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July 2011.

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JULY 2011
Voilà! A precise formula for human neuronal
engineering revealed
Creating fully functional neurons from non-neural somatic cells
or pluripotential stem cells is one of the Holy Grails of developmental and regenerative neurobiology. The scientific team led
by Südhof and Wernig recently made the remarkable discovery
that forced expression of a combination of just three transcription factors, Brn2 (also known as Pou3f2), Ascl1 and Myt1l,
could efficiently convert mouse fibroblasts into functional
induced neuronal (iN) cells. In this article, they capitalized on
their prior work to determine whether this same approach is
applicable to human cells. In the first set of experiments, they
showed that the same three transcription factors could generate
functional neurons from human pluripotent stem cells as early
as 6 days after transgene activation. When combined with the
basic helix–loop–helix transcription factor NeuroD1, these factors also converted fetal and postnatal human fibroblasts into
iN cells showing typical neuronal morphologies and expressing
multiple neuronal markers. Amazingly, this was maintained
even after downregulation of the exogenous transcription factors. The vast majority of human iN cells were able to generate
action potentials and many matured to receive synaptic contacts
when co-cultured with primary mouse cortical neurons. These
data demonstrate that non-neural human somatic cells, as well
as pluripotent stem cells, can be converted directly into neurons
by lineage-determining transcription factors. More work is
needed to determine how these neurons can be further differentiated into the multitude of subtypes found in the nervous system. Nonetheless, this latest finding constitutes a major leap
forward in stem cell biology - these methods will undoubtedly
facilitate the generation of patient-specific human neurons for
in vitro disease modeling or future applications in regenerative
medicine (Nature (26 May 2011) doi:10.1038).
Methylation, Methylation, Methylation
DNA methylation plays an important role in the development
of the mammalian central nervous system, including neuronal
and glial differentiation from neural stem cells. Recent work
suggests that DNA methylation also fulfills an important role
in the function of adult post-mitotic neurons and behavior. To
further describe the epigenetic status of neuronal cells, Iwamoto
and colleagues performed a comprehensive DNA methylation
analysis in purified neuronal and non-neuronal nuclei obtained
from post-mortem human prefrontal cortex. Using the extracted
DNA from the sorted fractions the authors quantified both,
global and site-specific DNA methylation and examined
genome-wide promoter methylation patterns. The study shows
that compared with non-neuronal nuclei, neuronal nuclei display high interindividual variations, but also a distinctive DNA
methylation blueprint, including low global DNA methylation
(except in astrocytes) and unique DNA methylation signatures
in the promoter regions. These observations were supported by
additional ontology and TF–binding site analyses. Altogether,
the results are consistent with the hypothesis that in the central
nervous system neuronal cells have an enhanced reserve to
change their epigenetic status in response to developmental and
environmental conditions compared with non-neuronal cells
(Genome Res 2011, 21:688–696).
Pure reasoning in pre-verbal infants
In this fascinating study, investigators used a fairly simple yet
quantifiable task of having infants look at moving images.
Using probabilistic inference that relies on Bayesian models,
they analyzed their experimental findings to show that preverbal
infants can reason. The idea is that one can measure infants
reasoning abilities by measuring their looking times to visually
presented events as an index of surprise. Longer looking implies
that infants have the ability to understand simple random processes so that when the unexpected happens, there will be an
attention to that new event. Infants viewed movies in which
four objects of two types, identified by different shapes and colors, bounced randomly inside a container with an opening on
its lower side. After a few seconds, the containers contents were
obscured from view and then one object visibly exited through
the bottom opening. They measured looking time to see how
surprised they were. There are rational predictions of which
object should exit using Bayesian principles, so computational
models could validate that the infants were indeed ‘‘looking
longer’’. These data show that preverbal infants have the ability
to reason about complex unseen events in a very sophisticated
manner but it is still unclear how these cognitive systems
develop or whether they are innate or experiential (Science
332:1054–59, 2011).
Exome sequencing indentifies new candidate genes for autism
Autism spectrum disorders (ASDs) are considered highly heritable, but recent observations suggest the possibility that the
genetic basis for ASDs in sporadic cases may differ from that of
families with multiple affected individuals, with the former
being more likely to result from de novo mutation events rather
than inherited variants. Remarkable methodological advancements have made rapid sequencing of the entire human exome
feasible and affordable leading to the recent discovery of mutations and genes in more than 40 Mendelian disorders. O’Roak
and colleagues sequenced the exomes of 20 individuals with
sporadic ASD and their parents, reasoning that these families
would be enriched for de novo mutations of major biological
effects. They identified potentially causative de novo events in 4
out of 20 probands in FOXP1, GRIN2B, SCN1A and LAMC3,
genes previously implicated in autism, intellectual disability and
epilepsy, suggesting that overlapping genetic pathways may lead
to a broad spectrum of neurodevelopmental outcomes depending on the genetic and environmental context (Nat Genet
43:585–589).
C 2011 American Neurological Association
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