurons in

human holoprosencephaly with severe striatal hypoplasia.

Cereb Cortex 19, 2196–2207.

Fietz SA, Kelava I, Vogt J, et al. (2010) OSVZ progenitors of

human and ferret neocortex are epithelial-like and expand by

integrin signaling. Nat Neurosci 13, 690–699.

Fish JL, Dehay C, Kennedy H, et al. (2008) Making bigger brains

– the evolution of neural-progenitor-cell division. J Cell Sci

121 (Pt 17), 2783–2793.

Fukuchi-Shimogori T, Grove EA (2003) Emx2 patterns the

neocortex by regulating FGF positional signaling. Nat Neurosci

6, 825–831.

Gadisseux JF, Goffinet AM, Lyon G, et al. (1992) The human

transient subpial granular layer: an optical, immunohisto-

chemical, and ultrastructural analysis. J Comp Neurol 324, 94–

114.

Garey L (2010) When cortical development goes wrong:

schizophrenia as a neurodevelopmental disease of micro-

circuits. J Anat 217, 324–333.

Goffinet AM, Rakic P (eds) (2000) Mouse Brain Development

Results and Problems in Cell Differentiation. p. 339. Bernon,

NewYork: Springer-Verlag.

Guerrini R, Dobyns WB, Barkovich JA (2008) Abnormal

development of the human cerebral cortex: genetics,

functional consequences and treatment options. Trends

Neurosci 31, 154–162.

Hannan AJ, Servotte S, Katsnelson A, et al. (1999) Character-

ization of nodular neuronal heterotopia in children. Brain

122, 219–238.

Hansen DV, Lui HJ, Parker PRL, et al. (2010) Neurogenic radial

glia in the outer subventricular zone. Nature (14 February

2010) doi:10.1038/Nature08845.

His W (1904) Die entwicklung des menschlichen Gehirns

wahrend der ersten Monate. p. 176. Leipzig: Hirzel.

Hochstetter F (1919) Beitrage zur Entwicklungsgeschichte des

menschlichen Gehirns I. p. 170. Vienna: Dueticke.

Hoerder-Suabedissen A, Wang WZ, Lee S, et al. (2009) Novel

markers reveal subpopulations of subplate neurons in the

murine cerebral cortex. Cereb Cortex 9, 1738–1750.

Huffman K, Molnar Z, van Dellen A, et al. (1999) Compression

of sensory fields on a reduced cortical sheet. J Neurosci 19,

9939–9952.

Ip BK, Wappler I, Peters H, et al. (2010) Investigating gradients

of gene expression involved in early human cortical

development. J Anat 217, 300–311.

Javaherian A, Kriegstein A (2009) A stem cell niche for

intermediate progenitor cells of the embryonic cortex. Cereb

Cortex 19 (Suppl 1), i70–i77.

Johnson MB, Imamura Kawasawa Y, Mason CE, et al. (2009)

Functional and evolutionary insights into human brain

development through global transcriptome analysis. Neuron

62, 494–509.

Jones EG (2009) The origins of cortical interneurons: mouse

versus monkey and human. Cereb Cortex 19, 1953–1956.

Jones AR, Overly CC, Sunkin SM (2009) The Allen Brain Atlas:

5 years and beyond. Nat Rev Neurosci 10, 821–828.

Judas M, Cepanec M (2007) Adult structure and developments

of the human fronto-opercular cerebral cortex (Broca’s

region). Clin Linguist Phon 21, 975–989.

Judas M, Sedmak G, Pletikos M (2010a) Early history of subplate

and interstitial neurons: from Theodor Meynert (1867) to the

discovery of the subplate zone (1974). J Anat 217, 344–367.

Judas M, Sedmak G, Pletikos M, et al. (2010b) Populations of

subplate and interstitial neurons in fetal and adult human

telencephalon. J Anat 217, 381–399.

Kanold PO, Luhmann HJ (2010) The subplate and early cortical

circuits. Annu Rev Neurosci 33, 23–48.

Kerwin J, Yang Y, Merchan P, et al. (2010) The HUDSEN Atlas: a

three-dimensional (3D) spatial framework for studying gene

expression in the developing human brain. J Anat 217, 289–299.

Konopka G, Bomar JM, Winden K, et al. (2009) Human-specific

transcriptional regulation of CNS development genes by

FOXP2. Nature 462, 213–217.

Kostovic I, Judas M (2007) Transient patterns of cortical

lamination during prenatal life: do they have implications for

treatment? Neurosci Biobehav Rev 31, 1157–1168.

Kostovic I, Rakic P (1980) Cytology and time of origin of

interstitial neurons in the white matter in infant and adult

human and monkey telencephalon. J Neurocytol 9, 219–242.

Kostovic I, Rakic P (1990) Developmental history of the transient

subplate zone in the visual and somatosensory cortex of the

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.286

macaque monkey and human brain. J Comp Neurol 297, 441–

470.

Kostovic I, Vasung L (2009) Insights from in vitro fetal magnetic

resonance imaging of cerebral development. Semin Perinatol

33, 220–233.

Kostovic I, Judas M, Rados M, et al. (2002) Laminar organization

of the human fetal cerebrum revealed by histochemical markers

and magnetic resonance imaging. Cereb Cortex 12, 536–544.

Letinic K, Kostovic I (1997) Transient fetal structure, the

gangliothalamic body, connects telencephalic germinal zone

with all thalamic regions in the developing human brain.

J Comp Neurol 384, 373–395.

Letinic K, Rakic P (2001) Telencephalic origin of human thalamic

GABAergic neurons. Nat Neurosci 4, 931–936.

Letinic K, Zoncu R, Rakic P (2002) Origin of GABAergic neurons

in the human neocortex. Nature 417, 645–649.

Levitt P (2005) Disruption of interneuron development. Epilepsia

46(Suppl 7), 22–28.

Lewis DA, Hashimoto T (2007) Deciphering the disease process

of schizophrenia: the contribution of cortical GABAergic

neurons. Int Rev Neurobiol 78, 109–131.

Lindsay S, Copp AJ (2005) MRC-Wellcome Trust Human Develop-

mental Biology Resource: enabling studies of human

developmental gene expression. Trends Genet 21, 586–590.

Lodygensky GA, Vasung L, Sizonenko SV, et al. (2010)

Neuroimaging of cortical development and brain connectivity

in human newborns and animal models. J Anat 217, 418–

428.

Lukaszewicz A, Cortay V, Giroud P, et al. (2006) The concerted

modulation of proliferation and migration contributes to the

specification of the cytoarchitecture and dimensions of

cortical areas. Cereb Cortex 16 (Suppl 1), i26–i34.

Lynch A, Gentleman S, Garey L (2002) Further observations on

neuronal somata and dendrites in chronic schizophrenia.

J Anat 200, 213.

Manger PR, Cort J, Ebrahim N, et al. (2008) Is 21st century

neuroscience too focussed on the rat ⁄ mouse model of brain

function and dysfunction? Front Neuroanat 2, 5.

Marin O, Rubenstein JL (2001) A long, remarkable journey:

tangential migration in the telencephalon. Nat Rev Neurosci

2, 780–790.

McQuillen PS, Ferriero DM (2005) Perinatal subplate neuron

injury: implications for cortical development and plasticity.

Brain Pathol 15, 250–260.

Ment LR, Hirtz D, Huppi PS (2009) Imaging biomarkers of

outcome in the developing preterm brain. Lancet Neurol 8,

1042–1055.

Merkle FT, Mirzadeh Z, Alvarez-Buylla A (2007) Mosaic

organization of neural stem cells in the adult brain. Science

317, 381–384.

Meyer G (2007) Genetic control of neuronal migrations in

human cortical development. Adv Anat Embryol Cell Biol 189,

1 p preceding 1, 1–11.

Meyer G (2010) Building a human cortex: the evolutionary

differentiation of Cajal-Retzius cells and the cortical hem.

J Anat 217, 334–343.

Miller SP, Ferriero DM (2009) From selective vulnerability to

connectivity: insights from newborn brain imaging. Trends

Neurosci 32, 496–505.

Mo Z, Zecevic N (2008) Is Pax6 critical for neurogenesis in the

human fetal brain? Cereb Cortex 18, 1455–1465.

Molnar Z, Metin C, Stoykova A, et al. (2006) Comparative

aspects of cerebral cortical development. Eur J Neurosci 23,

921–934.

Monier A, Adle-Biassette H, Delezoide AL, et al. (2007) Entry

and distribution of microglial cells in human embryonic and

fetal cerebral cortex. J Neuropathol Exp Neurol 66, 372–382.

Nie K, Molnar Z, Szele F (2010) Neuroblast proliferation but not

migration is associated with a vascular niche during

development of the rostral migratory stream. Dev Neurosci 32,

163–172.

Ojeman GA (1984) Common cortical and thalamic mechanisms

for language and motor functions. Am J Physiol 246, R901–

R903.

Ojemann GA, Fedio P, Van Buren JM (1968) Anomia from

pulvinar and subcortical parietal stimulation. Brain 91, 99–

116.

O’Leary DDM (1989) Do cortical areas emerge from a

protocortex? Trends Neurosci 12, 400–406.

O’Leary DDM, Borngasser D (2006) Cortical ventricular zone

progenitors and their progeny maintain spatial relationships

and radial patterning during preplate development indicating

an early protomap. Cereb Cortex 1 (Suppl), i46–i56.

O’Leary DDM, Sahara S (2008) Genetic regulation of

arealization of the cortex. Curr Opin Neurobiol 18, 90–100.

Perkins L, Hughes E, Srinivasan L, et al. (2008) Exploring cortical

subplate evolution using magnetic resonance imaging of the

fetal brain. Dev Neurosci 3, 211–220.

Petanjek Z, Berger B, Esclapez M (2009) Origins of cortical

GABAergic neurons in the cynomolgus monkey. Cereb Cortex

19, 249–262.

Pollard KS, Salama SR, Lambert N, et al. (2006) An RNA gene

expressed during cortical development evolved rapidly in

humans. Nature 443, 167–172.

Rakic P (1988) Specification of cerebral cortical areas. Science

241, 170–176.

Rakic P (2009) Evolution of the neocortex: a perspective from

developmental biology. Nat Rev Neurosci 10, 724–735.

Rakic P, Sidman RL (1968) Supravital DNA synthesis in the

developing human and mouse brain. J Neuropathol Exp

Neurol 27, 246–276.

Rakic P, Sidman RL (1969) Telencephalic origin of pulvinar

neurons in the fetal human brain. Z Anat Entwicklungsgesch

29, 53–82.

Rakic P, Suner I, Williams RW (1991) A novel cytoarchitectonic

area induced experimentally within the primate visual cortex.

Proc Natl Acad Sci USA 88, 2083–2087.

Rakic P, Ayoub AE, Breunig JJ, et al. (2009) Decision by division:

making cortical maps. Trends Neurosci 32, 291–301.

Rutherford M, Ramenghi LA, Edwards AD, et al. (2010)

Assessment of brain tissue injury after moderate hypothermia

in neonates with hypoxic-ischaemic encephalopathy: a nested

substudy of a randomised controlled trial. Lancet Neurol 9,

39–45.

Saunders NR, Dziegielewska KM, Møllgard K (1991) The

importance of the blood-brain barrier in fetuses and embryos.

Trends Neurosci 14, 14–15.

Saunders NR, Ek CJ, Habgood MD, et al. (2008) Barriers in the

brain: a renaissance? Trends Neurosci 31, 279–286.

Schmechel DE, Rakic P (1979) Golgi study of radial glial cells in

developing monkey telencephalon: Morphogenesis and

transformation into astrocytes. Anat Embryol 156, 115–152.

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. 287

Sidman RL, Rakic P (1973) Neuronal migration with special

reference to developing human brain: a review. Brain Res 62,

1–35.

Sidman RL, Rakic P (1982) Development of the human central

nervous system. In: Histology and Histopathology of the

Nervous System, (eds Haymaker W, Adams RD), pp. 3–145.

Springfield: C.C. Thomas.

Smart IH, Dehay C, Giroud P, et al. (2002) Unique morphological

features of the proliferative zones and postmitotic

compartments of the neural epithelium giving rise to striate

and extrastriate cortex in the monkey. Cereb Cortex 12, 37–53.

Squier W, Jansen A (2010) Abnormal development of the

human cerebral cortex. J Anat 217, 312–323.

Squier M, Chamberlain P, Zaiwalla Z, et al. (2000) Five cases of

brain injury following amniocentesis in mid-term pregnancy.

Dev Med Child Neurol 42, 554–560.

Squier W, Salisbury H, Sisodiya S (2003) Stroke in the

developing brain and intractable epilepsy: effect of timing on

hippocampal sclerosis. Dev Med Child Neurol 45, 580–585.

Staudt M (2010) Reorganization after pre- and perinatal brain

lesions. J Anat 217, 469–474.

Stubbs D, DeProto J, Nie K, et al. (2009) Neurovascular

congruence during cerebral cortical development. Cereb

Cortex 1 (Suppl), i32–i41.

Suarez-Sola ML, Gonzalez-Delgado FJ, Pueyo-Morlans M, et al.

(2009) Neurons in the white matter of the adult human

neocortex. Front Neuroanat 3, 7.

Vasung L, Huang H, Jovanov-Milosevic N, et al. (2010)

Development of axonal pathways in the human fetal fronto-

limbic brain: histochemical characterization and diffusion

tensor imaging. J Anat 217, 400–417.

Verney C, Monier A, Fallet-Bianco C, et al. (2010) Early

microglial colonization of the human forebrain and possible

involvement in periventricular white-matter injury of preterm

infants. J Anat 217, 436–448.

Vigneron DB (2006) Magnetic resonance spectroscopic imaging

of human brain development. Neuroimaging Clin N Am 16,

75–85.

Walther M, Juenger H, Kuhnke N, et al. (2009) Motor cortex

plasticity in ischemic perinatal stroke: a transcranial magnetic

stimulation and functional MRI study. Pediatr Neurol 41, 171–

178.

Wang WZ, Oeschger F, Lee S, et al. (2009) High quality RNA

from multiple brain regions simultaneously acquired by laser

capture microdissection. BMC Molecular Biology 10, 69.

Wang X, Lindsay S, Baldock R (2010a) From spatial-data to 3D

models of the developing human brain. Methods 50, 96–104.

Wang WZ, Hoerder-Suabedissen A, Oeschger FM, et al. (2010b)

Subplate in the developing cortex of mouse and human.

J Anat 217, 368–380.

Zecevic N, Chen Y, Filipovic R (2005) Contributions of cortical

subventricular zone to the development of the human

cerebral cortex. J Comp Neurol 491, 109–122.

Zecevic N, Hu F, Jakovcevski I (2010) Cortical interneurons in the

developing human neocortex. J Neurobiol, in press.

Zecevic N, Rakic P (2001) Development of layer I neurons in the

primate cerebral cortex. J Neurosci 21, 5607–5619.

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.288