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Maternal-fetal unit interactions and eutherian neocortical development and evolution


Abstract and Figures

The conserved brain design that primates inherited from early mammals differs from the variable adult brain size and species-specific brain dominances observed across mammals. This variability relies on the emergence of specialized cerebral cortical regions and sub-compartments, triggering an increase in brain size, areal interconnectivity and histological complexity that ultimately lies on the activation of developmental programs. Structural placental features are not well correlated with brain enlargement; however, several endocrine pathways could be tuned with the activation of neuronal progenitors in the proliferative neocortical compartments. In this article, we reviewed some mechanisms of eutherians maternal-fetal unit interactions associated with brain development and evolution. We propose a hypothesis of brain evolution where proliferative compartments in primates become activated by "non-classical" endocrine placental signals participating in different steps of corticogenesis. Changes in the inner placental structure, along with placenta endocrine stimuli over the cortical proliferative activity would allow mammalian brain enlargement with a concomitant shorter gestation span, as an evolutionary strategy to escape from parent-offspring conflict.
Exogenous signals from placenta would complement telencephalic-signaling control during brain development. (A) The upregulation of Wnt3a trough the canonical Wnt pathway induce self-renewal of radial glia, early differentiation of Tbr2 cortical intermediate progenitors (Munji et al., 2011) and restrict the expansion of the ventral pallium (antihem) driven by Pax6. The antihem express secreted Frizzled-Related Proteins (Sfpr1 and 2, not shown) that neutralize the action of dorsally derived signals like Wnts. Pax6 activates the expression of the dorsal proneural factor neurogenin 1/2 with the consequent activation of NeuroD1/2 and inhibition of Mash1, a proneural factor highly expressed in subpallial domains. Thus, the pallial/subpallial boundary is defined by the limit of expression of Ngn2 and Mash1 (red arrow in A, D–H). (B) Mash1 induces a first group of transcripts in the phase of expansion of neural progenitors (Castro et al., 2011) and activates a second group of genes at the subsequent phases of cell cycle exit and neuronal differentiation (Bertrand et al., 2002). (C–F) In situ hybridization (ISH) expression pattern of signaling factors in mouse at developmental stage E11.5 (G) Gene expression of signals/factors that helps to define the telencephalic compartmentalization. (H) Subpallial expression of Mash1 at E11.5. All ISH images were taken from the Allen Developing Mouse Brain Atlas, available from: . ch, cortical hem; LP, lateral pallium; MP, medial pallium; VP, ventral pallium; SP, subpallium.
Content may be subject to copyright.
“fnana-07-00022” 2013/7/17 20:48 page1—#1
published: 19 July 2013
doi: 10.3389/fnana.2013.00022
Maternal–fetal unit interactions and eutherian neocortical
development and evolution
Juan F. Montiel
*, Heidy Kaune
and Manuel Maliqueo
Centre for Biomedical Research, Facultad de Medicina, Universidad Diego Portales, Santiago, Chile.
Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Oxford, UK.
Laboratorio de Endocrinología y Metabolismo, Departamento de Medicina Occidente, Facultad de Medicina, Universidad de Chile, Santiago, Chile.
Edited by:
Eric Lewitus, Max Planck Institute for
Molecular Cell Biology and Genetics,
Reviewed by:
Alino Martinez-Marcos, Universidad
de Castilla, Spain
Anna Hoerder-Suabedissen,
University of Oxford, UK
Alexandre Bonnin, University of
Southern California, USA
Juan F. Montiel, Center for Biomedical
Research, Facultad de Medicina,
Universidad Diego Portales, Av.
Ejército 141, Santiago 8370068, Chile
The conserved brain design that primates inherited from early mammals differs from the
variable adult brain size and species-specific brain dominances observed across mammals.
This variability relies on the emergence of specialized cerebral cortical regions and sub-
compartments, triggering an increase in brain size, areal interconnectivity and histological
complexity that ultimately lies on the activation of developmental programs. Structural
placental features are not well correlated with brain enlargement; however , several
endocrine pathways could be tuned with the activation of neuronal progenitors in the
proliferative neocortical compartments. In this article, we reviewed some mechanisms
of eutherians maternal–fetal unit interactions associated with brain development and
evolution. We propose a hypothesis of brain evolution where proliferative compartments
in primates become activated by “non-classical” endocrine placental signals participating
in different steps of corticogenesis. Changes in the inner placental structure, along with
placenta endocrine stimuli over the cortical proliferative activity would allow mammalian
brain enlargement with a concomitant shorter gestation span, as an evolutionary strategy
to escape from parent-offspring conflict.
Keywords: cerebral cortex development, placenta, maternal–fetal unit, evolution, serotonin, eutherians, transcrip-
Placenta and brain are not recent innovations in vertebrate phy-
logeny (Aboitiz and Montiel, 2007; Renfree et al., 2013). Placental
species emerge in a wide variety of taxa, even among inverte-
brates and basal vertebrates, involving multiple cases of analogous
convergence (Blackburn, 1992; Renfree et al., 2013). In turn,
brain origin can be tracked before the emergence of vertebrates
(Aboitiz and Montiel, 2007). Both structures exhibit an impor-
tant level of anatomical diversification across vertebrates and
inside mammalian evolution. Placenta structural diversification
is associated with life-history, and functional, genomics, and envi-
ronmental requirements (Lewitus and Soligo,2011), whereas brain
shape variability is related to different functional dominances,
behavioral repertories, and cognitive capacities (Krubitzer, 2007).
The acquisition of a large brain size in mammalian evolution
(Rowe et al., 2011) is mainly explained by the activation of devel-
opmental programs that allow a radial and tangential laminar
expansion of the cerebral cortical surface (Cheung et al., 2007,
2010; Aboitiz and Montiel, 2012; Molnár and Clowry, 2012).
These events are correlated with the activation, and functional
specialization of cortical proliferative compartments, named ven-
tricular zone (VZ) and subventricular zone (SVZ; Kriegstein et al.,
2006; Molnár et al., 2006; Cheung et al., 2007, 2010; Molnár,
2011; Aboitiz and Montiel, 2012). These proliferative compart-
ments are susceptible to be regulated by locally, nearby, and
distantly originated signals. In this regard, brain development
is dependent on (1) local cues and in situ cell-autonomous-
specification (Franco et al., 2012), (2) neighboring information
from telencephalic-signaling centers and developing connections
(Dehay et al., 2001; Shimogori et al., 2004; Medina and Abellán,
2009; Aboitiz, 2011; Aboitiz and Montiel, 2012), and (3) distant
systemic interactions that coordinate intrauterine and environ-
mental regulations with brain development. This kind of control
has been less explored in evolutionary neurobiology since most
hypotheses about br ain origin and evolution are focused on the
intrinsic developmental control (local and neighboring signals)
and functional properties of the brain (Karten, 1969, 1997; Aboitiz
et al., 2003; Aboitiz and Montiel, 2007). During brain develop-
ment, some of these distantly generated molecules participate in
proliferative induction, myelination, cell differentiation, migra-
tion, growing of neuronal projections, and signaling (Vitalis and
Parnavelas, 2003). In addition, they provide information to the
fetus about environmental and maternal conditions through the
placenta. In this review, we describe some maternal–fetal interac-
tions and their plausible associations with brain evolution and
development. In an attempt to integrate evolutionary, devel-
opmental, and genomic data, we discuss (1) the evolutionary
origin of mammals, (2) the comparative morphology of pla-
centa, (3) neocortical development, (4) placenta–brain endocrine
interactions, (5) potential molecular placenta–brain interactions
extracted from transcriptome databases, and (6) finally we spec-
ulate about a hypothesis for the neocortical expansion observed
in mammalian evolution that integrates in situ and neighboring
cues with the control based on endocrine signals from placenta,
from which some represent new pathways that should be explored
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Montiel et al. Placenta and evolutionary development of the cerebral cortex
The mammalian lineage arises from synapsids, a mammal-like
reptile ancestor, diverged from other tetrapods about 300 mil-
lion years ago (Mya) in the Carboniferous (geological period
extended from 359 to 299 Mya; Gauthier et al., 1988). The
early mammal-like reptile Probainognathus had slender and elon-
gated cerebral hemispheres bearing a small dorsal slope that is
believed to be a forerunner of the neocortex (Quiroga, 1980;
Aboitiz et al., 2003; Aboitiz and Montiel, 2007). Synapsids gave
rise to pelycosaurs, lizard-like animals succeeded in the late Per-
mian (extended from 299 to 252 Mya) by the therapsids (Kemp,
2006). Most therapsids became extinct by the end of the Trias-
sic period (extended from 252 to 201 Mya), but one group
of carnivorous therapsids, called cynodonts, survived well into
the Jurassic period (extended from 201 to 145 Mya; Carroll,
1988). Early cynodonts had a restricted sensory repertory and a
poor sensory–motor integration with a relatively low encephaliza-
tion quotient (EQ; a measure of relative brain size as a function
of the total body size; Rowe et al., 2011). From cynodonts arose
the eucynodonts or mammaliaforms, this group includes Juras-
sic fossils such as Sinoconodon and Morganucodon, whose gross
morpholog y resembled that of some present-day insectivores (cur-
rently known as order Eulipotyphla; Rowe, 1996; Kaas, 2013).
Eucynodonts differ from their predecessors by having an increased
olfactory sensitivity, improved tactile resolution, and motor coor-
dination (Rowe et al., 2011), which are functional changes that
would contribute primarily to a first pulse of pre-mammalian
encephalization (Rowe et al., 2011). This hemispheric expansion
differentiates mammaliaforms from mammal-like reptiles and
most other vertebrates (Rowe et al., 2011). Considering this evi-
dence, it has been proposed that the brain expansion was a late
event in the lineage leading to mammals, more or less coincident
with the acquisition of modern mammalian characters observed
in fossils like the basal mammaliaform, Morganucodon, or in
the closest known extinct to mammals, Hadrocodium (Kielan-
Jaworowska et al., 2004; Aboitiz and Montiel, 2007; Rowe et al.,
2011). Mammalia arose from eucynodonts in/or before the Early
Jurassic (200 Mya; Kielan-Jaworowska et al., 2004). These ances-
tral mammals were characterized by an expansion of the olfactory
sensor y system, which has been linked to a genomic amplification
of the olfactory receptors (Niimura, 2009; Rowe et al., 2011). In
some descendant clades, the olfactory system was further elab-
orated, whereas in others it was reduced and replaced by other
sensor y modalities (Aboitiz et al., 2003; Aboitiz and Montiel, 2007;
Krubitzer, 2007; Rowe et al., 2011). Only much later, acute visual
and auditory systems evolved among mammals (Luo et al., 2011;
Aboitiz and Montiel, 2012).
Three mammalian subclasses became extinct in different evo-
lutionary moments. Triconodonta, the earliest lineage diverged
in mammalian phylogeny, disappeared at the end of the Cre-
taceous period (extended from 145 to 66 Mya) leading to
a lack of basal-related in living mammals. The second was the
Multituberculata, and the latest extinguished was the infraclass
of Theria called Palaeor yctoides. A recent analysis suggests that
the first modern placental orders (eutherians) emerged around
2–3 million years later than the Cretaceous–Paleogene (K–Pg)
extinction event occurred 66 Mya (O’Leary et al., 2013). It was
predicted that these ancestors had a hemochorial placenta w ith
trophoblast, gyrencephalic cerebral cortex and relatively high EQ
(over 0.25) when compared with other vertebrates (O’Leary et al.,
2013). Phylogenetic analyzes of the living eutherian mammals
identify four primary superordinal clades: Afrotheria, Xenarthra,
Euarchontoglires, and Laurasiatheria (for a list of species belong-
ing each group please see Table 1
). The basal diversification
Table 1
Primary clades of eutherian living mammals.
Class Supercohort Infraclass Superorder ORDER and/or Suborder; animal examples/
Mammalia Theria Eutheria Afrotheria AFROSORICIDA: Chrysochloridea; golden mole/ Tenrecidae; tenrecs/ MACROSCELIDEA;
elephant shrews (sengis)/ TUBULIDENTATA; aardvarks/ HYRACOIDEA (hyraxes); rock hyrax/
PROBOSCIDEA; elephants/ SIRENIA; sea cows (dunging and manatees)
Xenarthra Vermilingua; anteaters/ Folivora; tree sloths/ CINGULATA; armadillos
Euarchontoglires RODENTIA; rat, mouse, capybara/ LAGOMORPHA; rabbits and hares, treeshrews/
DERMOPTERA; colugos/ PRIMATES; prosimians and simians
Laurasiatheria EULIPOTYPHLA; shrews, hedgehogs/ PHOLIDOTA, pangolins/ CHIROPTERA; bats/
CETACEA; whales/ ARTIODACTYLA; most hoofed mammals (such as hippopotamuses)/
CARNIVORA; cats, dogs, bears, seals, etc
Metatheria DIPROTODONTIA; kangaroo, koala, possum, wombat/ DASYUROMORPHIA; tasmanian
devil, quolls, dunnarts, numbat/ MICROBIOTHERIA; monito del monte/ PERAMELEMOR-
PHIA; bilbies and bandicoots/ NOTORYCTEMORPHIA; Marsupial moles/ DIDELPHIMOR-
PHIA; opossums/ PAUCITUBERCULATA; shrew opossums.
Prototheria MONOTREMATA; Platybus, echidnas
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Different outputs for the basal relationships among eutherian
mammal superordinal clades. (A) Afrotheria as the most basal mammalian
clade, sister lineage of exafroplacentalia (all other eutherians, also called
notolegia). (B) Atlantogenata (Afrotheria and Xenarthra) as sister lineage of
Boreoeutheria (Euarchontoglires and Laurasiatheria). (C) Xenarthra as the
most basal clade, sister lineage of Epitheria (all other eutherians).
of eutherians has been historically considered an unstable node
(O’Leary et al., 2013) and the phylogenetic relationship between
these lineages is still under debate since different analyzes have
generated different outputs of ancestry (Figure 1). Using 18
homologous genes segments, Afrotheria was originally positioned
as the most basal mammalian clade, with Xenarthra as the second,
and Euarchontoglires and Laurasiatheria as the third branches
of the mammalian tree (Murphy et al., 2001; Figure 1A). Using
genomic sequences, the phylogenetic relationship of mammals has
been re-informed (Murphy et al., 2007) and “confirmed” (Prasad
et al., 2008), positioning Atlantogenata (Afrotheria and Xenarthra)
together as sister lineages of Boreoeutheria (Euarchontoglires and
Laurasiatheria; Figure 1B). A recent publication renewed this
debate resolving this basal relation as a split between Xenarthra
and Epitheria (Afrotheria, Laurasiatheria and Euarchontoglires;
O’Leary et al., 2013; Figure 1C).
Understanding the organization of the phylogenetic tree of mam-
mals allows the visualization of the evolutionary history of
different traits and the definition of the presumed ancestral
structure of the placenta (Wildman et al., 2006). The acqui-
sition of the placenta implies as first requirement, the emer-
gence of viviparity (live-bearing) since this made possible the
elaboration of specialized structures that allowed the develop-
ment of the eggs within the maternal body, providing nutri-
tion and protection. It has been postulated that placenta has
evolved concomitantly with the viviparity more than 100 times
in different lineages of non-mammal amniotes (Crespi and
Semeniuk, 2004). The most ancient evidence of viviparity in
amniotes arise from fossils of mosasauroids, a cretaceous marine
lizard, containing embryos along the posterior trunk region
(Caldwell and Lee, 2001). The reptile ancestor of mammalian
lineage was oviparous (egg-laying) since in reptiles viviparity
has evolved more recently than in mammals (Blackburn, 1992).
The mammalian common ancestor of monotremes (which lay
eggs) and ther ians was presumably egg-laying as well (Oftedal,
2002). Supporting evidence for this is that in reptiles ovipar-
ity can evolve into v iviparity via a sequential increase in the
duration of egg-retention, as it has been seen in lizards and
snakes (Blackburn, 1992). Once committed to viviparity, the
eggshell membrane thickness is drastically reduced, thus, return to
oviparity from viviparity has not been seen in amniotes (Oftedal,
The diversity of placental str uctures found among species is
remarkable. Differences in placental shape, degree of the rela-
tionship between the chorion and uterine wall, number of layers
of trophoblast, shape of maternal–fetal interdigitation (villous,
trabecular or labyrinthine), variations in the interhemal barrier
mainly characterized by different degrees of hypertrophy of mater-
nal endothelium and presence of cytotrophoblast and/or syncytial
trophoblast are commonly observed (Enders and Blankenship,
1999; Enders and Carter, 2004). Three main types of placentas
can be recognized according to the extent of how the fetal tissue
invades the wall of the uterus or the maternal vessels. In general,
epitheliochorial placenta is an extensive and diffuse structure,
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Montiel et al. Placenta and evolutionary development of the cerebral cortex
Placental level of invasiveness. The placenta varies across
mammalian species in the invasiveness and their access to maternal blood
flow. Epitheliochorial placentas, the least invasive, have three layers of
maternal tissue separating the fetus from maternal blood. Endotheliochorial
placentas are partially invasive and only the endothelial wall of the maternal
blood vessels, and some interstitial tissue, separates the fetus from the
maternal blood. Hemochorial placent ation is the most invasive and allows
fetal tissues to be bathed directly in the maternal blood. Epitheliochorial and
Endotheliochorial placent as can be found in Afrotheria, Euarchontoglires and
more frequently in Laurasiatheria. Hemochorial placent as are found in all
eutherian superorders (Wildman et al., 2006), showing a broad distribution of
placental types in the mammalian class.
lining the uterine wall, and exhibiting limited invasiveness without
trophoblast invasion of uterine vessels. In the endotheliochorial
placenta, a network of maternal capillary grows within the tro-
phoblast, allowing a better exchange between the mother and
fetus and reducing the risk of passing fetal cells into the mater-
nal circulatory system. Finally, in the hemochorial placenta, the
maternal blood is in direct contact with the trophoblast, which
has the advantage of a more efficient nutrient uptake and waste
elimination (Figure 2). This extensive maternal–fetal communica-
tion also implies some disadvantages like a major risk of maternal
bleeding after delivery and a greater chance of fetal cells transfer
to the maternal system (Enders and Carter, 2004).
The eutherian lineage displays a huge placentation diversifica-
tion. Mess and Carter (2006) developed an exhaustive analysis
of 19 morphological features and degrees of development at birth
across 35 mammalian species, getting a plausible placental pro-
file of the stem ancestor of living mammals (Carter and Mess,
2007; Capellini, 2012). The authors used a cladistics analysis
placing Afrotheria and Xenarthra as sister to other eutherians,
which agrees with the phylogeny of living mammals obtained
from genomic data (Murphy et al., 2007; Prasad et al., 2008).
Together with recent studies focused on defining the ancestral
structure of the eutherian placenta, these studies agreed that this
ancestral placenta had a hemochorial interface, discoid shape,
and labyrinthine maternal–fetal interdigitations (Wildman et al.,
2006; Capellini, 2012). Although the placenta organization is
highly variable between mammals, the ancestral hemochor ial and
discoid placenta structure has been preserved in haplorhine (tar-
siers, new and old word monkeys, and apes) primates (Voge l,
2005; Wildman et al., 2006; Lewitus and Soligo, 2011). As these
big-brained mammals conserve the ancestral placental organi-
zation and share this feature with small-brained mammals it is
questionable that structural differences in placenta can account
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Montiel et al. Placenta and evolutionary development of the cerebral cortex
for brain size expansion across mammalian evolution. However,
different structural placental features have been associated with
brain enlargement, leading to conflictive conclusions. One of
these relies on the brain as a highly expensive organ to grow
and maintain (Elliot and Crespi, 2008), so it was proposed
that a highly invasive hemochorial placentation (Figure 2)is
necessary for fetal brain growth. However, this relation is not
supported once the analyzes are refined (Sacher and Staffeldt,
1974; Capellini et al., 2011). Even more, dolphins, as humans,
have a relative larger brain; nevertheless, they possess an epithe-
liochorial placenta (Figure 2). Accordingly, invasiveness of the
placenta is not a requirement to develop large brains (Martin,
Bias in the inclusion of relatively small-brained marsupials
against the largest-brained placental mammals (Laurasiatheria
and especially Euarchontoglires), or the addition of preimplan-
tation stages lacking placenta formation would hamper these
comparisons between marsupial and eutherian mammals (Weis-
becker and Goswami, 2010; Capellini et al., 2011). Recently,
Capellini (2012) analyzed different placental attributes, conclud-
ing that whereas invasiveness association to fetal and brain growing
is not supported by comparative studies, species with highly inter-
digitated labyrinthine placentas produce neonates of similar body
and brain size but in less than half the gestational time than those
associated with less interdigitated (v illous and tr abecular) placen-
tas. Capellini suggested that the effects of placental interdigitation
on growth rates and the way that these are traded off against gesta-
tion length may be important for understanding the evolutionary
dynamics of parent-offspring conflict.
Most neurons in the neocortex derive from multipotent neural
stem cells in the proliferative epithelium of the VZ lining the ven-
tricular surface of the telencephalic wall. In the VZ, radial glial cells
will gener ate lower- and upper-layer neurons according to distinct
fate potentials (Franco et al., 2012), the Cux2 negative r a dial glia
first produces excitatory neurons, most of which migrate radially
to make up the embryonic preplate and the deepest cortical layers,
instead Cux2 positive radial glia are fated to generate upper-layer
neurons (Franco et al., 2012). Later in development, divisions of
the Cux2 positive radial glia produce cells called intermediate pro-
genitors, that detach from the ventricular surface and aggregate
in a zone overlying the VZ (Kriegstein et al., 2006; Franco et al.,
2012), the SVZ, a second proliferative compartment that is under
control of Pax6 transcr iptional factor and express Svet1, Cux2, and
Tbr2 genes. In the SVZ, cells undergo one to three more cell divi-
sions and then migrate to build up the superficial layers of the
neocortex. Neurons generated in successively later moments are
incorporated into progressively more superficial layers, generating
the inside-out neurogenetic gradient that is characteristic of the
According to recent models of neocortical growth, early tangential
expansion of the neocortex is based primarily on the divisions
of primary progenitors, which enlarge the surface of the VZ,
and later on the tangential growth and radial thickening (gen-
eration of superficial layers) of the neocortex depending mainly
on the proliferation of cortical intermediate progenitors (Dehay
and Kennedy, 2007; Pontious et al., 2008) and glial-like neurons
located in the SVZ (Reillo et al., 2011; Wang et al., 2011b; Molnár
et al., 2011). From a comparative perspective, there seem to be an
increased cell number in mammals in an arbitrary unit column
of cortex (Cheung et al., 2007, 2010). Adult mice or macaques
possess a significantly higher number of cerebral cortical neu-
rons compared with marsupials (Cheung et al., 2007, 2010). The
presence of intermediate (or basal) progenitor cell divisions and
gene expression patterns suggest that the SVZ emerged prior to
the Eutherian–Metatherian split and it might have been the major
driving force behind the evolution of the six-layered neocortex in
mammals (Cheung et al., 2007, 2010; Aboitiz, 2011; Aboitiz and
Montiel, 2012; Molnár and Clowry, 2012). Interestingly, while
a VZ has been described in all vertebrates that have been stud-
ied, a distinctive dorsal pallial SVZ appears only in some species.
Among mammals, the SVZ extends from the lateroventral aspect
of the hemisphere to the dorsal pallium. Across species, the
growth of the SVZ appears to correlate with the development
of the superficial neocortical layers, being especially complex in
primates and minimal in marsupials (Cheung et al., 2010; Mol-
nár, 2011). Underlying the neurogenetic development, there is
a molecular regionalization process in which the cortical neu-
roepithelium acquires its identity on the basis of the expression
of regulatory genes that control the pattern of differentiation,
yielding its characteristic adult phenotype. Molecular evidence
indicates that the embryonic cerebral hemispheres are patterned
according to several signaling centers from which mor phogens are
produced and expressed in gradients in different directions (Sur
and Rubenstein, 2005; O’Leary and Sahara, 2008; Medina and
Abellán, 2009). Thus, modulation of such gradients may yield to
important changes in brain development, expanding some regions
and reducing others (Medina and Abellán, 2009; Aboitiz, 2011;
Aboitiz and Montiel, 2012; Figure 3). We believe that several
traits of cortical neurodevelopment would account for the high
mean EQ of Euarchontoglires and especially of large-brained pri-
mates (Aboitiz and Montiel, 2012; Molnár and Clowry, 2012).
Primates developed a subcompartmentalized neocortical prolifer-
ative SVZ (García-Moreno et al., 2012), and an extra-laminated
transient subplate (Wang et al., 2010, 2011a; Montiel et al., 2011).
Together with other changes, these characteristics allowed a radial
and tangential cortical expansion and consequently allowed to
alter the conserved brain design that primates inherited from early
mammals (Aboitiz and Montiel, 2012).
In some way, placenta resembles the function of several endocrine
systems; thus it is positioned as the main endocrine organ through-
out intrauterine development. Placenta produces and releases a
number of signaling substances including cytokines, neuropep-
tides, neurosteroids, and amines (Petraglia et al., 1996). Some
of them are known for influencing fetal brain development, e.g.,
regulating the synthesis of neuroactive factors and corticogenesis
(Petraglia et al., 2010). Placenta is a crucial regulator of maternal–
fetal interactions (Hsiao and Patterson, 2012). Indeed, structural
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Montiel et al. Placenta and evolutionary development of the cerebral cortex
Exogenous signals from placenta would complement
telencephalic-signaling control during brain development. (A) The
upregulation of Wnt3a trough the canonical Wnt pathway induce self-renewal
of radial glia, early differentiation of Tbr2 cortical intermediate progenitors
(Munji et al., 2011) and restrict the expansion of the ventral pallium (antihem)
driven by Pax6. The antihem express secreted Frizzled-Related Proteins (Sfpr1
and 2, not shown) that neutralize the action of dorsally derived signals like
Wnts. Pax6 activates the expression of the dorsal proneural factor neurogenin
1/2 with the consequent activation of NeuroD1/2 and inhibition of Mash1, a
proneural factor highly expressed in subpallial domains. Thus, the
pallial/subpallial boundary is defined by the limit of expression of Ngn2 and
Mash1 (red arrow in A, D–H). (B) Mash1 induces a first group of transcripts in
the phase of expansion of neural progenitors (Castro et al., 2011) and
activates a second group of genes at the subsequent phases of cell cycle exit
and neuronal differentiation (Bertrand et al., 2002). (C–F) In situ hybridization
(ISH) expression pattern of signaling factors in mouse at developmental stage
E11.5 (G) Gene expression of signals/factors that helps to define the
telencephalic compartmentalization. (H) Subpallial expression of Mash1 at
E11.5. All ISH images were taken from the Allen Developing Mouse Brain
Atlas, available from: ch, cortical hem;
LP, lateral pallium; MP, medial pallium; VP, ventral pallium; SP,
changes in placenta are associated with the development of dis-
eases in later life (Barker et al., 1990). Moreover, placentas roles
in regulating nutrient t ransport, endocrine function and immune
tolerance are involved in growth restriction, hypoxia, and neuro-
logical complications (Fernandez-Twinn et al., 2003; Jansson and
Powell, 2007). Several functional pathways associate this organ
with brain development and, recently, reciprocal interactions from
the brain to placenta have been proposed (Ugrumov, 2010). In
addition, the tightening of the blood–brain barrier is a grad-
ual process, with an earliest angiogenesis phase occurring during
early brain developmental stages (E13–E14 in rat). This is charac-
terized by a high paracellular permeability (Liebner et al., 2011)
and therefore permitting fluent molecular interactions, which
potentially allows the placenta to participate in br ain development
(Bonnin et al., 2011).
One of these maternal–fetal interactions is through serotonin
(5-HT) pathway. This neuroactive factor has been associated
with proliferative activity, migration, and differentiation pro-
cesses during neocortical development (Vitalis and Parnavelas,
2003). Originally, it was though that endogenous sources of 5-
HT were responsible for the stimulation of corticogenesis, but
since there is a mismatch between this endogenous generation
of 5-HT (serotoninergic axons reach the corticostriatal junction
at E16 in rats) and the peak of cortical neurogenesis (E12–E17;
Vitalis and Parnavelas, 2003), placenta/brain interaction could
not be explained by endogenous sources of 5-HT (Figure 4).
Instead, the exogenous source of 5-HT produced by the placenta
is required to maintain normal levels of forebrain 5-HT during
early stages of brain development (Bonnin et al., 2011) and would
explain the developmental-functional association between 5-HT
and cortical development. Receptiveness to 5-HT during early
stages of cerebral cortical development depends on the expres-
sion of 5-HT receptor subtypes in the developing cortex (Lidow
and Rakic, 1995; Vitalis and Parnavelas, 2003). For an accurate
expression mapping of 5-HT1 receptors in mouse see Bonnin et al.
(2006). Interestingly, in monkeys, high levels of 5-HT receptors
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5-HT and 5-HT receptors in mouse developing cerebral
cortex. (A) Organization of the developing mouse cortex at E11, E14, and
E17, modified from Smart et al. (2002) with permission. (B) Dynamic of
5-HT brain sources during intrauterine development, early exogenous
(placenta; orange line) switch to a latter endogenous (5-HT brainstem
axons, purple line) 5-HT source, modified from Bonnin et al. (2011), with
permission. (C) Expression of 5-HT receptors during mouse cortical
development, ISH obtained from Allen Developing Mouse Brain Atlas,
available from: CP, cortical plate;
eCP, early cortical plate; eSP, early subplate; FL, fiber layer; LCP, lower
cortical plate; MZ, marginal zone; PP, preplate; SP, subplate; SVZ,
subventricular zone; VZ, ventricular zone; UCP, upper cortical plate.
expression have been reported in the proliferative zones of the
occipital lobe during neurogenesis (Lidow and Rakic, 1995). More-
over, some 5-HT receptors have been shown to be functional
before birth, suggesting that the y may orchestrate early steps
of cortical development. A postnatal injection of 5-HT1 recep-
tors agonist increases the number of hippocampal precursors and
neurons (Vitalis and Parnavelas, 2003), instead hippocampal pro-
liferation of precursors is repressed when the 5-HT synthesis is
pharmacologically inhibited (Brezun and Daszuta, 1999; Vitalis
and Parnavelas, 2003). 5-HT stimulation also promotes differen-
tiation, and therefore it is not clear whether 5-HT stimulation
mediates proliferation or simply speeds up the cell cycle (Vitalis
and Parnavelas, 2003). Interestingly, embryonic phar macological
depletion of 5-HT (Vitalis and Parnavelas, 2003) and cocaine
administration (which interacts with the 5-HT pathways; Clarke
et al., 1996), both induce microcephaly. Elevated 5-HT output
associated with a reduced 5-HT tr ansporter and 5-HT1A receptor
have been observed in hippocampus of adult animals that under-
went prenatal stress during fetal life, supporting the role of prenatal
imprinting on behavioral alterations in adult life (Van den Hove
et al., 2006; Mueller and Bale, 2008).
During pregnancy in mammals, placenta produces a large amount
of steroids, which are crucial for the survival, development, and
health of the developing embryo. Progesterone and estrogens
(estrone, estradiol, estriol, and its conjugated forms) are the
main hormones during pregnancy. Progesterone is fundamental
to modulate the maternal immune response allowing the maternal
tolerance of the fetal “semi-allograft.” On the other hand, estro-
gens are needed to promote the placental growth and angiogenesis
and influence fetal growth and metabolism. These steroids are
in extremely high concentrations in maternal circulation. How-
ever, placental tissue can metabolize them to inactive forms in
order to avoid fetal exposure. Many of these metabolites can act
as neurosteroids in adult brain, however, their contr ibution to
fetal brain development remains under debate. For example, allo-
pregnanolone, a progesterone metabolite modulates the activity
of GABAergic and glutamatergic neurons in fetal brain and may
mitigate the brain injury provoked by asphyxia in the hippocampal
region, since allopregnanolone can control the proliferation and
apoptotic patterns in cerebellum and hippocampus (Nicol et al.,
1999; Yawno et al., 2007, 2009).
Similar to sex steroids, glucocorticoids levels are lower in fetal
than in maternal circulation. This difference is attributable to
the high expression of 11β hydroxysteroid dehydrogenase type
2 (11β-HSD2) in both the placenta and fetus. In the placenta,
11β-HSD2 catalyzes the rapid inactivation of cortisol and cor-
ticosterone to inert 11 keto-products, and then it serves as
a glucocorticoid barrier, modulating the transfer of gluco-
corticoids to the fetus. In the placenta, 11β-HSD2 is highly
expressed in the syncytiotrophoblast of humans and in the
labyrinthine zone of rodents (Brown et al., 1996; Waddell et al.,
2012). Interestingly, animal models of maternal stress have been
associated with lower expression of placental 11β-HSD2 and
low birth weight in rodents, suggesting a relationship with fetal
programming (Fowden et al., 2008).
In general, normal concentrations of glucocorticoids are essen-
tial in the development of many organs, including central nervous
system. However, some conditions associated with elevated lev-
els of glucocorticoids, as stress or reduced capacity of placenta
to metabolize it, can leads to detrimental effects on brain devel-
opment and long-term behavioral effects, since glucocorticoid
receptors are hig hly expressed in some brain areas like hippocam-
pus (Reul and de Kloet, 1985). Primate models of stress and
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Montiel et al. Placenta and evolutionary development of the cerebral cortex
dexamethasone-exposure during pregnancy, exhibit degenerative
changes and reduction of brain volume, associated with lower
number of neurons in the hippocampus (Uno et al., 1989, 1990;
Coe et al., 2003). Moreover, these effects are maintained at least
until 2 years after birth, suggesting a possible long-term effect
in learning process and memory (Uno et al., 1994). In cere-
bral cortex, studies conducted in rodents have demonstrated a
reduction in dendritic arborization and synaptic loss in frontal
cortex of males but no effects were observed in females indicat-
ing a gender-specific mechanism of action (Barros et al., 2006).
In addition, cerebellum exhibits a reduction in the volume frac-
tion of granule cells nuclei in the gr anular layer with less synaptic
density (Ulupinar and Yucel, 2005). Some evidence points out
that prenatal glucocorticoid exposure can impact on serotoner-
gic and catecholamine pathways. Therefore, we can hypothesize
that the mechanism associated with endocrine function in pla-
centa can impact brain development, probably playing a central
role on brain evolution. However, the information about com-
parative endocrine function in different species is still limited,
making it difficult to interpolate these functions to the eutherian
High-throughput analysis of active transcripts is a powerful tool to
explore possible molecular interactions across organs and species.
Brain and placenta share some remarkable transcriptional fea-
tures as the expression of imprinted genes and the expression of
transcriptional pathways of immune interactions. Transcriptomes
from placenta (Hou et al., 2012; Figure 5A) and developing neo-
cortical brain compartments (Ayoub et al., 2011) can be clearly
differentiated between different mammalian species (Ayoub et al.,
2011; Hou et al., 2012). Comparing placenta transcriptomes
of representative species from three eutherian superorders: ele-
phant (Afrotheria), cow (Laurasiatheria), mouse, and human
(Euarchontoglires), Hou and collaborators found 2,963 genes
commonly expressed and a variable number of active transcr ipts
with species-specific expression (elephant, 904; cow, 436; mouse,
1,235; and human, 1,365; Hou et al., 2012; Figure 5A). At this
point of our on-going studies, we become interested in the pub-
lished list of human placental differentially expressed genes (Hou
et al., 2012), this species-specific set of genes exhibit significant
functional enrichment (the top five are reproduced from originals
in Figure 5B). The top one gene module is enriched in signal
molecules (this module was or iginally labeled as glycoproteins,
but we renamed it after reproduce this analysis to represent its
enrichment in signal genes, Figure 5B).
We compared these human placental signal-enriched tran-
scripts, and those transcripts from human developing cortex
(including the VZ, inner and outer SVZs, and cortical plate;
Fietz et al., 2012) looking for systemic protein–protein and gen-
eral functional interactions. To do this, we investigated known and
predicted protein interactions based on genomics, coexpression,
and literature data using STRING 9.05 (, a
network analysis database focused on protein interactions (Szk-
larczyk et al., 2011; Franceschini et al., 2013; Lv et al., 2013;
Figure 6).
Interactions analysis. (A) Distribution of placental transcripts
obtained by Hou et al. (2012) and reproduced with permission. (B) Top ve
functional enrichments of human species-specific placental transcripts
obtained by Hou et al. (2012) and reproduced with permission. The top one
enriched module (in red) was further analyzed in Figure 6.
We obtained 341 potential interactions from human placenta
active transcripts, ranging a STRING’s score from 0.404 to 0.998,
and initially not restricted to any target tissue. Then, we manually
projectedthis list onto the developinghuman cortextranscriptome
(Fietz et al., 2012) in order to detect plausible gene placenta–brain
interactions, obtaining 112 interactions, involving 73 transcripts
expressed only in the human placenta 20 transcripts coexpressed
in the human placenta and the human developing cortex, and
24 transcripts expressed only in the human developing cortex.
The genes expressed in the developing cortex and their placenta
interacting counterparts have been represented as a gene network
of protein interactions in the Figure 7.
Some of the identified pathways have been associated directly or
indirectly to proliferative activation, cell migration, and differen-
tiation during cortical development, and related to several neuro-
logical disorders. CSPG5 (chondroitin sulfate proteoglycan 5) is
expressed predominantly in the developing cortex participating in
dendrite branching and synapses formation (Aono et al., 2000).
CSPG5 interacts with the cell surface protein CD19 expressed
in the placenta, with the CSPG4 proteoglycan (chondroitin sul-
fate proteoglycan 4) and with the transmembrane protein SDC4
(syndecan 4) placenta–brain coexpressed genes. Interestingly,
transcriptomic analyzes have suggested that cell adhesion and
cell–extracellular matrix interactions promote the proliferation
and self-renewal of neural progenitors in the developing human
neocortex (Fietz et al., 2012). LGALS1 (lectin, galactoside-binding,
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Montiel et al. Placenta and evolutionary development of the cerebral cortex
STRING analysis of the interactions between placental
genes. The signals and glycoprotein enriched module of human placental
transcripts (Figure 5B) was analyzed using STRING 9.05 (,
a database of known and predicted protein interactions, which responds by
displaying a network of nodes (genes) connected by colored edges
representing functional relationships. Interactions of these genes were
identified based on the evidence indicated in the edges map. Unconnected
genes were removed.
soluble, 1), expressed in the developing cortex, encodes for
galectin, a known regulator of neural stem cell proliferation (Sak-
aguchi et al., 2006; Imamura et al., 2008) and interacts with the
cell surface glycoprotein CD8A placenta–brain coexpressed, and
CSH1 (chorionic somatomammotropin hormone 1 or placental
lactogen), CSH2 (chorionic somatomammotropin hormone 2),
GH2 (growth hormone 2), and VPREB1 (pre-B lymphocyte 1; also
named CD179A, cluster of differentiation 179A) placental genes.
PTK7 (protein tyrosine kinase 7) expressed in the developing
cortex, interacts with the peptide hormone CCK (cholecystokinin)
from placenta and encodes a transmembrane receptor in the
brain that controls a variety of developmental and physiologi-
cal processes, including cell polarity, cell migration, invasion, and
antagonize Wnt signaling (Peradziryi et al., 2011).
As mentioned above, placental 5-HT is an important regu-
lator of fetal brain development. Our transcriptomic analysis
suggests that other placental neuropeptides, as vasoactive intestinal
peptide (VIP) and CCK could be related to the fetal brain devel-
opment in humans. Moreover, according to comparative placental
transcriptomic analysis (Hou et al., 2012), these neuropeptides are
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Montiel et al. Placenta and evolutionary development of the cerebral cortex
Placental interactions with the developing human cerebral
cortex. From the subset of interactions generated from the STRING analysis
(Figure 6), we manually selected those genes interacting with human
developing cerebral cortex genes. Interacting human placental, human
developing cerebral cortex genes, and pairwise STRING’s interaction scores
were imported into Cytoscape 2.8.2. The human placenta–brain network was
constructed using a JGraph circle layout. Using NetworkAnalyzer, the
interactions across nodes were visualized in red lines, and the thickness of
the edges was weighted using the STRING’s score (Ss), which indicates the
level of interaction between nodes.
expressed in the human placenta but not in the mouse, cow or
elephant placentas. Observations in mice showed that VIP has an
influence over the brain and spinal cord development between
E11 and E17. In the brain, VIP effects are specifically restricted
to the cortex and tissue surrounding the ventricle. On the other
hand, in the mouse the maternal levels of VIP are increased dur-
ing E11, indicating a maternal VIP supply at early developmental
stages from sources other than placenta (Hill et al., 1996; Hou et al.,
2012). At difference, in humans has been found a placental source
of VIP (Hou et al., 2012). Other studies have demonstrated that
VIP can stimulate neurogenesis as well as differentiation and neu-
rite outgrowth (Hill, 2007). Thus, maternal VIP from two different
sources would be participating in the enlargement of the brain: a
placental source observed in humans, and a non-placental source
detected in mice.
Other gene interactions are elusive to be functionally inter-
preted, GABBR1 [gamma-aminobutyric acid (GABA) B receptor
1] is expressed in the developing cortex and interacts with other
GABA receptor in the placenta (GABRG2, GABA A receptor,
gamma 2). GABBR1 has been associated with anxiety (Le-
Niculescu et al., 2011), autism (Fatemi et al., 2009), schizophrenia
(Hegyi, 2013), and epilepsy (Peters et al., 1998), but there are not
reports about brain development implications. EDN (endothelin
3) is an endothelium-derived vasoactive peptide expressed in the
placenta, involved in a variety of biological functions and interact-
ing with EDNRA (endothelin receptor type A), which is expressed
in the developing cortex and upregulated after hypoxic precon-
ditioning in the immature br ain (Gustavsson et al., 2007). On
the other hand, CCK has been identified in different brain areas
through development. In mouse embryos, CCK expression first
appears at E8.5–E9.5 in the neural crest cells and their precursors
(Lay et al., 1999). In the embryonic rat brain CCK is expressed in
the ventral tegmental area and in the primordium of the medial
forebrain bundle from E15 onward. Cortical expression can be
initially detected prenatally at E21 in rats (Cho et al., 1983). Thus,
other CCK sources, as placenta in humans, would be relevant at
earlier developmental stages. CCK functional significance in the
intrauterine neurogenesis is unknown, however, CCK1 receptors
have been associated to adult neurogenesis (Sui et al., 2013). Our
transcriptome analysis revealed that VIP and CCK are associated
with CHGA (chromogranin A or parathyroid secretory protein 1;
Hocker et al., 1998), which encodes for the protein chromogranin
A, a prohormone susceptible to be cleavage, generating catestatin,
vasostatin and SgII-derived peptides like secretoneurin (Taupenot
et al., 2003). These proteins are involved in the biogenesis of secre-
tory g ranules,neurotransmitter accumulation, and in the control
of neurosecretion ( Montesinos et al., 2008). Chromogranin A is
strongly associated with Alzheimer’s disease. It is localized in
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Montiel et al. Placenta and evolutionary development of the cerebral cortex
neuritic plaques where it can induce inflammation by activa-
tion of the microglia (Yasuhara et al., 1994; Hooper et al., 2009).
On the other hand, a reduction in chromogranin A has been
found in the layers III–VI of the prefrontal cortex (Brodmann
area 9) of schizophrenic subjects, and associated to a lower num-
ber of presynaptic terminals and synaptic contacts, accompany
by a decreased synaptic t ransmission (Iwazaki et al., 2004). These
antecedents only demonstrate that chromogr anin A has a possi-
ble functional role in the human brain. Studies about the role of
this protein on brain development are needed to draw conclusions
about the developmental cortical expression and its association
with placental peptides. However, it is remarkable and intriguing
that CHGA also is predicted to be interacting with the transcript
of beta subunit of chorionic gonadotropin (CG). During preg-
nancy in some species,including human, CG is secreted by the
trophoblast and maintains the progesterone secretion from the
corpus luteum at the beginning of gestation. In humans, the
production of CG declines around 6–8 weeks of pregnancy. Inter-
estingly, receptors for luteinizing hormone (LH)/human chorionic
gonadotropin (hCG) have been identified in multiple areas of the
brain, including the cortex. Also, rat brain expresses these receptors
and neurotropic effects of LH and hCG have been demonstrated
in fetal rat brain (Lei and Rao, 2001). However, since there are
other human placental functionally enriched modules and other
species remain to be analyzed, this list can be easily extended
in order to obtain a better understanding about the significance
of this differential expression. We consider that these prelimi-
nar y findings are complementary to the better characterized 5-HT
signal originated in the placenta and interacting w ith the fetal
forebrain at early developmental stages, the characterization of
molecular interactions during development will open new oppor-
tunities to interpret evolutionary neurobiology and would reveal
the causal relations in the pathogenesis of various cortical devel-
opmental disorders (Bonnin et al., 2011). With the exception of
PILRA and CECR1, all human predicted transcripts are expressed
in the developing cortex of the mouse. Because of this pre-
served pattern of cortical expression, species-specific interactions
seem to be originated in the differentially activated transcripts in
human placenta.
The main idea proposed in this article is that the evolutionary
expansion of the eutherian brain (specially in primates) would be
associated with developmental long distance interactions through
molecular signals displayed by the placenta. This hypothesis is
complementary to those relied on the intrinsic control of neocor-
tical development. In addition to the currently described 5-HT
developmental interactions between the placenta and the cerebral
cortical proliferative compartments, our transcriptomic analysis
indicates new candidates for promoting neocortical expansion
(e.g., CSPG5, LGALS1, PTK7). Thus, the active interaction
between the placenta and the proliferative cortical compartments
would amplify the number of neural progenitors as a strategy
to increase the total number of neurons in the mature brain.
If this proposal is correct, it not only allows to obtain a big-
ger brain, but also it would permit to reduce the length of
the pregnancy required to generate bigger brains, supporting a
developmental strategy to escape from fetal-maternal parental
conflict. Interestingly, such interactions would conduce to fetal
programming changes representing plausible adaptive advan-
tages to environmental demands before and after birth, or
maladaptation when there is a mismatch between the program-
ming and the environment requirements (Hsiao and Patterson,
2012). For example, the known effect of maternal undernutr i-
tion over offspring metabolism and subsequent susceptibility to
obesity later in life (Krechowec et al., 2006; Hsiao and Patter-
son, 2012). Several maternal insults, including maternal infection
and maternal malnutrition, increase susceptibility to intrauterine
growth restriction and all these factors are linked to schizophre-
nia, autism and cerebral palsy in the offspring (Brown and
Susser, 2008; Atladóttir et al., 2010; Brown and Patterson, 2011;
O’Callaghan et al., 2011). We are aware that detection of pla-
cental transcripts expression and their targets alone does not
necessarily involves an effective functional interaction, there-
fore more studies are necessary to establish which mechanisms
are implicated at the molecular level. However, according to
our preliminary findings, it is remarkable that se veral path-
ways would be implicated in placenta–brain interactions and
these could have a high impact in order to expand the cur-
rent understanding of the evolutionary dynamics of neocortical
We thank to Gracielle Pereira and Javiera Palma for their crit-
ical comments on this manuscript. Heidy Kaune is a recipient
of Becas Chile PhD scholarship from the Government of Chile
and PhD scholarship for Academics from Universidad Diego Por-
tales, Chile. Juan F. Montiel and Manuel Maliqueo are recipients
of Becas Chile postdoctoral fellowship from the Government of
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Conflict of Interest Statement: The
authors declare that the research was
conducted in the absence of any com-
mercial or financial relationships that
could be construed as a potential con-
flict of interest.
Received: 31 March 2013; paper pend-
ing published: 22 April 2013; accepted:
25 June 2013; published online: 19 July
Citation: Montiel JF, Kaune H and
Maliqueo M (2013) Maternal–fetal unit
interactions and eutherian neocortical
development and evolution. Front. Neu-
roanat. 7:22. doi: 10.3389/fnana.2013.
Copyright © 2013 Montiel, Kaune and
Maliqueo. This is an open-access arti-
cle distributed under the terms of the
Creative Commons Attribution License,
which permits use, distribution and
reproduction in other forums, pro-
vided the original authors and source
are credited and subject to any copy-
right notices concerning any third-party
graphics etc.
Frontiers in Neuroanatomy July 2013
Volume 7
Article 22
... This could be related to a prolonged neurogenic period that correlates with the duration of gestation, exposing the developing neocortex to maternal environment for a longer period of time. This includes a whole variety of circulating factors, such as hormones, that are delivered by the blood vessels and the cerebrospinal fluid system and potentially influence neurogenesis (Montiel et al., 2013;Stepien et al., 2021). ...
Full-text available
Evolutionary studies indicate that the nervous system evolved prior to the vascular system, but the increasing complexity of organisms prompted the vascular system to emerge in order to meet the growing demand for oxygen and nutrient supply. In recent years, it has become apparent that the symbiotic communication between the nervous and the vascular systems goes beyond the exclusive covering of the demands on nutrients and oxygen carried by blood vessels. Indeed, this active interplay between both systems is crucial during the development of the central nervous system (CNS). Several neural-derived signals that initiate and regulate the vascularization of the CNS have been described, however less is known about the vascular signals that orchestrate the development of the CNS cytoarchitecture. Here, we focus on reviewing the effects of blood vessels in the process of neurogenesis during CNS development in vertebrates. In mammals, we describe the spatiotemporal features of vascular-driven neurogenesis in two brain regions that exhibit different neurogenic complexity in their germinal zone, the hindbrain and the forebrain.