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"Thomas, C."
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Direct conversion of fibroblasts to functional neurons by defined factors
Cellular differentiation and lineage commitment are considered to be robust and irreversible processes during development. Recent work has shown that mouse and human fibroblasts can be reprogrammed to a pluripotent state with a combination of four transcription factors. This raised the question of whether transcription factors could directly induce other defined somatic cell fates, and not only an undifferentiated state. We hypothesized that combinatorial expression of neural-lineage-specific transcription factors could directly convert fibroblasts into neurons. Starting from a pool of nineteen candidate genes, we identified a combination of only three factors,
Ascl1
,
Brn2
(also called
Pou3f2
) and
Myt1l
, that suffice to rapidly and efficiently convert mouse embryonic and postnatal fibroblasts into functional neurons
in vitro
. These induced neuronal (iN) cells express multiple neuron-specific proteins, generate action potentials and form functional synapses. Generation of iN cells from non-neural lineages could have important implications for studies of neural development, neurological disease modelling and regenerative medicine.
Nerve cells direct
The discovery that differentiated cells such as fibroblasts can be reprogrammed to pluripotency, producing iPS (induced pluripotent stem) cells, has generated much interest because of their potential therapeutic uses. Now Vierbuchen
et al
. show that mature differentiated cells can be directed, using a cocktail of transcription factors distinct from those used for generating iPS cells, to form functional neurons
in vitro
, without having to revert the fibroblasts to an embryonic state. Just three factors,
Ascl1
,
Brn2
(
Pou3f2
) and
Myt1l
, suffice to convert mouse embryonic and postnatal fibroblasts into functional neurons.
Mouse and human fibroblasts can be reprogrammed to a pluripotent state with a combination of four transcription factors. Here, mature differentiated cells are directed, via a combination of a few transcription factors (distinct from those described for generating iPS cells), to form functional neurons
in vitro
, without having to revert the fibroblasts to an embryonic state.
Journal Article
A Neural Circuit for Memory Specificity and Generalization
Increased fear memory generalization is associated with posttraumatic stress disorder, but the circuit mechanisms that regulate memory specificity remain unclear. Here, we define a neural circuit—composed of the medial prefrontal cortex, the nucleus reuniens (NR), and the hippocampus—that controls fear memory generalization. Inactivation of prefrontal inputs into the NR or direct silencing of NR projections enhanced fear memory generalization, whereas constitutive activation of NR neurons decreased memory generalization. Direct optogenetic activation of phasic and tonic action-potential firing of NR neurons during memory acquisition enhanced or reduced memory generalization, respectively. We propose that the NR determines the specificity and generalization of memory attributes for a particular context by processing information from the medial prefrontal cortex en route to the hippocampus.
Journal Article
Neuroligins and neurexins link synaptic function to cognitive disease
The brain processes information by transmitting signals at synapses, which connect neurons into vast networks of communicating cells. In these networks, synapses not only transmit signals but also transform and refine them. Neurexins and neuroligins are synaptic cell-adhesion molecules that connect presynaptic and postsynaptic neurons at synapses, mediate signalling across the synapse, and shape the properties of neural networks by specifying synaptic functions. In humans, alterations in genes encoding neurexins or neuroligins have recently been implicated in autism and other cognitive diseases, linking synaptic cell adhesion to cognition and its disorders.
Journal Article
Membrane Fusion: Grappling with SNARE and SM Proteins
The two universally required components of the intracellular membrane fusion machinery, SNARE and SM (Sec1/Munc18-like) proteins, play complementary roles in fusion. Vesicular and target membrane-localized SNARE proteins zipper up into an α-helical bundle that pulls the two membranes tightly together to exert the force required for fusion. SM proteins, shaped like clasps, bind to trans-SNARE complexes to direct their fusogenic action. Individual fusion reactions are executed by distinct combinations of SNARE and SM proteins to ensure specificity, and are controlled by regulators that embed the SM-SNARE fusion machinery into a physiological context. This regulation is spectacularly apparent in the exquisite speed and precision of synaptic exocytosis, where synaptotagmin (the calcium-ion sensor for fusion) cooperates with complexin (the clamp activator) to control the precisely timed release of neurotransmitters that initiates synaptic transmission and underlies brain function.
Journal Article
Induction of human neuronal cells by defined transcription factors
Neurons from fibroblasts
Three papers in this issue demonstrate the production of functional induced neuronal (iN) cells from human fibroblasts, a procedure that holds great promise for regenerative medicine. Pang
et al
. show that a combination of the three transcription factors
Ascl1
(also known as
Mash1
),
Brn2
(or
Pou3f2
) and
Myt1l
greatly enhances the neuronal differentiation of human embryonic stem cells. When combined with the basic helix–loop–helix transcription factor NeuroD1, these factors can also convert fetal and postnatal human fibroblasts into iN cells. Caiazzo
et al
. use a cocktail of three transcription factors to convert prenatal and adult mouse and human fibroblasts into functional dopaminergic neurons. The three are
Mash1
,
Nurr1
(or
Nr4a2
) and
Lmx1a
. Conversion is direct with no reversion to a progenitor cell stage, and it occurs in cells from Parkinson's disease patients as well as from healthy donors. Yoo
et al
. use an alternative approach. They show that microRNAs can have an instructive role in neural fate determination. Expression of miR-9/9* and miR-124 in human fibroblasts induces their conversion into functional neurons, and the process is facilitated by the addition of some neurogenic transcription factors.
Somatic cell nuclear transfer, cell fusion, or expression of lineage-specific factors have been shown to induce cell-fate changes in diverse somatic cell types
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. We recently observed that forced expression of a combination of three transcription factors,
Brn2
(also known as
Pou3f2
),
Ascl1
and
Myt1l
, can efficiently convert mouse fibroblasts into functional induced neuronal (iN) cells
13
. Here we show that the same three factors can 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 could also convert fetal and postnatal human fibroblasts into iN cells showing typical neuronal morphologies and expressing multiple neuronal markers, even after downregulation of the exogenous transcription factors. Importantly, 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. Our 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. These methods may facilitate robust generation of patient-specific human neurons for
in vitro
disease modelling or future applications in regenerative medicine.
Journal Article