RESEARCH NEWS & VIEWS

Catriona Jamieson is in the Division of

Regenerative Medicine, Department of
Medicine, and Moores Cancer Center,
University of California, San Diego, La Jolla,
California 92093-0820, USA.
Leukaemia e-mail: cjamieson@ucsd.edu
1. Coombs, C. C. et al. Cell Stem Cell http://dx.doi.
Mutation org/10.1016/j.stem.2017.07.010 (2017).
2. Nowell, P. C. & Hungerford, D. A. Science 132, 1497
(1960).
3. Adamson, J. W., Fialkow, P. J., Murphy, S., Prchal, J. F.
& Steinmann, L. N. Engl. J. Med. 295, 913–916
• Smoking Cell
Clonal (1976).
• Age interactions?
haematopoiesis 4. Daley, G. Q., Van Etten, R. A. & Baltimore, D. Proc.
• Toxic therapy
HSC Pre-leukaemic Natl Acad. Sci. USA 88, 11335–11338 (1991).
cells Solid tumour 5. James, C. et al. Nature 434, 1144–1148 (2005).
6. Wernig, G. et al. Blood 107, 4274–4281 (2006).
Figure 1 | From haematopoietic stem cells (HSCs) to solid tumours.  Smoking, ageing and toxic 7. Jamieson, C. H. M. et al. N. Engl. J. Med. 351,
treatments such as chemotherapy or radiation therapy can all cause mutations in blood-forming HSCs. 657–667 (2004).
If these mutations confer a fitness advantage, they can trigger clonal haematopoiesis — a phenomenon in 8. Jamieson, C. H. M. et al. Proc. Natl Acad. Sci. USA
103, 6224–6229 (2006).
which mutant subpopulations of blood cells expand to form a population of pre-leukaemic cells. This, in 9. Jaiswal, S. et al. N. Engl. J. Med. 371, 2488–2498
turn, can lead to leukaemia. Coombs et al.1 have demonstrated that clonal haematopoiesis is associated (2014).
with the progression of solid tumours, presumably owing to interactions between the cells of these 10. Genovese, G. et al. N. Engl. J. Med. 371, 2477–2487
tumours and pre-leukaemic cells. (Figure based on a graphic from ref. 1.) (2014 ).
11. Crews, L. A. et al. Cell Stem Cell 19, 599–612
(2016).
12. Zipeto, M. A. et al. Cell Stem Cell 19, 177–191
clonal haematopoiesis. Extrinsic influences haematopoiesis is shedding light on the fuel (2016).
such as chemotherapy and radiation therapy, that feeds cancer. Perhaps by understanding 13. Alexandrov, L. B. et al. Nature 500, 415–421
although aimed at keeping solid tumours at that we cannot always eradicate tumours with- (2013).
bay, might also cause mutations that enhance out correcting the ‘bad blood’ within them, we 14. Chandel, N. S., Jasper, H., Ho, T. T. & Passegué, E.
Nature Cell Biol. 18, 823–832 (2016).
the fitness of clonal HSCs. In doing so, they will be able to devise more-effective cancer 15. Beerman, I. et al. Cell Stem Cell 15, 37–50 (2014).
could actually contribute to solid-tumour eradication strategies. ■ 16. Walter, D. et al. Nature 520, 549–552 (2015).
progression (Fig. 1), by providing microenvi-
ronmental cues that act to promote the fitness
of solid-tumour stem cells. This will need to be N EUR O SC I ENCE
investigated in further studies.
It is possible that the mutations observed
by Coombs et al. in PPM1D and some other
genes are germline (inherited) mutations, and
Mum’s bacteria linked
to baby’s behaviour
so are present in all cells of the body, rather
than arising specifically in HSCs. However, a
major contribution of germline mutations to
clonal haematopoiesis, which usually emerges
with advanced age, seems unlikely. Moreover, Infection during pregnancy increases the risk of neurodevelopmental disorders,
the association between clonal haematopoiesis such as autism, in offspring. Mouse studies now reveal a link between gut bacteria
during ageing and the development of leukae- and atypical brain-circuit connections. See Article p.482 & Letter p.528
mia suggests that these mutations are drivers
of cancer, rather than passengers, again argu-
ing against a germline origin. Nonetheless, the CRAIG M. POWELL response in the mother that is termed maternal
functional contribution of inherited mutations immune activation (MIA), which can lead to

to clonal haematopoiesis and tumour progres-
sion has not been fully explored and should be
addressed in future.
Clonal haematopoiesis has been thought of
as caused mainly by DNA mutations acquired
during ageing9,10. But equally important might
be ageing-associated disruption of RNA pro-
cessing. Such disruption induces a loss of
normal human HSC dormancy, survival and
self-renewal, and thus reduces overall HSC
fitness11. In addition to these cell-intrinsic
injuries to DNA and RNA, mutations in both
molecules can be induced during ageing by
extrinsic inflammatory signalling molecules
and metabolic dysfunction12–16. These factors,
too, might enhance clonal haematopoiesis and
the development of both blood-related and
solid tumours.
As a body of work, research into clonal
W
hat do pregnancy, viral infection,
gut bacteria, the immune response
and the function of a neuronal
circuit in the brain have in common? More
than you might expect, according to a pair of
studies, by Kim et al.1 and Yim et al.2, reported
on pages 528 and 482, respectively.
Animal studies and epidemiological analysis
in humans have shown that if a mother is
infected by certain viruses during pregnancy,
there is a risk that her offspring will develop
autism or other neurodevelopmental dis­
orders3,4. This phenomenon is often studied
using a mouse model in which viral infection
is mimicked by exposing pregnant animals
to a synthetic molecule called poly(I:C) that
is structurally similar to double-stranded
RNA, a common hallmark of viral infection
(Fig. 1). This exposure triggers an immune
atypical social and repetitive behaviours in her
offspring5. However, the molecular and cellu­
lar basis for this phenomenon has remained
poorly understood until now.
In a previous study5, Kim, Yim and their
colleagues used this mouse model of MIA to
show that interleukin 17a (IL-17a), a protein
secreted into the pregnant mother’s blood-
stream, is required for the behavioural abnor-
malities to develop in offspring. The authors
also found that IL-17a is secreted by maternal
immune cells called T helper 17 (TH17) cells.
Kim et al. now reveal key missing links in the
process that activates this TH17-cell immune
response in mothers. First, they found that
IL-17a secretion did not occur in non-preg-
nant female mice that had undergone MIA,
indicating that pregnancy is an important fac-
tor. The authors also showed that specific bac-

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 NEWS & VIEWS RESEARCH

authors expressed light-sensitive ion channels

a b
S1DZ region
TeA
TH17 cell Segmented Mouse brain
Striatum
filamentous
Poly(I:C) bacteria
IL-17a
Atypical Atypical
social repetitive
behaviour behaviour
Pregnant mouse Offspring
Figure 1 | Maternal immune response and the brain circuits underlying atypical offspring behaviour.  both regions being modulated, to some degree,
Viral exposure during pregnancy can sometimes result in offspring that have neurodevelopmental
disorders3,4. This phenomenon is linked to a maternal immune response5 associated with TH17 cells
and the signalling molecule IL-17a. a, Kim et al.1 and Yim et al.2 investigated this process using a model
in which pregnant mice are injected with a molecule called poly(I:C) that is structurally similar to the
double-stranded RNA characteristic of viral infection. The authors demonstrated that the presence of
a type of gut microbe called segmented filamentous bacteria is required for the animals’ offspring to
show atypical behaviours. b, Applying a technique known as optogenetics, in which light of a certain
wavelength (shown here in blue) is used to activate or inhibit neurons genetically engineered to express
light-sensitive ion channels, the authors reveal that activation of the S1DZ region of the cortex is
associated with atypical offspring behaviour. They found that neurons in the S1DZ connect to neurons in
a brain region called the temporal association area (TeA) that influence social behaviours, and to neurons
in the striatum that affect repetitive behaviours.
teria must be present in the mother’s intestine satisfied with correlation alone, the authors
for the TH17 immune cells to respond to the carried out a remarkable series of manipula-
mimicked state of viral infection. Pretreat- tions of this tiny brain region to examine how
ment with antibiotics decreased this maternal it affects behaviour.
immune response. More­over, after antibiotic A technique called optogenetics, in which
pretreatment, offspring did not show abnor- animals are genetically engineered to express
mal brain development or atypical behaviours, light-responsive versions of ion-channel pro-
revealing a link between microbes present in teins, enabled the authors to use specific wave-
the pregnant mother and the risk of autism- lengths of light to control neuronal activation.
like features developing in her offspring. When they engineered animals to express such
The authors investigated which bacteria proteins in the S1DZ, they found that activat-
targeted by the antibiotic might be respon- ing this brain region caused atypical social
sible for the changes observed. They tested a and repetitive behaviours in the offspring of
type of bacterium commonly resident in the wild-type mice that had not undergone MIA.
gut called segmented filamentous bacteria, Crucially, when the authors used a light-
which are associated with higher levels of TH17 responsive channel to inhibit neuronal activity
cells than are found in mice without these bac­ in the S1DZ in the offspring of mothers that
teria6. Using micro­scopy and analysis of DNA had undergone MIA, the change in neuronal
in faecal samples, they confirmed that these activity in this region alone was sufficient to
microbes were the antibiotic target. When stop the atypical behaviour that these animals
mice lacking the bacteria underwent MIA, had shown. Indeed, the authors obtained simi-
their offspring did not show atypical brain lar effects on behaviour by using optogenetics
development or behaviour. However, if the either to specifically activate just the excitatory
mice were exposed to segmented filamentous neurons or to inhibit the inhibitory neurons in
bacteria, either through direct introduction this brain region. Such specific recapitulations
of the microbes or by coming into contact with of behaviour by the manipulation of a subset of
mice that harboured them, the animals’ off- neurons in a precise cortical region is a state-
spring showed both of these abnormal features. of-the-art experimental demonstration of the
Yim and colleagues delved further into the link between an individual brain region and
underlying mechanism by trying to determine distinct behaviours.
exactly where in the brain the MIA-associated In a final tour de force, using a viral-based
abnormalities occur. Microscope analysis of technique to determine cellular connections,
brain regions revealed that abnormalities in Yim and colleagues identified a region of the cor-
the dysgranular zone of the primary somato­ tex called the temporal association area (TeA),
sensory cortex (S1DZ) were most closely together with the striatum, as the brain areas
correlated with the atypical behaviour. Not to which cells in the S1DZ project. When the
in the subset of S1DZ neurons projecting to the
TeA, stimulation of these neurons in offspring
of wild-type mice that had not undergone MIA
resulted in atypical social behaviours, but not in
repetitive behaviours. Inhibition of these neu-
rons in offspring of mothers that had undergone
MIA restored normal social behaviours, but
not repetitive behaviours. Similar experiments
on S1DZ neurons projecting to the striatum
showed effects on repetitive behaviours but not
on social behaviours. The authors could there-
fore implicate a subregion of the brain as a key
circuit hub for atypical behaviours that resemble
features of autism in humans. They also discov-
ered that the two behaviours, social and repeti-
tive, were linked to different brain regions, with
by the S1DZ hub.
Do cortical abnormalities due to maternal
viral infections have a role in the development
of autism in humans? This link has not been
clearly established, but infections during the
first and second trimesters of pregnancy are
probably risk factors3, and areas of abnor-
mally developed cortex have been identified
in individuals with autism7. Additional exper-
imental work and analyses of post-mortem
brain samples will be required to answer this
question. If this connection were confirmed,
one might consider strategies to reduce the
risk of harm from maternal infections during
pregnancy through something as straight-
forward as manipulation of the mother’s
intestinal bacterial population, whether by
simple dietary modification or by other means.
Even if the mechanisms described by Kim
et al. and Yim et al. are not involved in autism
in humans, these papers still provide valuable
insights by revealing the complexity of the
interactions between gut bacteria, the immune
system and brain development. Furthermore,
the authors have identified a specific brain cir-
cuit in mice that has a role in modulating social
and repetitive behaviours, offering a major
advance in our understanding of the circuits
responsible for such atypical characteristics. ■
Craig M. Powell is in the Departments of
Neurology and Neurotherapeutics, and
of Psychiatry and of Neuroscience,
University of Texas Southwestern Medical
Center, Dallas, Texas 75390, USA.
e-mail: craig.powell@utsouthwestern.edu
1. Kim, S. et al. Nature 549, 528–532 (2017).
2. Yim, Y. S. et al. Nature 549, 482–487 (2017).
3. Patterson, P. H. Trends Mol. Med. 17, 389–394 (2011).
4. Estes, M. L. & McAllister, A. K. Science 353,
772–777 (2016).
5. Choi, G. B. et al. Science 351, 933–939 (2016).
6. Ivanov, I. I. et al. Cell 139, 485–498 (2009).
7. Stoner, R. et al. N. Engl. J. Med. 370, 1209–1219
(2014).
The author declares competing financial interests:
see go.nature.com/2hqnpsd for details.
This article was published online on 13 September 2017.

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 RESEARCH NEWS & VIEWS

CORRECTION
The News & Views ‘Neuroscience: Mum’s
bacteria linked to baby’s behaviour’ by
Craig M. Powell (Nature 549, 466-467;
2017) omitted to mention that the author
has declared competing financial interests.
The News & Views has been amended
online to include this.

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