Reprogramming of the Mammalian
Central Nervous System
Ryoji Amamoto and Paola Arlotta*
Background: Differentiated cells can be reprogrammed to switch identities from one cell type to
another under the direction of powerful transcription factors. In the mammalian central nervous
system, this approach has been used experimentally to generate new categories of neuronal cells.
The protocols are inspired by what we have learned from normal development, but the applications
lie outside of normal embryogenesis. The research is changing how scientists think about regeneration of lost neurons and modeling of neuronal function in the central nervous system. The
approaches also allow for new ways to study human neuronal development, a process that cannot
be studied in vivo.
Advances: Neurons are a highly specialized cell type, with their ability to transmit electrical signals. Beyond that, though, neurons also specialize into an astonishing diversity of classes. Although
reprogramming with known transcription factors is a comparatively blunt tool, researchers have
used knowledge of normal neuronal development to identify suites of factors that can convert
mouse or human non-neuronal cells into induced neuronal cells showing class-specific features.
These protocols have provided a renewable source of neuronal cells for high-throughput studies,
which is particularly useful when source tissue is rare or unavailable. One exciting application of
lineage reprogramming has been the generation of new neurons in situ by the direct conversion of
other cell types already resident within the brain. Astrocytes have been converted into neurons in
vivo. Even neurons have been changed from one subtype to another in young animals, indicating
that postmitotic neurons may not be as immutable as once thought. These provocative results may
foster the development of strategies for neuronal replacement that rely on “code-switching” of
neuronal identity on the spot.
Outlook: Direct lineage reprogramming is a nascent but promising field. Although both unspecialized and specialized neuronal cells have already been generated by these methods, we still
need more refined understanding of how reprogramming works, how the cellular context constrains
reprogramming routes, and what synergistic effects arise with various reprogramming factors.
Better-defined criteria are needed to classify neurons obtained by reprogramming and to determine how they differ from their endogenous counterparts. Functional analyses are also necessary
to clarify when a new neuron achieves the needed function, even if its other features do not match
endogenous neurons. The challenge requires
collaborative expertise in stem cell biology,
embryology, and fundamental neuroscience.
Future ability to reprogram postmitotic neurons in the adult brain will be important for
the growth of this field and likely influence
the way we think about neuronal stability,
regeneration, and function.
Generation of Development-Inspired
Potency of Developmental Transcription
Factor Modules to Generate Neurons
Inducing Neuronal Diversity
Challenges of Generating Neuronal Diversity
In Vivo Neuronal Reprogramming
Looking into the Future of Induced
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Development-inspired signals directly reprogram non-neuronal cells into induced neuronal cells. Pools of transcription factors initially
selected based on functional roles during
developmental neurogenesis have been reduced to
“modules” able to promote the conversion of
differentiated cells into neuronal cells. Non-neuronal cells—including astrocytes, fibroblasts, pericytes, and hepatocytes—have been converted into
neuronal cells. Young postmitotic neurons and
astrocytes have been reprogrammed from one class
into another from within the brain.
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Cite this article as R. Amamoto and P. Arlotta,
Science 343, 1239882 (2014).
Department of Stem Cell and Regenerative Biology, Sherman Fairchild Building 7 Divinity Avenue, Harvard University, Cambridge, MA 02138, USA.
*Corresponding author. E-mail: firstname.lastname@example.org