Download Genomic imprinting effects on brain development and function

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Genomic imprinting effects on
brain development and function
Lawrence S. Wilkinson, William Davies and Anthony R. Isles
Abstract | In a small fraction of mammalian genes — at present estimated at less than 1% of
the total — one of the two alleles that is inherited by the offspring is partially or completely
switched off. The decision as to which one is silenced depends on which allele was inherited
from the mother and which from the father. These idiosyncratic loci are known as imprinted
genes, and their existence is an evolutionary enigma, as they effectively nullify the
advantages of diploidy. Although they are small in number, these genes have important
effects on physiology and behaviour, and many are expressed in the brain. There is increasing
evidence that imprinted genes influence brain function and behaviour by affecting
neurodevelopmental processes.
Parthenogenetic embryos
Embryos that develop in the
absence of fertilization by a
male. Parthenogenetic cells
contain two copies of the
maternal genome, but have no
paternal contribution.
Androgenetic embryos
Embryos that develop in the
absence of a contribution from
a female. Androgenetic cells
contain two copies of the
paternal genome.
Behavioural Genetics Group,
School of Psychology and
Department of Psychological
Medicine, School of Medicine,
Cardiff University,
Tower Building, Park Place,
Cardiff, CF10 3AT, UK.
Correspondence to L.S.W.
e-mail:
[email protected]
doi:10.1038/nrn2235
Published online 10 October 2007
At the moment of conception, each parent contributes
one copy of each autosomal gene to their offspring. In
most cases, the expression of these genes is indifferent to
parental origin. However, imprinted genes are special in
that they are subject to a form of epigenetic control that
is mediated by chemical marking of the DNA and associated proteins. This leads to the selective expression of
one of the two alleles, depending on whether they pass
through the egg or the sperm1 (FIG. 1). The upshot of
this epigenetic control is a ‘parent-of-origin’ pattern
of imprinted gene expression in the somatic tissues of
the offspring. Many of the genes that are known to be
subjected to imprinting are expressed in the placenta
and the brain2,3. The existence of genomic imprinting
raises many questions, including why it exists at all:
where silencing is complete, imprinted genes are effectively haploid, which negates the considerable benefits
of diploidy. The most resilient (but not exclusive; see
BOX 1 for alternative views) hypothesis that has been
put forward to explain this evolutionary conundrum
is that imprinted genes represent the consequences of
a form of ‘intragenomic conflict’ that arises from the
differing interests of maternal and paternal genomes
in aspects of the physiology and behaviour of the offspring. These different interests arise, in turn, from
asymmetries of relatedness between the offspring and
the parents4 (BOX 1).
In this Review, we focus on genomic imprinting in
the brain and discuss the emerging evidence that brainexpressed imprinted genes can influence brain function
and behaviour through effects on neurodevelopment. In
particular, we emphasise recent data that indicate how
832 | November 2007 | volume 8
imprinted genes affect cell survival and differentiation
and associated cell-signalling pathways. Our Review
brings together a number of diverse areas, including brain development, mother–infant interactions,
long-term programming of behaviour and the risk of
neuropsychiatric disorders. It also addresses the extent
to which the pattern of genomic-imprinting effects on
neurodevelopment can be explained by the way in which
imprinted genes have evolved.
Effects on brain size and organization
Imprinted genes and growth. Growth and development are key processes for the action of imprinted
genes. Some of the first experimental evidence for the
existence of genomic imprinting arose from the failure
of parthenogenetic (PG) and androgenetic (AG) mouse
embryos to develop normally and survive to term5,6.
Subsequently, the first imprinted genes to be identified
encode growth factors, namely paternally expressed
insulin-like growth factor 2 (Igf2) 7 and maternally
expressed insulin-like growth factor 2 receptor (Igf2r)8.
The discovery of these genes and the fact that they were
reciprocally imprinted caused great excitement, as their
existence confirmed earlier theoretical predictions,
and their antagonistic actions on growth provided
strong initial evidence in favour of the general notion
of intragenomic conflict 9. These seminal data also
encouraged the idea that the allocation of resources
from the mother to the offspring is an important arena
for conflict between the male and female genomes10.
According to this idea, the paternal interest seeks to
maximise resource allocation to the fetus in the current
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Zygote
Adult animal
Gene 1 Gene 2
Gene 1 Gene 2
Somatic
lineages
Gene 1 Gene 2
Fertilization
Gene 1 Gene 2
Germline lineage
Sperm
Gene 1 Gene 2
Gene 1 Gene 2
Gene 1 Gene 2
Germline
establishment
Egg
Gene 1 Gene 2
Gene 1 Gene 2
Gene 1 Gene 2
Figure 1 | The cycle of genomic imprinting. The parental-allele expression that is
displayed by imprinted genes is achieved by parent-of-origin-specific
epigenetic
Nature Reviews
| Neuroscience
modifications (represented by orange lollipops) — chiefly, DNA methylation at key
control regions and/or histone modifications1. This epigenetic marking results in
differential reading by the transcriptional machinery and, as a consequence, the gene is
expressed predominantly from one parental allele. The epigenetic marks are erased and
reset in the nascent germline of each developing embryo. Thus, depending on whether
an individual is destined to become a mother or a father, the marking that controls
imprinted-gene expression is reset in the developing eggs and sperm, respectively. This
inherited set of marks is then maintained in the somatic cell lineages of the offspring, but
in their germ cells the whole cycle is repeated once again. As a result of this cycle of
epigenetic marking, an allele of a maternally expressed gene (represented as pink boxes)
in a male individual will not be expressed in that male’s offspring, as it will now be
inherited as a paternal allele (represented as blue boxes). As a consequence, the
inheritance of imprinted traits is non-Mendelian, and is often characterized by passage
down a parental line and/or skipping of generations. Figure modified, with permission,
from REF. 114  (2004) Elsevier Science.
pregnancy (IGF2 is growth-enhancing), whereas it is in
the interest of the maternal genome to share resources
equally across all of the mother’s offspring (IGF2R is
growth-inhibiting) (BOX 1). In terms of growth phenotypes, this view is supported by most, but not all, of the
findings that have been obtained to date.
Early work in mouse chimaeras. A powerful early demonstration that, in addition to their influence on growth
in general, imprinted genes can have specific effects on
brain size and organization, came from elegant work
using mouse chimaeras. These chimaeras were created
by adding normal cells (N) to PG and AG embryos at
an early stage of development, which produced PG–N
and AG–N animals, respectively. Both types of low contribution (<40% PG or AG) chimaera mice survived to
term, but they had different brain phenotypes11,12: the
brains of PG–N chimaeras, especially the forebrain,
were relatively large in comparison with those of wildtype controls, despite the animals’ smaller overall body
nature reviews | neuroscience
size. By contrast, AG–N chimaeras had relatively small
brains but larger bodies. In an additional experimental
refinement, the PG and AG cells were engineered to
express the reporter gene lacZ, which made it possible to
observe their location in the brain in detail. This analysis
showed that the distribution of PG and AG cells was not
random — rather, it had distinct patterns. Although both
AG and PG cells were distributed throughout the brain
early in development, they each established persistent
localizations in different brain regions later in embryogenesis (BOX 2). AG cells were preferentially localized to
the hypothalamic, septal and pre-optic areas of the bed
nucleus of the stria terminalis, but were excluded from
the overlying cortex. Conversely, PG cells contributed
substantially to neocortical areas, to the striatum and
to the hippocampus, but were not present in the brain
regions that were colonized by the AG cells.
The chimaera data were important because they
strongly implicated imprinted genes in processes of
neurodevelopment and indicated that the maternal and
paternal genomes could have dissociable effects on functionally distinct brain systems. This observation made
it tempting to place the chimaera data in the context
of ‘genomic conflict’ as applied to brain functioning.
Did the parent-of-origin effects on neurodevelopment
in the chimaeras reflect differing interests of the parental genomes in the brain function and behaviour of the
offspring12? If so, one interpretation of the data might
be that the maternal interests are, in broad terms, mediated by neurodevelopmental effects on ‘higher’ cognitive
systems, whereas the paternal interests are mediated by
effects on brain systems that sub-serve ‘emotional’ or
‘autonomic’ functions13. However, two caveats indicate
that the situation might be more complex than was first
envisaged. First, there is no reason to assume that the
final locations of the AG and PG cells are a result of
the net effects of all paternally (in AG cells) and maternally (in PG cells) expressed imprinted genes. Instead,
the localization of AG and PG cells in the brain might
arise from the large effects of a few imprinted genes.
Indeed, this possibility has been put forward as an explanation for the failure of pure (as opposed to chimeric)
parthenogenetic embryos to survive14. Second, as data on
the spatial expression patterns of individual imprinted
genes have accumulated, it has become apparent that,
although for many genes the pattern of imprinting corresponds to that seen in the chimaeras, there are several
exceptions2. This discrepancy might arise from the ‘few
genes, large effects’ caveat, but it could also be the result
of a contribution to conflict at the molecular level (in
addition to functional brain systems), with maternally
and paternally expressed genes counteracting one another’s expression, or acting in an antagonistic manner on
biochemical pathways2.
Imprinted-gene expression in neurodevelopment. Any
consideration of the specific mechanisms by which
genomic imprinting might influence neurodevelopment has to take account of the complex spatial and
temporal expression patterns that are exhibited by
imprinted genes in the brain2. A large proportion of the
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Box 1 | The evolution of genomic imprinting
The unique epigenetic status of imprinted genes has led to several theories as to why
they exist. These include ideas that they occur to prevent parthenogenesis99, as a
means to give rise to rapid evolution at certain loci100, and to promote the coadaptation of the physiology and behaviour of the mother and her offspring67,101.
Although all these scenarios are valid, the theory that best explains most current data,
at least in terms of growth phenotypes, is the idea that genomic imprinting evolved as a
consequence of intragenomic conflict, which occurs when the maternal and paternal
genomes have different ‘interests’. In this respect, imprinted genes represent classic
‘selfish’ genes102, in that paternal and maternal genes ‘act’ in their own interests,
despite the fact that these interests might not be optimal for the individual in which
the genes find themselves.
One scenario in which intragenomic conflict might arise is when asymmetries of
relatedness occur. This is best summarized by David Haig, who said that “my mother’s
kin are not my father’s kin”103. The ‘maternal half’ of an individual’s genome is closely
related to that of relatives in the maternal line, and it is generally not at all related to
the genome of relatives in the paternal line (and vice versa): what is good for maternally
related genes might not be good for paternally related genes. In mammals, this ‘battle
of the sexes’ is felt most acutely with regard to the allocation of resources between
mother and offspring9. Here, paternal genes are expected to maximize resources to an
individual offspring, whereas maternal genes limit them so that they are equally
distributed among all the mother’s offspring — an idea that is supported by the number
of imprinted genes that affect placental function, in utero growth and suckling
behaviour10. The classic examples are the Igf2 and Igf2r genes in the mouse7,8,9. IGF2, the
product of the paternally expressed Igf2 gene, promotes growth in the offspring when
it binds to its main receptor, IGF1R. However, IGF2 also binds to the IGF2 receptor
(IGF2R, the product of Igf2r), which is maternally expressed, and here it is targeted for
destruction, thus reducing any effects on growth.
Such asymmetries of relatedness also occur in matrilineal and patrilineal social
groups, in which maternal and paternal genes, respectively, are more common and are
shared with other group members. Here, the differential interests between parental
genomes are predicted to affect social and affiliative behaviours81,103.
Yeast two-hybrid screen
A molecular method for
determining whether proteins
interact. The binding and
activation domains of the
transcription factor GAL4 are
split and fused to the proteins
in the assay. If the two proteins
interact, the reconstituted
GAL4 initiates the transcription
of a reporter gene.
BAX
A well characterized regulator
of apoptosis that exerts its
effects through
heterodimerization with BCL2.
100 or so imprinted genes that have been discovered so
far are expressed in brain tissue (although not necessarily exclusively). These genes can show substantial
variability in terms of where (including in what cell
type) and when they are expressed and also, in some
cases, in their imprinting status. For example, imprinting of Ube3a, which encodes the ubiquitin ligase protein UBE3A (formerly known as E6-associated protein,
E6AP) and is maternally expressed, is confined to
discrete neuronal populations of the olfactory bulb,
the hippocampus and the cerebellum; elsewhere in the
brain and in other body tissues, UBE3A is biallelically
expressed15,16. Imprinting can also be short-lasting, as
in the case of copper metabolism (Murr1)-domaincontaining 1 (Commd1), which is preferentially maternally expressed in adulthood but exhibits biallelic
expression in neonates17. These examples emphasize
the dynamic nature of imprinted-gene expression
in the brain, which can add a further subtle level of
control to imprinted-gene function.
We do not yet have a full picture of the developmental
profiles of brain-expressed imprinted genes and, on the
basis of these limited data, no organizational patterns
have yet emerged with regard to the direction of imprinting (that is, whether a gene is maternally or paternally
expressed), apart from a bias in terms of spatial location,
which might be argued to reflect the dichotomy that is
seen in the mouse chimaeras. Nonetheless, it is clear that
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imprinted genes are active at key developmental time
points (TABLE 1). Note, however, that the expression of these
genes is not confined to the prenatal period: expression
and imprinting can persist into the postnatal period and
beyond, sometimes into the adult brain15,18. It would seem
that, although many imprinted genes are in a position to
influence early brain development and differentiation
in utero, they might also contribute to processes of brain
development and sculpting that continue after birth. The
persistence of imprinting in the adult brain might also, of
course, indicate that imprinted genes have functions that
are independent of neurodevelopment altogether.
Effects on cell survival and differentiation. Our understanding of the cellular and molecular mechanisms by
which imprinted genes can modify brain development
has recently been enhanced by in vitro molecular screening methods (commonly yeast two-hybrid screens) that
have been used to examine the binding and interactions
of imprinted-gene products with other molecules. One of
the most extensively characterized imprinted genes in
this regard is paternally expressed gene 3 (Peg3), which
encodes a large multidomain protein that might act as a
transcription factor owing to its putative DNA-binding
activity19. Peg3 is highly expressed in the brain20. The
main phenotypic feature of female mice that lack
paternally inherited Peg3 is a reduction in the number
of oxytocin-producing neurons in the hypothalamus,
consistent with the functional deficits in maternal
behaviour and milk let-down that have been observed
in these mice20.
The precise events that lead to a reduction in
oxytocin neurons are unknown, but there is indirect evidence that they might involve interactions of
PEG3 protein with p53-mediated cell-death pathways
(FIG. 2a). In normal transfected mouse fibroblasts, Peg3
expression is upregulated in cells that co-express p53
and the proto-oncogene Myc; these cells are poised to
enter apoptosis. Elegant follow-up studies indicated
that PEG3 and the p53-inducible gene product, seven
in absentia 1A (SIAH1A), cooperate as downstream
mediators of p53-induced cell death, with PEG3 being
the critical ‘switch’ protein that enables cells to undergo
apoptosis as opposed to growth arrest21. Importantly,
the findings obtained in non-neural tissue and from
molecular screens regarding the role of PEG3 in apoptosis seem to be generalizable to the brain in the context
of both an ischaemia/hypoxia model22 and work in neuronal cell cultures. Indeed, data from neuronal cultures
indicate that PEG3 enables apoptosis by encouraging
the translocation of BCL2-associated X protein (BAX)
from the cytosol to the mitochondria23. PEG3 has been
suggested to interact with TNF receptor-associated
factor 2 (TRAF2), which potentiates nuclear factor κB
(NF‑κB) activation in response to tumour necrosis factor (TNF)24; as NF‑κB activation confers resistance to
apoptosis25, PEG3 might therefore, in some instances,
promote cell survival. However, the sensitivity of primary embryonic fibroblasts derived from Peg3-knockout
mice to the cytotoxic action of TNF does not differ from
that of cells derived from control mice26.
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Box 2 | The distribution of parthenogenetic and androgenetic cells in the brain of chimeras
Results from mouse chimaera experiments11,12 have
Striatum
Hippocampus
indicated a reciprocal distribution of parthenogenetic
Frontal cortex
(PG; shown in pink) and androgenetic (AG; shown in blue)
cells in the brain. Although early in brain development
both cell types are found throughout the brain, PG cells
are selectively excluded from hypothalamic and pre-optic
areas, and instead accumulate in the cortex and the
striatum. The opposite pattern is seen for AG cells, which
are excluded from the cortex and the striatum, and are
enriched in hypothalamic and pre-optic areas. AG and PG
cells are also found in other brain regions, but not to any
great extent and not in numbers that exceed the numbers
of normal cells in N–N control chimaeras11,12. PG cells have
Pre-optic area
Hypothalamus
also been found to contribute to other neural areas,
including the retina, the main olfactory mucosa and the
vomeronasal organ (VNO). The main olfactory mucosa and
Nature Reviews | Neuroscience
the VNO are of particular interest, because in the main olfactory system, the distribution of PG cells is bilaterally
symmetrical, possibly reflecting a contribution of imprinted genes to the patterning of specific olfactory neurons11.
In addition to the reciprocal distribution pattern of cells, the neurodevelopmental abnormalities in AG–N or PG–N
chimaeras are striking. AG–N chimaeras, despite having increased body weight, have reduced brain weight and a
reduced brain/body weight ratio, relative to controls12. Conversely, PG–N chimaeras have reduced body weight and,
when normalized for body weight, an increased brain/body weight ratio, possibly due in its entirety to the proliferation
of PG cells in the forebrain area11. Furthermore, in PG–N chimaeras, this increased brain/body weight ratio correlates
with the relative contribution of PG cells. This paradoxical effect (brain size normally positively co-varies with body
weight104) suggests that maternal and paternal genomes have differential interests with regard to the allocation of
resources to brain and body development13.
Given the difficulty of generating these chimaeras, behavioural studies of adult low contribution chimaeras are limited.
However, some analysis of sexual and aggressive behaviours has been performed for PG–N chimaeras. Remarkably, in a similar
manner to the brain-weight data, the level of aggressive behaviour positively correlated with the contribution of PG cells11.
Angelman syndrome
A neurodevelopmental
disorder that is characterized
by mental retardation, ataxia
and a ‘happy’ disposition. It
results from a lack of
maternally expressed genes on
chromosome 15, at positions
q11–q13.
Ube3a is another well studied imprinted gene that is
expressed in the brain. The paternal allele of this gene
is silenced and the maternal allele is expressed. Like PEG3,
UBE3A protein is present in both the cytoplasm and the
nucleus27. A priori, UBE3A seems to have the potential to
affect neurodevelopment in several ways (FIG. 2b). UBE3A
was originally identified as a factor that associates with
the papillomavirus E6 oncoprotein to bring about the
ubiquitin-dependent degradation of p53 (hence its original name, E6-associated protein)28. In vivo studies have
shown that UBE3A can also promote the degradation of
p53, even in the absence of viral E6 (Ref. 29). In addition,
UBE3A can ubiquitylate, and thereby target for destruction, the DNA-repair and cell-cycle-progression proteins
HHR23 and O-6-methylguanine-DNA methyltransferase
(MGMT)30,31 and the putative neuronal outgrowth Rho
guanine nucleotide exchange factor ECT2 (Ref. 32).
In addition to its ubiquitin ligase activity, UBE3A
functions as a transcriptional co-activator, directly interacting with the progesterone and androgen receptors in
a hormone-dependent manner. Recent experiments
in mice have indicated that a fundamental role of UBE3A
(in the prostate gland at least) might be to promote
growth and development through effects on androgenreceptor function and by limiting p53-mediated apoptosis29,33,34. UBE3A is also thought to mediate degradation
of the oestrogen receptor, with this interaction being
modulated by a Ca2+–calmodulin complex35. Although
their interpretation is speculative, these data indicate that
UBE3A might modulate the effects of gonadal hormones
on brain development and function.
nature reviews | neuroscience
At the gross level, Ube3a-knockout mice in which
the maternal allele is deleted and the paternal allele is
not expressed have a normal neuroanatomy. However,
more subtle anatomical abnormalities might be present,
as these animals show deficits in context-dependent
learning, long-term potentiation, hippocampal electroencephalographic (EEG) recordings and cerebellar
activity36–40. Furthermore, consistent with an in vivo role
for UBE3A in degrading p53, cytoplasmic p53 levels are
elevated in Ube3a-knockout mice37. In humans, specific
mutations of UBE3A are associated with the neurodevelopmental disorder Angelman syndrome (see below).
Individuals with Angelman syndrome have anatomical
abnormalities, including cortical atrophy, cerebellar
dysmyelination and Purkinje cell loss, and ventricular
enlargement2. In most cases of Angelman syndrome, it
appears that it is the ubiquitin ligase function of UBE3A
that is lost, rather than the co-activator function41,
implying that the neurodevelopmental phenotype of
Angelman syndrome results primarily from aberrant
ubiquitylation.
The three other brain-expressed imprinted genes that
have been characterized to some extent (in terms of the
molecular interactions of their products) are paternally
expressed necdin (Ndn), growth-factor-receptor-bound
protein 10 (Grb10) and delta-like 1 (Dlk1).
Ndn, the most extensively characterized of the three,
is a member of the melanoma-associated antigen gene
(MAGE) superfamily. Work in cell-culture systems
indicates that its gene product, necdin, can influence multiple pathways that are involved in neuronal
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Table 1 | Imprinted gene expression in the brain is a spatiotemporally dynamic process
Features of
the gene
Examples
Direction of
imprinting
Function of the
gene product
Expression dynamics
Chromosomal
location
Highly
expressed
during
embryogenesis
and in the
neonatal
period
Ndn
Paternally
expressed
Regulator of neuronal
differentiation and
axonal outgrowth
In the mouse brain, Ndn is expressed during
early periods of neuronal generation and
differentiation; peak levels of expression occur
between postnatal days 1–4 (Ref. 115)
Central chromosome 7
(mouse);
15q11–15q13 (human)
Gtl2
Maternally
expressed
Untranslated RNA with In the mouse brain, the highest expression of Gtl2 Chromosome 12
possible regulatory
is between E12.5 and P0 (Ref. 116)
(mouse); 14q32
function
(human)
H19
Maternally
expressed
Untranslated RNA with In the fetal brain (6–12 weeks of gestation), H19
possible regulatory
is highly expressed; in the adult brain, H19 has
function
low expression that is limited to the pons and the
globus pallidus117
Chromosome 7
(mouse); 11p15.5
(human)
Nesp
Maternally
expressed
Neuroendocrine
secretory protein,
involved in both
constitutive and
regulated secretion
Chromosome 2
(mouse); 20q13.2
(human)
SnrpnsnoRNA
Paternally
expressed
The gene is a long
In the brain, Snrpn-snoRNA is imprinted into
transcript that encodes adulthood118
various products
Chromosome 7
(mouse); 15q11–
15q13 (human)
Biallelic
Commd1
expression
during
embryogenesis;
imprinted
Igf2
expression in
adulthood
Maternally
expressed
Involved in copper
metabolism; the
encoded protein
interacts with NF‑κB
Commd1 is biallelically expressed in the
embryonic and neonatal mouse brain, but
maternally expressed in the adult mouse brain17
Chromosome 11
(mouse); 2p15 (human)
Paternally
expressed
Promotes growth
Igf2 undergoes biallelic expression in the fetal
brain (6–12 weeks of gestation), with monoallelic
expression in other fetal tissues; in the adult
brain, there is biallelic expression in the pons and
monoallelic expression in the globus pallidus, the
Raphe nucleus and the hypothalamus117
Chromosome 7
(mouse); 11p15.5
(human)
Brain (region)specific
imprinting
Ube3a
Maternally
expressed
Ubiquitin ligase and
transcriptional coactivator activities
In the mouse brain, Ube3a is maternally
expressed in Purkinje neurons, the hippocampus
and the mitral cells of the olfactory bulb, and
exhibits biallelic expression elsewhere15; in
humans, UBE3A imprinting is restricted to
the brain16. Ube3a shows cell-type-specific
expression119
Central chromosome 7
(mouse);
15q11–15q13 (human)
Imprinted in all
tissues apart
from the brain
Zim1
Maternally
expressed
Transcriptional
regulator
In the mouse, Zim1 is biallelically expressed in the Chromosome 7
neonatal and adult brain120
(mouse); no human
orthologue
Speciesspecific
imprinting
Commd1/
COMMD1,
U2af1-rs1
Maternally
expressed,
paternally
expressed
COMMD1 protein is
involved in copper
metabolism. U2af1-rs1
encodes a zinc finger
protein
In the mouse, Commd1 is maternally expressed,
Chromosome 11
and contains the paternally expressed
(mouse); 2p15 (human)
U2af1-rs1 in the first intron. In humans, COMMD1
is biallelically expressed, and does not contain a
homologue of U2af1-rs1 (Ref. 121)
Polymorphic
imprinting
Dlx5
Maternally
expressed
DNA binding;
downstream effects on
axonogenesis
Dlx5 is polymorphically imprinted in the
human brain122 but biallelically expressed in the
mouse brain50
Chromosome 6
(mouse); 7q22 (human)
Htr2a/
HTR2A
Maternally
expressed?
Serotonin receptor
subunit
HTR2A is monoallelically expressed in 4 out of 18
adult human brains123
Chromosome 14
(mouse); 13q14
(human)
Imprinted into
adulthood
Nesp is imprinted throughout development and
in adulthood79
Additional information is available on the author’s homepage (see Further information). Commd1, copper metabolism (Murr1)-domain-containing 1; Dlx5, distal-less
homeobox 5; E12.5, embryonal day 12.5; Gtl2, gene trap locus 2; Htr2a, 5-hydroxytryptamine receptor 2A; Igf2, insulin-like growth factor 2; Ndn, necdin; Nesp,
neuroendocrine secretory protein; P0, postnatal day 0; snoRNA, small nucleolar RNA; Snrpn, small nuclear ribonucleoprotein N; U2af1-rs1, U2 small nuclear
ribonucleoprotein auxiliary factor, small subunit 1; Ube3a, ubiquitin protein ligase E3A; Zim1, zinc finger, imprinted 1.
survival, differentiation and outgrowth (FIG. 2c). The main
cellular targets for necdin are proteins that are involved
in nerve growth factor (NGF)-mediated cell survival
and apoptosis. In the cytoplasm, necdin facilitates the
association of the NGF receptors p75 and TRKA with
each other42,43; following endocytosis, the intracellular
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domains of these receptors are cleaved by γ-secretase44
and translocated to the nucleus, possibly with necdin
attached. In the nucleus, necdin binds to the transcription factors E2F1 (Ref. 45) and p53 (Ref. 46), and also to
its homologous MAGE protein, MAGED1 (also known
as DLXIN1 and NRAGE)47, which is a specific facilitator
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a
p53
PEG3
MYC
p53
MYC
p53
Peg 3
Siah1a
p53
BAX
SIAH1A
Apoptosis
Nucleus
Mitochondrion
b
Ubiquitin
Ubiquitin
ligase
activity
Transcriptional
co-activator
activity
Androgen
receptor
Androgen-receptordependent gene
transcription
UBE3A
protein
Target protein
Ubiquitin
Target protein Ubiquitin
c
Necdin MAGED1
DLX2 DLX5
p53
Necdin E2F1
Wnt1
Cdc2
Nucleus
Figure 2 | Molecular interactions of imprinted-gene products. In vitro data from
molecular screens (including yeast two-hybrid screens), followed
in vivo |confirmation
NaturebyReviews
Neuroscience
studies, are beginning to further our knowledge of the cellular processes and pathways
that are affected by imprinted-gene products. Three of the best-characterized
imprinted-gene products (in terms of their molecular interactions) are paternally
expressed gene 3 (PEG3), the ubiquitin ligase protein UBE3A and necdin. a | Increased
expression of the tumour-suppressor protein p53 and of the oncoprotein MYC in
response to cellular signals results in the induction of the Peg3 and seven in absentia 1A
(Siah1a) genes21. The PEG3 and SIAH1A proteins might cooperate to induce neuronal
apoptosis, possibly by mediating the transport of BCL2-associated X protein (BAX) to the
mitochondria23. b | UBE3A has two distinct functions: it is a ubiquitin ligase that facilitates
ubiquitin addition to specific proteins (for example, p53), thereby targeting them for
destruction, and a transcriptional co-activator for gonadal hormone receptors29. In
Angelman syndrome, it appears to be the ligase function of the enzyme that is lost41. c | In
the nucleus, necdin associates with melanoma antigen, family D, 1 (MAGED1), distal-less
homeobox 2 (DLX2) and DLX5 to promote cellular differentiation through WNT1
signalling51. Necdin might also bind p53 and E2F1 to inhibit apoptosis by repression of
cell division cycle 2 (CDC2) transcription49.
nature reviews | neuroscience
of NGF-dependent apoptosis48. E2F1 is a cell-cycleprogression factor that transcriptionally activates many
pro-apoptotic genes, including that which encodes the
cyclin-dependent protein kinase cell division cycle 2
(CDC2). Recent work indicates that the interaction
between necdin and E2F1 has some functional relevance, insofar as necdin can repress E2F1-dependent
CDC2 gene transcription in neuronal cultures and
thereby attenuate the apoptosis of postmitotic neurons49.
The functional relevance of necdin binding to p53 in
neural tissues is less clear, although this binding inhibits
p53-mediated apoptosis in osteosarcoma cells46.
In addition to its functions as an anti-apoptotic factor, necdin can also modify neuronal differentiation. It
binds through MAGED1 to the homeodomain proteins
distal-less homeobox 2 (DLX2) and DLX5 (the genes
for which are imprinted in a species-specific manner50)
to upregulate activation of the Wnt1 promoter and hence
enhance the differentiation of GABA (g-aminobutyric
acid)-releasing neurons in the embryonic mouse forebrain51. Furthermore, necdin modulates intracellular
processes that are essential for neurite outgrowth, by
binding to the axonal outgrowth protein FEZ1 and to
Bardet–Biedl syndrome protein 4 (BBS4) in the vicinity
of the centrosomes52.
The findings about necdin in cell-culture systems
are recapitulated, to an extent, in vivo. Consistent with
predicted roles for necdin in neuronal survival and differentiation, mice that lack Ndn show a reduced number
of neurons in the hypothalamus that produce oxytocin
and luteinizing hormone-releasing hormone53, as well
as a reduced number of forebrain GABA-releasing
neurons 51, dorsal root ganglion neurons and substance-P‑producing neurons42. Moreover, they show
morphological abnormalities in axonal outgrowth and
fasciculation in several neuronal cell types54. In humans,
expression of NDN is lost in Prader–Willi syndrome (PWS),
a neurodevelopmental disorder in which dysregulation
of GABA-mediated signalling is thought to be a key
contributor to some aspects of the phenotype55.
Grb10 is paternally expressed in the mouse brain, owing
to the presence of brain-specific promoter regions that are
active on the paternal allele56 (elsewhere, Grb10 is maternally expressed), and it encodes a SRC homology domain 2
(SH2)-containing adaptor protein. There is some indirect
evidence linking the GRB10 protein to the growth and
development of the brain, through its ability to bind many
plasma membrane receptors (including tyrosine kinases
and growth receptors) that are involved in the development of the nervous system57,58. It has been postulated
that GRB10 regulates signalling between these receptors
and the apoptosis-inducing machinery on the mitochondrial outer membrane by modulating the apoptotic
activity of the mitochondrial protein RAF1 (Ref. 59).
Paternally expressed Dlk1 encodes a membranespanning and secreted protein in the epidermal growth
factor-like homeotic family (with homology to members of
the Notch–Delta developmental signalling pathway)60. It
is expressed in the monoaminergic nuclei in the rodent
and human brains61 and has been implicated in the
differentiation of midbrain dopaminergic neurons62.
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Currently, little is known about the specific molecular
mechanisms by which DLK1 protein influences neuronal survival and differentiation. In adipocytes, it seems
to inhibit differentiation, and might be co-regulated
with necdin63. DLK1 is also more highly expressed in
gliomas than in normal brain tissue, which indicates
that it might interact with p53 (Ref. 64).
Wnt1 promoter
Wnt1 encodes a secreted
signalling protein that is
involved in developmental
processes, including the induction of the
mesencephalon and the cerebellum.
Prader–Willi syndrome
A neurodevelopmental
disorder that is characterized
by early hypotonia, followed by
compulsive eating, mild mental
retardation, several
behavioural abnormalities and
hypogonadism. It results from
a lack of paternally expressed
genes on chromosome 15, at
positions q11–q13.
SH2-containing adaptor
protein
A protein that is an accessory
to the main proteins in a signal
transduction pathway and that
contains an SH‑2 domain
(which binds phosphorylated
tyrosine residues).
Epidermal growth factor-like
homeotic family
A group of proteins that are
involved in cell signalling and
subsequent neurodevelopment
or neural patterning and which
have homology with epidermal
growth factor.
In vivo significance. Although some degree of caution is
advisable in the interpretation of all molecular screens
(it is in their nature to produce significant numbers of
false positives65), the products of imprinted genes seem
to affect several signalling cascades that are involved in
cell survival and differentiation, notably acting through
the tumour suppressor and key neurodevelopmental
protein p53. However, because much of this screening
work has been carried out in cell culture, often in the
context of investigating the molecular processes that are
involved in cancer, the extent to which these findings
can be extrapolated to in vivo events that occur during
normal mammalian neurodevelopment remains to be
determined. In some cases, findings from humans and
whole-animal models are consistent with the in vitro
molecular findings, for example, regarding the role of
Ube3a/UBE3A and Ndn/NDN in brain development and
neurodevelopmental disorders. However, there is a relative lack of systematic data linking the effects of particular
brain-expressed imprinted genes on cell survival and differentiation pathways with specific neurodevelopmental
outcomes. Certainly, on the basis of the current data, we
do not have clear evidence of any pattern of effects with
respect to the direction of imprinting that might throw
light on the curious behaviour of AG and PG cells during
brain development.
Functional consequences
Mother–infant interactions. Whatever the eventual
usefulness of the molecular findings that implicate
imprinted genes in the cellular processes of brain growth
and differentiation, there is substantial evidence for the
influence of genomic imprinting, evident early in development, on brain function and behaviour. An important
time during which imprinting influences the brain is
the pre-weaning period, when mammalian infants are
still highly dependent on the mother for resources. In
animals, genomic imprinting has important effects on
suckling behaviour by the offspring. For example, Gnasxl
is paternally expressed and encodes an isoform of the
stimulatory G‑protein subunit Gsα (XLαs). Mouse pups
bearing a targeted deletion of Gnasxl fail to thrive, and
many die before weaning. Their core deficit is an inability to suckle, which is consistent with the expression of
Gnasxl in the motor areas of the brain that control the
muscles of the jaw and tongue66.
Advocates of the genomic conflict hypothesis in the
context of maternal resource distribution might argue
that these data are predictable, insofar as they reflect
the paternal interest in increasing the extraction of food
resources from the mother — here, imprinted genes
in the brain are proposed to continue in postnatal life
the effects that were mediated by the placenta in utero.
838 | November 2007 | volume 8
Consistent with this idea, knocking out Peg3, another
imprinted gene that is paternally expressed in the brain,
also leads to problems in suckling behaviour67.
The intragenomic conflict hypothesis cannot, however, explain all imprinted-gene effects on mother–
infant interactions. For example, Peg3-null mothers
show deficits in aspects of maternal care, such as milk
let-down, nest building and pup retrieval. These effects
are independent of those that arise in the pups67, but are
due (in all probability) to the reduction in hypothalamic oxytocin-expressing neurons in Peg3-null adult
females20. These effects are difficult to reconcile with
the genomic conflict hypothesis because of the erasure
and re-setting of the imprinting mark in the germ line
(FIG. 1) and the fact that relatedness asymmetries are
not carried over generations. Therefore, because grandoffspring are just as related to their maternal grandmother
as to their grandfather, there is no selective advantage
(under intragenomic conflict) of a paternally derived
gene influencing maternal behaviour and survival
of the grand-offspring68. Rather, it has been suggested
that the effects of Peg3 on mother and infant behaviours
are an example of co-adaptation of imprinted-gene traits
that, through different evolutionary routes and presumably different neurodevelopmental mechanisms, ensure
adequate provisioning of the pre-weaning infant67.
Studies in humans also emphasize mother–infant
interactions as a key area for imprinted-gene function. Angelman syndrome and PWS are complex
neurodevelopmental conditions that are associated
with the disruption of a cluster of imprinted genes on
human chromosome 15, specifically at 15q11–15q13.
Angelman syndrome arises from disruptions that lead
to a lack of maternally expressed gene product(s); PWS
results from disruptions that lead to a lack of paternally
expressed gene product(s)69. Angelman syndrome is
characterized by severe learning difficulties, ataxia,
seizures and EEG abnormalities70, whereas PWS is
characterized by a failure to thrive in infancy, mild
learning difficulties and, on emerging from infancy,
a grossly abnormal satiety response to food intake71.
Both conditions are associated with various changes
in the structure 72,73 and function 74,75 of the brain.
GABAA-receptor function is particularly affected 76,
consistent with the major contribution of the lack of
paternally expressed NDN to the PWS phenotype and
the possibility of cytogenetic abnormalities disrupting
GABAA-receptor-subunit gene expression in Angelman
syndrome and PWS (BOX 3).
Again, these human imprinted syndromes give rise,
apparently, to effects on the mother–infant relationship that can be accommodated (tentatively, given the
complex nature of the conditions) in the predictions of
the genomic conflict hypothesis in terms of drawing on
maternal resources. First, there is the well-established
observation that infants with PWS have difficulty suckling71. More recently, work has focused on the unusually
sociable disposition of individuals with Angelman syndrome — these individuals laugh and smile frequently
and show much-reduced displays of negative-affect
signals, such as crying and tantrums70,77. Previously,
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Disomies
The presence of two sets of
chromosomes — the normal
situation in diploid organisms
such as humans and mice. In
uniparental disomies, both sets
of chromosomes originate from
one parent.
Box 3 | Angelman syndrome and Prader–Willi syndrome (PWS): the GABAA connection
There are several mechanisms that can cause the lack of maternally expressed gene products that results in Angelman
syndrome. Most common are deletions in maternally inherited chromosomes, followed by paternal uniparental disomies
and then mutations of the imprinting centre, which are the rarest variants. In PWS, which is often termed the sister
disorder to Angelman syndrome, similar but reciprocal disruptions lead to a lack of paternally expressed gene product(s)69.
Disruption of the GABA (γ-aminobutyric acid) type A (GABAA) receptor system is thought to be an important
contributor to some of the behavioural and neurological abnormalities that are seen in individuals with Angelman
syndrome or PWS. This is evidenced by their phenotypes (epilepsy in Angelman syndrome; psychosis in PWS) and their
response to GABA-related treatments. One candidate imprinted gene that has been shown to have a direct action on
GABA-mediated neuron differentiation is the paternally expressed necdin (see main text), but there are now indications
that additional mechanisms lead to GABA-related problems in Angelman syndrome and PWS.
Adjacent to the imprinted-gene cluster that is disrupted in Angelman syndrome and PWS are three genes that encode
the GABAA-receptor subunits β3, α5 and γ3. These are not thought to be part of the imprinting cluster per se, but recent
data indicate that they are sensitive to the changes in epigenetic status that occur as a result of the mutations that lead to
Angelman syndrome and PWS92. Of particular importance is the β3 subunit which, along with ubiquitin protein ligase E3A
(UBE3A), is regulated by the methyl CpG binding protein MECP2. This provides a molecular link between Angelman
syndrome, PWS and other neurodevelopmental disorders with similar behavioural abnormalities, such as autism and
Rett syndrome94. Therefore, loss of expression of these GABAA subunits, either directly (by physical deletion) or through
epigenetic mechanisms, might underlie some aspects of the neurological and behavioural deficits that are seen in
Angelman syndrome and PWS. This idea is supported by positron emission tomography studies of the benzodiazepine
binding site in individuals with Angelman syndrome. These studies showed a dissociation in the binding deficits between
individuals with a maternal 15q11–15q13 deletion encompassing the β3 subunit and individuals with Angelman syndrome
resulting from a mutation in UBE3A105 — findings that were supported by similar results in two different mouse models of
Angelman syndrome76. A similar pattern of decreased binding has been seen in individuals with PWS caused by the
15q11–15q13 deletion that encompasses the β3 subunit106. However, the conclusive study (comparing the phenotype that
results from the 15q11–15q13 deletion with those that result from chromosome 15 maternal uniparental disomy and/or
imprinting centre genotypes (where no direct disruption of the GABAA cluster has occurred)) has yet to be performed.
these positive-affect behaviours were thought to occur
indiscriminately. However, more detailed analysis has
provided evidence that they occur specifically in a social
context, namely in response to adult speech, eye contact
and touch78. These findings, and the increased negativeaffect signals shown by children with PWS71, have led to
the idea that, in addition to influencing resource allocation from the mother to the offspring through effects on
suckling behaviour, brain-expressed imprinted genes
can also influence the social resources that the offspring
receives, through effects on behaviours that elicit care
from the mother (BOX 4). The direction of the effects seen
in Angelman syndrome and, to some extent, those seen in
PWS would, according to the conflict hypothesis, suggest
that the interest of the paternal genome is to maximize
the amount of care and attention received from the
mother by the current offspring and that the interest
of the maternal genome is to divide these resources
more equally across all her maternally related kin. It is
unknown what neurobiological mechanisms, including
effects on neurodevelopment, might mediate these influences on the early social interplay between mother and
infant, and how these mechanisms relate to the complex
genomic aetiology of Angelman syndrome and PWS.
Adult behaviour. The persistence, in many cases, of
genomic imprinting in the brain into adulthood begs
the question of whether all effects of brain-expressed
imprinted genes have a developmental basis. The gene
Commd1, for example, is only fully imprinted in the adult
brain17. A steadily increasing number of examples show
that manipulating brain-expressed imprinted genes in
animal models gives rise to effects on a range of adult
nature reviews | neuroscience
behaviours2,20,37,53. In a limited number of situations, for
example, in mice that lack the maternally imprinted
gene product NESP55, this occurs in the absence of any
obvious gross developmental effects79. However, in
the absence of ‘conditional’ genetic models, which allow the
temporal control of gene activity, subtle effects on brain
development and function cannot be excluded.
Nonetheless, it seems that genomic imprinting has
the potential to influence adult behaviour through several mechanisms. First, it can have effects on brain development. This can occur either through the influence of
imprinted genes on nutrient supply by the placenta 3
or through more specific effects of brain-expressed
imprinted genes on brain structure, connectivity and
differentiation. Second, there is ongoing, persistent
imprinted-gene function in the adult brain. Third, it
is possible that brain-expressed imprinted genes have
enduring effects on adult behaviour indirectly, through
their influence on mother–infant interactions, variations in which have been consistently shown to have
significant long-term effects on offspring behaviour80.
The existence of imprinted-gene effects on adult
behaviour has stimulated the debate about whether these
effects could be adaptive in evolutionary terms. Here, in
another facet of genomic conflict, it has been argued that
the effects of imprinted genes on adult behaviour might be
a consequence of the asymmetries of relatedness that arise
in social groups (BOXes 1,4), and that the behaviours that
are affected are likely to be those that underlie the effective
manipulation of social interactions in a group. This would
extend the functional consequences of imprinted-gene
action in the brain into complex areas such as language,
empathy and cooperative behaviours81.
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Linkage
A technique for identifying
candidate chromosomal
regions that underlie a
particular trait, based on the
extent to which that trait is co-inherited with certain
genetic markers.
Autism spectrum disorders
(ASD). A number of
phenotypically overlapping
neurodevelopmental
conditions, including autism,
Asperger’s disorder, childhood
disintegrative disorder and
pervasive developmental
disorder — not otherwise
specified.
Linkage peaks
Chromosomal regions,
identified by linkage analysis,
that contain closely linked
markers that are often co-inherited in probands.
Epigenetic hotspot
A region of the genome that is
especially sensitive to
perturbation of gene
expression through effects on
DNA methylation and/or
histone modification.
Risk of neuropsychiatric disorders. Alongside the widening repertoire of behavioural and cognitive functions
that are influenced by genomic imprinting, there is
increasing evidence that suggests there is an important role for imprinted genes in a number of common
mental and neurological disorders, many of which
have suspected neurodevelopmental antecedents 82.
The evidence ranges from parent-of-origin effects on
the symptomatology or inheritance patterns of certain
disorders (for example, Tourette’s syndrome82 and multiple sclerosis83) to more convincing parent-of-origin
effects in specific linkage studies (for example, studies
of bipolar disorder84, of handedness and susceptibility to schizophrenia85, of the maternal origin of the
X chromosome in Turners syndrome, and of autism86).
In all cases, it is important to differentiate between
parent-of-origin effects that are due to imprinting and
those that arise as a result of other mechanisms, such
as the preferential expansion of trinucleotide repeats
or mutations in mitochondrial DNA (which is always
maternally inherited)82.
Some of the clearest evidence linking genomic
imprinting to neuropsychiatric disease has come from
genome-wide scans that examined linkage to autism spectrum disorders (ASD). Here, several of the linkage peaks
overlap with, or are in close proximity to, imprinted
regions, especially the imprinted-gene clusters located
at 7q21–7q31.31, 7q32.3–7q36.3 and 15q11–15q13
(Ref. 87) . The linkage peak at 15q11–15q13, which
encompasses the region that is disrupted in Angelman
syndrome and PWS, has been termed an epigenetic
Box 4 | Conflict in the mind?
An important arena for the genomic ‘battle of the sexes’ might be the allocation of
maternal resources. There is strong evidence supporting this idea from imprinted
genes that are known to influence placental function and suckling behaviour10.
Although the idea is speculative at this stage, it is thought that some genes in the
q11–q13 region of chromosome 15 (the interval that is disrupted in Angelman
syndrome and Prader–Willi syndrome (PWS)) might also act antagonistically on the way
in which infants elicit care from their mother. A key characteristic of Angelman syndrome
is an unusually sociable disposition and reduced display of negative-affect signals70,77.
These positive-affect behaviours were originally considered to occur inappropriately107,
but now they are thought to occur specifically in a social context108–110. This indicates that
one or both of the two known maternally expressed genes in the critical region
(ubiquitin protein ligase E3A (UBE3A) and ATP10A) normally act as brakes that limit
positive-affect signals. In Angelman syndrome, in which these gene products are absent,
this ‘braking’ function is lost. Conversely, individuals with PWS show increased
negative-affect signals (stubbornness and temper tantrums) and are prone to mood
instability and non-psychotic depression111. In maternal chromosome-15 uniparental
disomy, and in PWS imprinting-centre genetic sub-types in particular, there is a ‘double
dose’ of the maternally expressed UBE3A and ATP10A gene products (owing to the
presence of two maternal copies and to a relaxation of the silencing of the paternal
copy, respectively). This might lead to a greater-than-normal application of the brake
that limits positive-affect signals, resulting in an increased propensity to develop
affective psychosis112,113. This idea is predicted by the kinship theory (see BOX 1)81, the
suggestion being that these positive-affect signals manipulate the sensory systems of
receivers with respect to the allocation of social ‘resources’. In the same manner in
which it manipulates nutrient resources through its effects on placental function and
suckling, it is in the ‘interest’ of the paternal genome to maximize the amount of social
resources received from the mother, whereas it is in the ‘interest’ of the maternal genome
to equalize the amounts of these resources across all maternally related offspring.
840 | November 2007 | volume 8
hotspot for ASD gene candidates87. Cytogenetic abnor-
malities that disrupt gene expression in this region are
a common feature in patients with ASD (they are found
in up to 5% of ASD patients), particularly abnormalities
that give rise to duplications of the maternally inherited
copy of chromosome 15 (Refs 87,88). This observation
has focused attention on the two known maternally
expressed imprinted genes in the 15q11–15q13 interval, UBE3A89 and ATP10A90,91. However, there are several
other candidate genes that might convey an ASD risk
in this complex genomic region, including the genes
that encode the GABAA-receptor subunits GABRB3,
GABRA5 and GABRG3. These genes are probably not
imprinted themselves, but they lie close to the imprinted
cluster and could become aberrantly expressed as a result
of disrupted epigenetic regulation92.
The linkage of 15q11–15q13 to the risk of ASD
has generated numerous hypotheses, one of the most
attractive of which suggests that abnormalities in the
methylation of UBE3A lead to reduced UBE3A protein
levels in the brain. Considering that reduced expression
of UBE3A is also found in post-mortem brain samples
taken from individuals with Angelman syndrome and
Rett syndrome, it is possible that misexpression of UBE3A
constitutes a common molecular lesion that underlies
these phenotypically related disorders87,93. In addition
to UBE3A, several of the imprinted genes in the vicinity of 15q11–15q13 might have a role in ASD, owing to
their position on the chromosome and to their known
neurobiological function; however, exactly how specific
molecular abnormalities in these genes translate into
abnormal brain development and function remains to
be established.
An important challenge with respect to ASD
and other neurodevelopmental conditions in which
imprinted mechanisms have been implicated, such as
Angelman and Rett syndromes, is how to explain the
delay in behavioural symptoms: individuals with these
disorders often have normal development initially and
only begin to show deficits later in infancy. This pattern
suggests an important role for postnatal brain maturation, including experience-dependent plasticity94. One
provocative hypothesis on which to end this Review is
the suggestion that brain-expressed imprinted genes
have the potential to contribute to the long-term risk of
psychopathology by modifying the postnatal experience
of infants, and the idea that they could do this by controlling key components of the early-life environment,
notably mother–infant interactions.
Conclusions and future directions
Since the discovery and characterization of the first
imprinted genes approximately sixteen years ago, it has
become clear that growth and development, and in particular, brain development, are prime areas for imprintedgene function. However, it is equally clear that, in terms
of neurodevelopment, there is much more to learn. At the
molecular level, data are accumulating that show possible
interactions of brain-expressed imprinted genes with several of the signalling pathways that coordinate the initial
patterning, pruning and differentiation of brain cells. But
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Rett syndrome
A neurodevelopmental
disorder that occurs mainly in
females and is characterized by
cognitive impairments and
autism-like behaviours. In most
cases, the disorder is caused
by a mutation in the X‑linked
methyl CpG binding protein 2
gene. In males, this mutation is
nearly always lethal.
we still do not know, in many cases, how these molecular
interactions ultimately lead to variations in brain structure
and function. We are also unsure of the significance of the
persistence of genomic imprinting in the postmitotic brain
throughout adulthood. Genetic animal models will allow
the dissociation of imprinted-gene effects that occur early
in life (in utero and postnatally) from those that influence
adult brain function and behaviour.
Another important issue is the extent to which
genomic-imprinting effects on neurodevelopment
reflect the selective pressures under which imprinted
genes have evolved. This is a controversial area, but the
concepts of intragenomic conflict and the ultimate selfish gene account for many of the data that have been
obtained from functional studies in which imprintedgene functioning is perturbed, such as in certain human
conditions or as a result of genetic engineering in animal
models. The issue is, are these functional effects subserved by the effects of differential maternal and paternal
interests on neurodevelopment? The short answer is
that, with the notable exception of the findings in mouse
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Acknowledgements
Our work is funded by a Cardiff University link chair, the
Biotechnology and Biological Sciences Research Council UK,
the Medical Research Council (MRC) UK, GlaxoSmithKline plc,
Lilly UK (L.S.W.), the Beebe Trust and Health Foundation UK
nature reviews | neuroscience
(A.I.) and Research Councils United Kingdom (W.D.). We would
like to thank our collaborator P. Burgoyne and colleagues
G. Kelsey, W. Reik, and A. Holland. L.S.W. is a member of the
MRC Co-operative on Imprinting in Health and Disease.
DATABASES
Entrez Gene: http://www.ncbi.nlm.nih.gov/entrez/query.
fcgi?db=gene
ATP10A | BBS4 | CDC2 | Commd1 | Dlk1 | DLX2 | DLX5 | E2F1 |
ECT2 | FEZ1 | GABRA5 | GABRB3 | GABRG3 | Grb10 | HHR23 |
Igf2 | Igf2r | MAGED1 | MGMT | Ndn | p53 | p75 | Peg3 | RAF1 |
SIAH1A | TNF | TRAF2 | TRKA | Ube3a |
OMIM: http://www.ncbi.nlm.nih.gov/entrez/query.
fcgi?db=OMIM
Angelman syndrome | Bardet–Biedl syndrome | PWS | Rett
syndrome
FURTHER INFORMATION
Lawrence S. Wilkinson’s homepage: http://www.BGG.
cardiff.ac.uk
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