Download PDF - Oxford Academic - Oxford University Press

Genetic Control of Cortical Development
John L.R. Rubenstein and Pasko Rakic1
Nina Ireland Laboratory of Developmental Neurobiology,
Center for Neurobiology and Psychiatry, Department of
Psychiatry and Programs in Neuroscience, Developmental
Biology and Biomedical Sciences, 401 Parnassus Avenue,
University of California at San Francisco, CA 94143-0984 and
1
Section on Neurobiology, Yale University School of Medicine,
SHM, C-319, 333 Cedar Street, New Haven, CT 06510, USA
The cerebral cortex is the highest achievement of biological
evolution and the neural substrate of human mental abilities.
Molecular biological techniques have opened the possibility of
investigating how specific regulator y genes and morphoregulatory molecules mediate formation of this complex
structure. During evolution, the cerebral cortex has undergone
disproportionate growth relative to the rest of the brain
[reviewed by Northcutt and Kaas (Northcutt and Kaas, 1995)].
This increase predominately affected its surface area, rather than
its thickness, and was accompanied by the addition and elaboration of functional subdivisions. Furthermore, the [deletion]
region that has increased in size the most, the neocortex,
acquired a characteristic laminar structure that is not readily
apparent in the cortex of non-mammalian vertebrates. These
changes in the size, complexity and histological organization of
the cerebral cortex presumably ref lect the elaboration of the
cortical circuitry which ultimately endowed the human brain
with its extraordinary capacity for reasoning and language.
The cortex, or pallium, is comprised of several subdivisions.
In mammals, these functionally distinct regions include the
hippocampus, parahippocampal areas, neocortex, entorhinal
cortex, olfactory cortex, claustrum and olfactory bulb. Each
has characteristic histological features, wiring diagrams and
functionally distinct subdomains. Based on cytoarchitectonic
criteria, the human cerebral cortex was subdivided into more
than 50 areas (Brodmann, 1909). More recent methods are
revealing even greater complexity in the categories, number and
functional significance of cortical parcellation (Felleman and
Van Essen, 1991). The remarkable conservation of the pattern of
areal divisions within a given species suggests the existence of a
highly conserved and rigidly regulated regional specification
program that controls their development (Rakic, 1988). The
evidence presented in this issue of Cerebral Cortex is in accord
with the view that neocortical regional specification depends on
interactions between intrinsic properties of cortical cells with
input from subcortical structures.
Cortical development has been scrutinized by developmental
neurobiologists during this century. Their studies provide an
essential physiological, anatomical and cellular foundation for
elucidating the molecular mechanisms that regulate its assembly.
The discovery of genes that regulate brain development is now
revolutionizing our ability to understand the intricacies of neuroembryology, and to identify how neuropathological processes
derail cortical development.
Genetic studies of invertebrate development in f lies and
nematodes have had a fundamental role in expediting the
progress. The identification of genes that regulate regional
specification (e.g. gap and homeotic genes), segmentation (e.g.
segment polarity genes), neurogenesis (e.g. neurogenic and
proneural genes) and programmed cell death (apoptotic genes)
provided key insights into regulatory genes that could control
early development of the vertebrate brain. In the mid-1980s,
the first mammalian homologs of genes that control early
development in Drosophila were identified; these included the
Hox genes. The expression of these genes have distinctive
anteroposterior boundaries in the vertebrate spinal cord and
hindbrain. Their expression patterns provided new evidence for
a neuromeric, or segmental organization of the hindbrain
[reviewed by McGinnis and Krumlauf (McGinnis and Krumlauf,
1992)]. Vertebrate homologs of Drosophila segment polarity
genes, such as engrailed and wingless, have been found to be
expressed in the midbrain and hindbrain [reviewed by Joyner
(Joyner, 1996)]. By the late 1980s, the first candidates for genetic
regulators of forebrain development began to be reported. These
are the Brn genes, which were identified by their homology to
the POU family of transcription factors that regulate mammalian
pituitary development, and other developmental processes in
f lies and worms [reviewed by Wegner et al. (Wegner et al.,
1993)]. The Brn genes are expressed in the forebrain and in
other regions of the central nervous system (CNS). In 1990, a
mouse homolog of the Drosophila neurogenic basic helix–loop–
helix transcription factor achaete-scute (Mash1) was reported;
like the Brn genes, Mash1 is expressed in the forebrain, as well
as in more posterior regions of the CNS (Lo et al., 1991). Then,
in 1991, the first forebrain-specific regulatory genes were
reported: Dlx1, Dlx2 and Nkx2.1 (TTF1; T/ebp) [reviewed by
Rubenstein and Puelles (Rubenstein and Puelles, 1994)]. These
homeobox genes were identified either through a directed
search for forebrain regulatory genes, or by their homology to
other homeobox genes, or by serendipity. Within a year, the Otx
and Emx genes, homologs of the orthodenticle and empty
spiracle genes that control Drosophila head development, were
found to be expressed in nested patterns in the mouse forebrain
and midbrain [reviewed by Boncinelli et al. (Boncinelli et al.,
1993)].
By 1993, vertebrate homologs of Drosophila genes encoding
secreted morphogens and patterning molecules, such as hedgehog and decapentaplegic, were demonstrated to be expressed in
longitudinal stripes along the ventral and dorsal aspects of the
entire neuraxis [reviewed by Tanabe and Jessell (Tanabe and
Jessell, 1996) and Shimamura and Rubenstein (Shimamura and
Rubenstein, 1997)]. Finally, several genes that regulate the
number and survival of cells in the nematode, through regulating
apoptosis (Metzstein et al., 1998), were found to play a similar role
in the mammalian forebrain (e.g. caspase-3 and -9) (Kuida et al.,
1996, 1998). The regional distribution of apoptotic cells in the
mouse CNS appears to be regulated by the combination of
Jnk1 and Jnk2 kinases (Kuan et al., 1999), genes that were also
identified in Drosophila [reviewed by Haydar et al. (Haydar et al.,
1999)].
The expression patterns of these regulatory genes frequently
exhibit discrete anteroposterior (transverse) and dorsoventral
© Oxford University Press 1999
Cerebral Cortex Sep 1999;9:521–523; 1047–3211/99/$4.00
(longitudinal) boundaries, which suggested a Cartesian-like
organization for parts of the forebrain. These findings led to the
Prosomeric Model, which suggests that the diencephalon, and
perhaps more rostral forebrain regions, have a segment-like
organization similar to that of the hindbrain (Puelles and
Rubenstein, 1993; Rubenstein et al., 1994). In parallel with the
discoveries of genes that control brain patterning and differentiation, genes were identified which encoded secreted and
cell-surface proteins that regulate cell–cell interactions, axon
path-finding and cell migration. The advent of targeted mutagenesis in mouse has made it possible to discover the functions
of these genes, and in most cases has confirmed their essential
roles in controlling brain development.
The papers in this Special Issue of the Cerebral Cortex focus
on genes that are implicated in controlling regionalization, morphogenesis and differentiation of the cerebral cortex, processes
which undoubtedly control cortical size, cell-type specification
and connectivity. The papers review recent advances in molecular
genetics that have illuminated mechanisms of cortical development beginning from its earliest stages through early postnatal life.
The chapters by Acampora et al. (Acampora et al., 1999), Arimatsu
et al. (Arimatsu et al., 1999), Dou et al. (Dou et al., 1999), Eagleson
and Levitt (Eagleson and Levitt, 1999), Rubenstein et al.
(Rubenstein et al., 1999), and Grove and Tole (Grove and Tole,
1999) review possible mechanisms for induction and regionalization of the cortex. Rubenstein et al. describe patterning
centers in the neural plate and prosencephalon which produce
potential morphogens, and some of the transcription factors that
interpret these patterning signals (Rubenstein et al., 1999).
Acampora et al. focus on the early roles of the Otx homeobox
transcription factors in patterning the midbrain and forebrain,
and their later roles in cortex differentiation (Acampora et al.,
1999). Dou et al. describe the role of BF1, which encodes a
winged-helix transcription factor that is required for telencephalic
patterning and proliferation (Dou et al. 1999). Arimatsu et al. and
Eagleson and Levitt review studies that have used the latexin,
lamp and other genes to study the process of regional specification of the lateral cortex (Arimatsu et al., 1999; Eagleson and
Levitt, 1999). Grove and Tole consider mechanisms that control
patterning of the medial cortex, the region that gives rise to the
hippocampus (Grove and Tole, 1999).
Several of the papers describe genes whose expression
defines regional boundaries in the developing cerebral cortex.
These genes are useful markers in experiments aimed at
elucidating the mechanisms that generate cortical subdivisions.
For instance, in the paper by Rubenstein et al. evidence is
presented that expression of the Id2 gene respects the boundary
of the sensory and motor neocortex (Rubenstein et al., 1999).
Papers by Hatanaka and Jones, and Grove and Tole describe
several genes that are regionally expressed in medial aspects of
the cortex, particularly in the region of the hippocampus
(Hatanaka and Jones, 1999; Grove and Tole, 1999). Papers by
Donoghue and Rakic, Mackarehtschian et al. and Rubenstein et
al. describe the regional expression of Eph receptor tyrosine
kinases and their ligands (ephrins) in the cerebral cortex
(Donoghue and Rakic, 1999; Mackarehtschian et al., 1999;
Rubenstein et al., 1999). These genes, some of which are
expressed in gradients, and others in discrete domains, are likely
candidates for regulating topographic maps and distribution of
inputs to the cortex as has been suggested in subcortical
structures (O’Leary and Wilinson, 1999).
The papers by Gitton et al. and Rubenstein et al. discuss the
roles of thalamic afferents in regulating regionalization of the
522 Genetic Control of Cortical Development • Rubenstein and Rakic
neocortex, and review the evidence that a considerable degree
of regionalization of the cerebral cortex occurs before the arrival
of thalamic afferents, as predicted by the existence of an
intrinsic protomap within the cerebral vesicle (Gitton et al.,
1999a; Rubenstein et al., 1999) [see also Rakic (Rakic, 1988)].
Gitton et al.’s study suggests that some neocortical regions are
specified at ver y early stages of telencephalon development
although this prepattern is revealed only once thalamic afferents
grow into the neocortex (Gitton et al., 1999a) [see also Gitton et
al. (Gitton et al. 1999b)]. Finally, Rubenstein et al. (Rubenstein
et al., 1999) refer to recent experiments demonstrating a remarkable degree of neocortical regionalization in the absence of
thalamic inputs (Miyashita-Lin et al., 1999).
Evolution of the cortex has been postulated to occur in part
through changes in the proliferation of neuronal precursors in
the ventricular zone and allocation of postmitotic cells to their
proper laminar and areal positions in the cortical plate (Caviness,
1995; Rakic, 1995). Papers by Dou et al. and Warren et al.
discuss the roles of the BF1 and Pax6 genes, respectively, in
regulating proliferation in the developing cortex (Dou et al.,
1999; Warren et al., 1999). The number of cortical neuronal and
glial cells also depends also on programmed cell death (PCD or
apoptosis) that occur in the germinal layers prior to onset of
neurogenesis. Targeted disruption of cell death-effector genes
such as caspase-3 and caspase-9 and Jnk1/2 revealed that cells
must die on schedule and in the proper position in the proliferative zones. Knockout mice lacking both copies of these genes
have an increased number of founder cells in the ventricular
zone that eventually generate supernumerary cortical neurons
resulting in an expanded cerebral surface that shows sign of
convolutions (Haydar et al., 1999).
The control of cell-type identity within the cortex is the subject
of the paper by Anderson et al. (Anderson et al., 1999). Of the two
major classes of neurons in the cortex — projection neurons,
which are glutaminergic, and interneurons, which are mainly
GABAergic — several studies now indicate that many of the latter
are produced in the basal ganglia, rather than derived from the
proliferative zone of the neocortex. While GABAergic neurons
originating from the basal ganglia migrate tangentially into the
cerebral cortex, most projection neurons originating in the
ventricular zone migrate radially (Ware et al., 1999). GABAergic
neurons appear to originate from at least two distinct sources and
migrate along at least two distinct pathways. Furthermore, the
genetic control of interneuron and projection neuron development appears to be distinct, as the Dlx genes regulate the former
and genes such as Pax6, Otx1 and Tbr1 regulate the latter. New
evidence is presented which suggests that Dlx genes can in fact
induce the GABAergic phenotype (Anderson et al., 1999). Thus
radial and tangential cell migration seem to be used by distinct cell
types in cortical development. The modes of migration and genes
that regulate their allocation to the cortex are discussed by Ware et
al. (Ware et al., 1999). Advances in this area are beginning to
provide insights into the etiologies of neuronal migration
disorders in humans (Walsh, 1999).
Finally, inroads into the mechanisms controlling axon pathfinding are illuminating how cortical connections are formed.
Discussion of some aspects of this subject is presented in the
chapters by Arimatsu et al., Hatanaka and Jones, and Rubenstein et
al. (Arimatsu et al., 1999; Hatanaka and Jones, 1999; Rubenstein et
al., 1999). A number of mouse mutants are yielding new insights
into the molecules and mechanisms that connect cortical cells to
cortical and subcortical targets. Thus, in spite of the differences in
functional requirements, cortical representation of the somato-
sensory and visual systems can be established independently of
cues by synaptic activity, as has been found in the olfactory system
(Bulfone et al., 1998; O’Leary et al. 1999).
In conclusion, rapid progress is being made in the identification of the genes controlling cortical development. The stage
is now set to describe in detail the genetic programs that regulate
the processes that control regional specification, morphogenesis,
cell type specification, neuronal migration and connectivity.
Inroads have been made in identifying genes that control the size
of the cerebral cortex through regulation of proliferation and cell
death. Regionalization of the cortex appears to be controlled by
patterning centers that control the activation of transcription
factors that determine areal fate and the expression of cell surface
molecules that control the topographic organization of synaptic
inputs and outputs. Specific cell types appear to be generated in
distinct locations within the telencephalon. Tangential migration
introduces interneurons that are generated in the basal ganglia but
destined to migrate to the cerebral cortex. On the other hand,
radial migration pathways are used to generate the characteristic
laminar structure of the mammalian cerebral cortex and are
probably essential for maintaining the positional information of
projection neurons that is required for correct connectivity.
Finally, while inputs from the thalamus appear to have little
inf luence on early regionalization of the cortex, they are
necessary for controlling its maturation.
It is likely that understanding these fundamental processes will
shed light on the similarities and differences of cortical structure
in distinct vertebrate species and the mechanisms that have
constrained evolutionary change. We also expect that this
information will help in the search for methods to diagnose and
treat human neuropsychiatric and neurological disorders. Finally,
we hope that this Special Issue of Cerebral Cortex will provide a
useful resource to scientists interested in this subject, and that it
will stimulate new ideas and experimental approaches.
References
Acampora D, Barone P, Simeone A (1999) Otx genes in corticogenesis and
brain development. Cereb Cortex 9:533–542.
Anderson S, Mione M, Yun K, Rubenstein JLR (1999) Differential origins
of neocortical projection and local circuit neurons: role of Dlx genes
in neocortical interneuronogenesis. Cereb Cortex 9:646–654.
Arimatsu Y, Ishida M, Sato M, Kojima M (1999) Corticocortical associative
neurons expressing latexin: specific cortical connectivity formed in
vivo and in vitro. Cereb Cortex 9:569–576.
Boncinelli E, Gulisano M, Broccoli V (1993) Emx and Otx homeobox
genes in the developing mouse brain. J Neurobiol 24:1356–1366.
Brodmann K (1909) Vergleichende Localisationsationslehre der Grosshirhinde. Leipzig: Barth.
Bulfone A, Wang F, Hanver R, Anderson S, Cutforth R, Chen S, Maneses J,
Pedersen R, Axel R, Rubenstein JLR (1998) An olfactory sensory map
develops in the absence of normal projection neurons or GABAergic
inernurons. Neuron 21:1273–1282.
Caviness VS, Jr, Takahashi T, Nowakowski RS (1995) Numbers, time and
neocortical neuronogenesis: a general developmental and evolutionary model. Trends Neurosci 18:379–383.
Donoghue MJ, Rakic P (1999) Molecular gradients and compartments in
the embryonic primate cerebral cortex. Cereb Cortex 9:586–600.
Dou CL, Li S, Lai E (1999) Dual role of brain factor-1 in regulating growth
and patterning of the cerebral hemispheres. Cereb Cortex 9:543–550.
Eagleson KL, Levitt P (1999) Complex signaling responsible for molecular
regionalization of the cerebral cortex. Cereb Cortex 9:562–568.
Felleman DJ, Van Essen DC (1991). Distributed hierarchical processing in
the primate cerebral cortex. Cereb Cortex 1:1–47.
Gitton Y, Cohen-Tannoudji M, Wassef M (1999a) Role of thalamic axons in
the expression of H-2Z1, a mouse somatosensor y cortex specific
marker. Cereb Cortex 9:611–620.
Gitton Y, Cohn-Tannoudji M, Wassef M (1999b) Specification of somatosensory area identity in cortical explants. J Neurosci 19:4889–4898.
Grove EA, Tole S (1999) Patterning events and specification signals in the
developing hippocampus. Cereb Cortex 9:551–561.
Hatanaka Y, Jones EG (1999) Novel genes expressed in the developing
medial cortex. Cereb Cortex 9:577–585.
Haydar TF, Kuan C-Y, Flavell R A, Rakic P (1999) The role of cell death in
regulating the size and shape of the mammalian forebrain. Cereb
Cortex 9:621–626.
Joyner A (1996) Engrailed, Wnt and Pax genes regulate midbrain–
hindbrain development. Trends Genet 12:1520.
Kuan C, Yang DD, Semanta Roy DR, Davis RJ, Rakic P, Flavell A (1999) The
Jank1 and Jank2 protein kinases are required for regional-specific
apoptosis during early brain development. Neuron 22:667–676.
Kuida K, Zheng TS, Na S, Kuang C, Yang D, Karasuyama H, Rakic P, Flavell
R (1996) Decreased apoptosis in the brain and premature lethality in
CPP32-dificient mice. Nature 384:368–372.
Kuida K, Haydar T, Kuan C, Yong G, Taya C, Karasuyama A, Su SH, Rakic
P, Flavell RS (1998) Reduced apoptosis and cytochrome c-mediated
caspase activation in mice lacking Caspase-9. Cell 94:325–333.
Lo LC, Johnson JE, Wuenschell CW, Saito T, Anderson DJ (1991)
Mammalian achaetescute homolog 1 is transiently expressed in
spatially restricted subsets of early neuroepithelial and neural crest
cells. Genes Dev 5:1524–1537.
Mackarehtschian K, Lau CK, Caras I, McConnell SK (1999) Regional
differences in the cortical subplate revealed by ephrin-A5 expression.
Cereb Cortex 9:601–610.
McGinnis W, Krumlauf R (1992) Homeobox genes and axial patterning.
Cell 68:283–302.
Metzstein MM, Stanfield GM, Hor vitz HR (1998). Genetics of programmed cell death in C. elegans: past, present and future. Trends
Genet 14:410–416.
Miyashita-Lin EM, Hevner R, Montzka Wassarman K, Martinez S,
Rubenstein JLR (1999) Early neocortical regionalization in the
absence of thalamic innervation. Science (in press).
Northcutt RG, Kaas J (1995) The emergence and evolution of the
mammalian neocortex. Trends Neurosci 18:373–379.
Puelles L, Rubenstein JLR (1993) Expression patterns of homeobox and
other putative regulatory genes in the embryonic mouse forebrain
suggest a neuromeric organization. Trends Neurosci 16:472–479.
O’Leary DDM,Wilinson DG (1999) Eph receptors and ephrins in neural
development Curr Opin Neurobiol 9:65–73.
O’Leary DDM, Yates PSA, McLaughlin T (1999) Molecular development of
sensor y maps: representing sights and smells in the brain. Cell
96:255–269.
Rakic P (1988) Specification of cerebral cortical areas. Science 241:
170–176.
Rakic P (1995) A small step for the cell, a giant leap for mankind: a
hypothesis of neocortical expansion during evolution. Trends
Neurosci 18:383–388.
Rubenstein JLR, Anderson S, Shi L, Miyashita-Lin E, Bulfone A, Hevner R
(1999) Genetic control of cortical regionalization and connectivity.
Cereb Cortex 9:524–532.
Rubenstein JLR, Puelles L (1994) Homeobox gene expression during
development of the vertebrate brain. Curr Top Dev Biol 29:1–64.
Rubenstein JLR, Martinez S, Shimamura K, Puelles L (1994) The
embr yonic vertebrate forebrain: the prosomeric model. Science
266:578–580.
Shimamura K, Rubenstein JLR (1997) Regulation of patterning and
differentiation in the embryonic vertebrate forebrain. In: Molecular
and cellular approaches to neural development (Cowan WM, Jessell
TM, Zipursky SL), pp. 356–390.
Tanabe Y, Jessell TM (1996) Diversity and pattern in the developing spinal
cord. Science 274:1115–1123.
Walsh C (1999) Genetic malformations of the human cerebral cortex.
Neuron 23:19–29.
Ware ML, Tavazoie SF, Reid CB, Walsh CA (1999) Coexistence of
widespread clones and large radial clones in early embryonic ferret
cortex. Cereb Cortex 9:636–645.
Warren N, Caric D, Pratt T, Clausen JA, Asavaritikrai P, Mason JO, Hill RE,
Price DJ (1999) The transcription factor, Pax6, is required for cell
proliferation and differentiation in the developing cerebral cortex.
Cereb Cortex 9:627–635.
Wegner M, Drolet DW, Rosenfeld MG (1993) POU-domain proteins:
structure and function of developmental regulators. Curr Opin Cell
Biol 5:488–498.
Cerebral Cortex Sep 1999, V 9 N 6 523