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Simposio Internacional: Descifrando el desarrollo del cerebro: aproximaciones
interdiscilinares hacia la comprensión y tratamiento de sus patologías
International Symposium: Building up the brain: new interdisciplinary
perspectives to understand and treat brain diseases
Madrid, 15 y 16 de octubre de 2013
Madrid, October 15-16, 2013
RESÚMENES/ABSTRACTS
v
1. A top-down systems biology approach to novel therapeutic strategies in
Alzheimer´s disease, Patrick Aloy
2. Psychosis: the final pathway for an abnormal neurodevelopment, Celso
Arango
3. Transcriptional control of cortex development, Suzana Atanasoski
4. Alzheimer´s disease pathogenesis: insights from neural development,
Paola Bovolenta
5. Establishing bilateral brain wiring, Eloisa Herrera
6. Input-dependent controls over visual circuit assembly, Denis Jabaudon
7. Plasticity of specific inhibitory inputs in the visual cortex, Christiaan Levelt
8. Molecular Logic of Neocortical Projection Neuron Development and
Diversity, Jeffrey D. Macklis
9. Cux transcription factors control plasticity to specify circuits in mammals,
Marta Nieto
10. From wires to behavior: tools from computational neurobiology, Gonzalo
de la Polavieja
11. LKB1 kinase as a master regulator of axon morphogenesis in mammalian:
roles in axogenesis, axon branching and presynaptic function, Franck
Polleux
12. Endogenous Hypercortisolism: a model for memory impairment, Eugenia
Resmini
13. Unveiling network circuitry from spontaneous activity in neuronal cultures,
Jordi Soriano Fradera
14. Genetic and post-mitotic control of area identity and cell-type specification
in the developing mouse neocortex, Michèle Studer
15. Role of feedback signaling in neocortical development, Victor Tarabykin
16. Cellular mechanisms regulating patterns of converging inputs onto retinal
neurons, Rachel O.L. Wong
FUNDACIÓN RAMÓN ARECES
Simposio Internacional: Descifrando el desarrollo del cerebro: aproximaciones
interdiscilinares hacia la comprensión y tratamiento de sus patologías
International Symposium: Building up the brain: new interdisciplinary
perspectives to understand and treat brain diseases
Madrid, 15 y 16 de octubre de 2013
Madrid, October 15-16, 2013
RESÚMENES/ABSTRACTS
A top-down systems biology approach to novel therapeutic strategies in
Alzheimer´s disease, Patrick Aloy
High-throughput interaction discovery initiatives are providing thousands of novel
protein interactions which are unveiling many unexpected links between
apparently unrelated biological processes. In particular, analyses of the first draft
human interactomes highlight a strong association between protein network
connectivity and disease. Indeed, recent exciting studies have exploited the
information contained within protein networks to disclose some of the molecular
mechanisms underlying complex pathological processes. These findings suggest
that both protein-protein interactions and the networks themselves could emerge
as a new class of targetable entities, boosting the quest for novel therapeutic
strategies. In this talk, I will summarize our work towards the characterization and
modelling of the protein-interaction network underlying Alzheimer´s disease,
together with our most recent attempts to decipher complex cell networks to the
point of being able to predict how the perturbation of a node might affect the
system as a whole.
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Psychosis: the final pathway for an abnormal neurodevelopment, Celso Arango
Schizophrenia is a complex disorder caused by abnormal neurodevelopment
with many different biological and psychosocial risk factors. The risk of having
psychotic symptoms over a lifetime, as the persistence of those symptoms, the
severity and disability they cause, and their recurrence over time depends on the
interaction between genes and environmental factors. Environmental factors are
more important the earlier they interfere with the normal neurodevelopment. That
a brain with an abnormal neurodevelopmental trajectory ends up producing one
symptomatology or another is a matter of the balance between risk and
protective factors. Prevention of such severe mental disorders as schizophrenia
syndrome through early interventions that act at the level of those risk factors is
encouraging and augurs a promising future. As pluripotential stem cells can
differentiate into different cell types depending on the environment, a given
genotype can produce a brain with a higher or lower risk of developping
dysfunctions such as psychosis, negative symptoms, or cognitive impairment
depending on the environmental factors to which it is exposed. There are many
FUNDACIÓN RAMÓN ARECES
Simposio Internacional: Descifrando el desarrollo del cerebro: aproximaciones
interdiscilinares hacia la comprensión y tratamiento de sus patologías
International Symposium: Building up the brain: new interdisciplinary
perspectives to understand and treat brain diseases
Madrid, 15 y 16 de octubre de 2013
Madrid, October 15-16, 2013
RESÚMENES/ABSTRACTS
pathways to what is called schizophrenia in the DSM-5 diagnostic criteria.
Knowledge of those pathways will put an end to the use of the term
schizophrenia and shed light on our current ignorance.
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Transcriptional control of cortex development, Suzana Atanasoski
In the developing dorsal telencephalon, neural stem and progenitor cells
generate a large variety of neurons with specific functions in the mature cortex.
The proto-oncogene Ski is a transcriptional regulator linked to the human 1p36
deletion syndrome, which involves a set of phenotypes including brain
abnormalities. Ski shows a dynamic expression pattern during cortical
development, and accordingly, the phenotype of Ski-deficient cortices is
complex, involving altered cell cycle characteristics of neural progenitors,
disturbed timing of neurogenesis, and misspecification of projection neurons. Ski
is likely to play a role in various pathways by its ability to interact with a range of
signalling molecules, thereby modulating transcriptional activity of corresponding
target genes. Cell-type specific interacting partners and downstream targets of
Ski in cortical cells will be discussed.
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Alzheimer´s disease pathogenesis: insights from neural development, Paola
Bovolenta
The A Disintegrin And Metalloproteases (ADAMs) are a family of membrane
proteases that cleave the extracellular domains of a variety of membrane bound
proteins, releasing soluble peptides that modulate cell-to-cell communication or
priming the substrate for further cleavage. Prominent examples of ADAM
FUNDACIÓN RAMÓN ARECES
Simposio Internacional: Descifrando el desarrollo del cerebro: aproximaciones
interdiscilinares hacia la comprensión y tratamiento de sus patologías
International Symposium: Building up the brain: new interdisciplinary
perspectives to understand and treat brain diseases
Madrid, 15 y 16 de octubre de 2013
Madrid, October 15-16, 2013
RESÚMENES/ABSTRACTS
substrates are the Notch receptor, N-cadherin, L1, several cytokines and the
amyloid precursor protein (APP). All these proteins control different events in
CNS development and homeostasis, suggesting that ADAM activity must be
tightly regulated to allow proper brain development and function. However, the
identification of such regulators is just at the beginning. A recent example is
Secreted Frizzled Related Protein1 (Sfrp1), which binds to and negatively
regulates the proteinase activity ADAM10, a specific member of this family. As a
consequence, genetic inactivation of Sfrp1 in mice increases Notch, N-Cadherin,
L1 and APP processing. I will discuss the functional consequences of Sfrp1
inactivation in developmental events as well as in a mouse model of Alzheimer
Disease (AD). I will discuss the relevance of these consequences in the possible
treatment of AD.
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Establishing bilateral brain wiring, Eloisa Herrera
Bilaterally symmetric organisms face the problem of how to integrate functions
across the two sides of the body so that behavioral outputs can be properly
coordinated. The importance of bilateral integration is especially evident in
sensory perception such as binocular vision or in the control of movements. The
integration of sensory inputs coming from both sides of the nervous system is
possible thanks to the existence of commissural fibers that project from one side
to the other during embryonic development. Axon midline crossing has revealed
as a powerful model to investigate how growing axons are guided along specific
pathways and, as a consequence, many of the main mechanisms that control
this process are currently known. However, most axons in the CNS do not cross
the midline but project ipsilaterally to transmit specific information into the same
side of the brain. Work in our laboratory has recently revealed some of the main
mechanisms controlling the cellular and molecular mechanisms underlying the
formation of major ipsilaterally-projecting tracts in the CNS.
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FUNDACIÓN RAMÓN ARECES
Simposio Internacional: Descifrando el desarrollo del cerebro: aproximaciones
interdiscilinares hacia la comprensión y tratamiento de sus patologías
International Symposium: Building up the brain: new interdisciplinary
perspectives to understand and treat brain diseases
Madrid, 15 y 16 de octubre de 2013
Madrid, October 15-16, 2013
RESÚMENES/ABSTRACTS
Input-dependent controls over visual circuit assembly, Denis Jabaudon
The molecular mechanisms that control distinct subtypes of neurons assemble to
form input-specific circuits are poorly understood. Although input from the
sensory periphery is required for modality-specific circuits to form, the cell-type
specific mechanisms underlying these processes are largely unknown. Here, we
investigate this question in retinogeniculate circuits, and examine the role of
retinal input in the migration, differentiation, and synaptic integration of inhibitory
interneurons in the visual thalamus. Using a combination of genetic,
pharmacological, surgical and electrophysiological approaches in vivo and in
vitro, we report that the targeted navigation and synaptic integration of dLGN
within thalamic visual circuits is controlled by retinal input, providing an inputdependent control over thalamocortical neuron excitability. This reveals an inputdependent mechanism regulating circuit inhibition, which may account for the
progressive recruitment of INs into expanding excitatory circuits during evolution.
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Plasticity of specific inhibitory inputs in the visual cortex, Christiaan Levelt
The development of inhibitory innervation is an important factor determining the
onset and closure of the critical period of ocular dominance plasticity in the visual
cortex. The mechanisms through which inhibition regulates cortical plasticity and
the types of interneurons involved are not well known. Using in vivo imaging
techniques we provide evidence that structural plasticity of inhibitory synapses
onto pyramidal neurons is a major component of plasticity in the neocortex. Post
hoc immunohistochemical analyses show that this structural plasticity involves
inputs from specific interneuron subsets. An optogenetic approach was used to
address the functional implications of inhibitory synapse plasticity and which
interneuron subsets it involves. We show that parvalbumin expressing
interneurons are the main regulators of neuronal activity during the assessment
of ocular dominance. Their influence on eye specific responses alters during
ocular dominance plasticity and the functional implications will be discussed.
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FUNDACIÓN RAMÓN ARECES
Simposio Internacional: Descifrando el desarrollo del cerebro: aproximaciones
interdiscilinares hacia la comprensión y tratamiento de sus patologías
International Symposium: Building up the brain: new interdisciplinary
perspectives to understand and treat brain diseases
Madrid, 15 y 16 de octubre de 2013
Madrid, October 15-16, 2013
RESÚMENES/ABSTRACTS
Molecular Logic of Neocortical Projection Neuron Development and Diversity,
Jeffrey D. Macklis
Given the heterogeneity of CNS neuronal subtypes (of cerebral cortex /
neocortical projection neurons in particular), and the complexity of their
connections, detailed understanding of molecular controls over specification,
differentiation, connectivity, and survival of specific neuronal subtypes and
lineages will contribute not only to 1) understanding the development,
organization, function, and evolution of CNS circuitry, but also to 2) identification
of developmental and degenerative disease mechanisms and mono/polygenic
vulnerability genes, to 3) support or regeneration of vulnerable populations in
neurodegenerative (e.g. ALS, HSP/PLS, HD, PD) or acquired disease (e.g. SCI),
to 4) enabling cellular models of neuron type-specific disease, and to 5) attempts
to functionally repair CNS circuitry. For example, data from our lab and others
demonstrate that new neurons can be added to adult neocortical and other CNS
circuitry via manipulation of transplanted or endogenous progenitors in situ
(including induction of limited neurogenesis of clinically important corticospinal
motor neurons– CSMN– in adult mice), indicating that cellular repair of cortical
and cortical output circuitry is possible, if controls over specific lineage
differentiation are understood. Using FACS-purified CSMN and other neocortical
projection neuron populations (including callosal projection neurons, corticothalamic projection neurons, cortico-brainstem projection neurons, corticostriatal
projection neurons, and target-specific subsets of these populations) at critical
stages of development in vivo, we have identified a set of multi-stage,
combinatorially interacting developmental controls – both novel and largely
uncharacterized transcriptional regulators and other genes, and cell-extrinsic
controls – that are instructive for development of specific neuron subtypes as
they develop in vivo (in particular, for CSMN, callosal, corticothalamic, and
related projection neuron populations). These control key developmental
processes from progenitor parcellation and progenitor subtype restriction, to
subtype-specific differentiation, to acquisition of precise areal identity, to targetspecific axonal outgrowth. Loss- and gain-of-function analyses for multiple
identified genes / molecules reveal a nested (~Boolean) “molecular logic” of
progenitor-stage and post-mitotic, areally specific, combinatorial molecular
controls over the precise development of key neocortical projection neuron
populations. Some of these developmental controls are directly implicated or
linked to human disease, and might both elucidate disease mechanisms and
(polygenic) vulnerability, and enable directed control of neural progenitors (or ES
/ iPS cells) toward accurate disease models, neuronal support or regeneration,
and functional CNS repair.
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FUNDACIÓN RAMÓN ARECES
Simposio Internacional: Descifrando el desarrollo del cerebro: aproximaciones
interdiscilinares hacia la comprensión y tratamiento de sus patologías
International Symposium: Building up the brain: new interdisciplinary
perspectives to understand and treat brain diseases
Madrid, 15 y 16 de octubre de 2013
Madrid, October 15-16, 2013
RESÚMENES/ABSTRACTS
Cux transcription factors control plasticity to specify circuits in mammals, Marta
Nieto
The development of precise intrahemispheric and interhemispheric connections
is essential for the high order functions of the cerebral cortex. This balanced
connectivity is affected in several human brain disorders, such as schizophrenia,
epilepsy or autism. We focus our study on how Cux1 transcription factor
determine the connectivity of cortical layer II-III neurons. Our recent work
demonstrates that Cux1 regulates the excitability and plastical adaptative
response of layer-II-III neurons during early postnatal development as a
mechanisms to determine the f connectivity of the final circuit. Lack of plasticity
as a result of Cux1 deficiency induces aberrant interhemispheric connectivity but
does not affect local intrahemispheric circuits. I will discuss the cellular and
molecular elements involved in this developmental mechanism, the
consequences for the formation of the functional networks, and the implications
for the understanding and treatment of mental disorders of developmental origin
and other diseases of the nervous system.
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From wires to behavior: tools from computational neurobiology, Gonzalo de la
Polavieja
I will describe how tools from computational neurobiology can help us
understand the structure and function of neuronal circuits. I will concentrate on
three aspects: neuroanatomy, processing and behavior. For neuranatomy, I will
show that the very simple idea of wiring economy can quantitative predict many
neuroanatomical structures. Tools for the understanding of processing will be
discussed for both single neurons and networks. Finally, I will discuss new tools
for the analysis of social behavior, a particularly challenging type of behavior
because it implies the complexities of interactions among animals.
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FUNDACIÓN RAMÓN ARECES
Simposio Internacional: Descifrando el desarrollo del cerebro: aproximaciones
interdiscilinares hacia la comprensión y tratamiento de sus patologías
International Symposium: Building up the brain: new interdisciplinary
perspectives to understand and treat brain diseases
Madrid, 15 y 16 de octubre de 2013
Madrid, October 15-16, 2013
RESÚMENES/ABSTRACTS
LKB1 kinase as a master regulator of axon morphogenesis in mammalian: roles
in axogenesis, axon branching and presynaptic function, Franck Polleux
The developmental mechanisms underlying axon morphogenesis of specific
populations of mammalian neurons in vivo are still poorly understood at the
cellular and molecular levels. Operationally, axon development can be divided in
three major steps: (1) axon specification during neuronal polarization, (2) axon
growth and guidance towards their final targets and (3) terminal axon branching
and presynaptic development. A few years ago, we and others identified that the
serine/threonine kinase LKB1 (also called Par4 and STK11) is required for axon
specification in the developing cortex in vivo (Barnes et al Cell 2007). We
recently discovered that at later time point, LKB1 is also required for axon
branching in vivo. Interestingly, these two functions of LKB1 required two
separate sets of downstream kinases (SAD-A/B kinases for axon specification
vs. NUAK1 for axon branching). Furthermore, we demonstrated that LKB1NUAK1 kinase pathway regulate terminal axon branching by controlling
mitochondrial capture at nascent presynaptic sites (Courchet, Lewis et al., Cell
2013).
Some of the central unresolved questions raised by our recent results are: (1)
what are the cellular and molecular mechanisms anchoring mitochondria
presynaptically?, (2) how do presynaptic mitochondria regulate axon branching ?
and (3) more generally what is the function of mitochondria once captured
presynaptically? I will summarize these recently published results as well as
some preliminary data demonstrating that, beyond being important for ATP
production, presynaptic mitochondria play a critical role in calcium clearance
through a unique calcium channel called the Mitochondrial Calcium Uniporter
(MCU) which in turn plays a critical role in specifying presynaptic release
properties in neurons. Interestingly, LKB1 seems to regulate axon branching
through regulation of MCU abundance in mitochondria, affecting presynaptic
accumulation during neurotransmitter release and presynaptic release
properties.
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FUNDACIÓN RAMÓN ARECES
Simposio Internacional: Descifrando el desarrollo del cerebro: aproximaciones
interdiscilinares hacia la comprensión y tratamiento de sus patologías
International Symposium: Building up the brain: new interdisciplinary
perspectives to understand and treat brain diseases
Madrid, 15 y 16 de octubre de 2013
Madrid, October 15-16, 2013
RESÚMENES/ABSTRACTS
Endogenous Hypercortisolism: a model for memory impairment, Eugenia
Resmini,
Chronic exposure to endogenous hypercortisolism in Cushing’s syndrome (CS)
is associated with negative effects on memory and hippocampal volumes (HV),
even after biochemical cure. Hippocampus, which is critical for learning and
memory, is rich in glucocorticoid (GC) receptors and is therefore particularly
vulnerable to GC excess. With the advent of structural and functional
neuroimaging techniques, the role of different nervous system structures and the
hypothalamic-pituitary-adrenal axis can be investigated directly.
HV have been calculated in CS patients using a 3tesla MRI and an automated
procedure (Freesurfer) and compared to healthy subjects. Metabolites in the
hippocampi of these CS patients have been also investigated with proton
magnetic resonance spectroscopy (1H-MRS), a sensitive, non-invasive imaging
technique capable of measuring brain metabolites in vivo. Concentrations of Glu
(Glutamate), Glx (Glutamate+Glutamine), NAA (NAcetyl-aspartate), total-NAA
(NAcetyl-aspartate+N-Acetyl-aspartyl-Glutamate), Cho (Glycerophosphocholine
and Phosphocholine compounds), Cr (Creatine) and MI (mionositol) were
measured (mmol/l).
Verbal and visual memory performance has been evaluated. We hypothesized
that in CS patients, impaired memory performances and decreased HV would be
found, due to long term exposure to hypercortisolism.
We found that CS patients had lower performances in verbal and visual memory
tests compared with matched controls, but only those with severe memory
impairments also had reduced HV. Brain atrophy and reduction in total and
cortical gray matter volumes were observed in CS patients compared with
controls, however subcortical gray matter reduction was seen only in those with
severe memory impairment, in parallel to the findings of reduced HV. The
negative effect of hypercortisolism on memory and HV was not totally reversible
after biochemical cure.
Moreover persistently abnormal metabolites have been demonstrated in the
head of both hippocampi of CS patients, using 1H-MRS, despite endocrine cure
of hypercortisolism. Low levels of NAA indicate neuronal dysfunction and/or loss,
while high levels of Glx suggest concomitant glial proliferation, as a repair
mechanism. These functional abnormalities could be considered early markers of
GC neurotoxicity, would precede hippocampal volume reduction and could be
implicated in the memory impairments evidenced in these patients. Whether less
exposure to hypercortisolism by earlier diagnosis and successful treatment of CS
would avoid the progression of memory problems and the reduction of HV
remains to be confirmed.
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FUNDACIÓN RAMÓN ARECES
Simposio Internacional: Descifrando el desarrollo del cerebro: aproximaciones
interdiscilinares hacia la comprensión y tratamiento de sus patologías
International Symposium: Building up the brain: new interdisciplinary
perspectives to understand and treat brain diseases
Madrid, 15 y 16 de octubre de 2013
Madrid, October 15-16, 2013
RESÚMENES/ABSTRACTS
Unveiling network circuitry from spontaneous activity in neuronal cultures, Jordi
Soriano Fradera
Spontaneous activity (brain rhythms) plays a fundamental role in shaping
neuronal circuits during embryonic development, while in the mature brain it is
involved in tasks as important as motor coordination and memory. Despite the
importance of spontaneous activity, the mechanisms that govern its initiation and
maintenance are poorly understood. In this talk I will introduce neuronal cultures
as a versatile experimental platform to investigate, on the one hand, the
generation and richness of spontaneous activity patterns. On the other hand, I
will introduce theoretical and numerical tools that help understanding the
interplay between activity and connectivity in neuronal circuits. Finally, I will show
how neuronal cultures, in combination with these multidisciplinary resources,
provide a valuable platform to investigate dysfunctional neuronal circuits, for
instance those associated with Alzheimer’s and Huntington’s disorders.
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Genetic and post-mitotic control of area identity and cell-type specification in the
developing mouse neocortex, Michèle Studer
Corticogenesis involves the formation of six distinct layers and of functionally
specialized areas characterized by specific sets of pyramidal neurons with
distinctive morphologies, connectivity, and gene expression profiles. Partitioning
of the neocortex, also known as arealization, is thought to be decided at early
stages by the expression of several patterning genes in neuronal progenitors.
Recently, few post-mitotically expressed genes have been described to influence
the correct specification and positioning of functional areas at later stages.
However, whether post-mitotically expressed genes just refine and/or maintain
area features imparted by progenitors or independently specify functional areas
is still unclear. We have previously shown that the transcriptional regulator
COUP-TFI, expressed in progenitors and newborn neurons, is required in
balancing the neocortex into motor and sensory areas (1) by regulating a genetic
program leading to the correct differentiation of deep layer projection neurons
(2). In this study, we show by loss- and gain-of-function approaches that post-
FUNDACIÓN RAMÓN ARECES
Simposio Internacional: Descifrando el desarrollo del cerebro: aproximaciones
interdiscilinares hacia la comprensión y tratamiento de sus patologías
International Symposium: Building up the brain: new interdisciplinary
perspectives to understand and treat brain diseases
Madrid, 15 y 16 de octubre de 2013
Madrid, October 15-16, 2013
RESÚMENES/ABSTRACTS
mitotic function of COUP-TFI is necessary and sufficient in imparting areal- and
laminar-specific properties during corticogenesis. We also found that postmitotically expressed COUP-TFI exerts a negative feedback on the expression of
mitotically genes promoting rostral identity. This envisages a crucial decisional
function of COUP-TFI in post-mitotic cells during neocortical area and cell-type
specification and reveals a high level of plasticity in setting up functional area
properties during corticogenesis.
1) Armentano M., Chou S. J., Srubek Tomassy G., Leingärtner A., O’Leary
D.D.M. and Studer M. COUP-TFI regulates the balance of cortical patterning
between frontal/motor and sensory areas. Nature Neuroscience, 10, 2007, 12771286.
2) Tomassy Srubek G., De Leonibus E., Jabaudon D., Lodato S., Alfano C.,
Mele A., Macklis J.D. and Studer M. Area-specific temporal control of
corticospinal motor neuron differentiation by COUP-TFI. PNAS, 2010, 107(8):
3576-81.
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Role of feedback signaling in neocortical development, Victor Tarabykin
The neocortex is designated as the seat of our highest cognitive abilities.
Comprised of functionally distinct neurons, the mammalian neocortex develops
from progenitors lining the dorsal aspects of the lateral ventricles. The fate and
position of these neurons is decided by the time they leave the germinal zone.
However, little is known about how cortical progenitors learn how many neurons
of each type to produce and when to make the switch from producing one
neuronal type to the next. One source of instructions to the progenitors comes
from the cortical plate itself, creating a feedback loop. Recently we identified Sip1
as a master regulator controlling the timing of corticogeneis. Sip1 is a
transcriptional repressor, which interacts with the activated Smads, the
transducers of TGF-ß signaling and with the NuRD complex. In my talk I will
discuss molecular mechanisms down-stream of Sip1 that control the feedback.
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FUNDACIÓN RAMÓN ARECES
Simposio Internacional: Descifrando el desarrollo del cerebro: aproximaciones
interdiscilinares hacia la comprensión y tratamiento de sus patologías
International Symposium: Building up the brain: new interdisciplinary
perspectives to understand and treat brain diseases
Madrid, 15 y 16 de octubre de 2013
Madrid, October 15-16, 2013
RESÚMENES/ABSTRACTS
Cellular mechanisms regulating patterns of converging inputs onto retinal
neurons, Rachel O.L. Wong
Neurons must connect with the appropriate presynaptic cell types as well as
establish a stereotypic number of synapses with each input type in order to
perform their specific functions. To attain stereotyped connectivity patterns,
developmental processes are in place to control the matching of synaptic
partners, the relative convergence of distinct input types, and the number of
connections formed by an individual axon onto a given postsynaptic cell. Indeed,
many mechanisms that navigate axons and dendrites toward their synaptic
partners are now known. However, what remain largely unidentified are the
cellular interactions that regulate the number of synapses formed by each input
type onto a common target cell. We have taken advantage of two wellcharacterized circuits in the vertebrate retina (mouse and zebrafish) to unravel
the precise roles of activity-dependent and independent interactions that shape
the connectivity of converging inputs. Perturbations to neurotransmission of
specific presynaptic cell types in vivo enabled us to distinguish between cellautonomous and non-autonomous roles of activity. Targeted cell ablations in vivo
helped unmask the importance of contact with presynaptic cells independent of
their activity. Our findings in both systems underscore a key role for the dominant
input in regulating the connectivity of other afferent types with the postsynaptic
cell during development. A future direction is to better understand the capacity
and mechanisms engaged to re-establish the wiring patterns of retinal circuits
during regeneration and repair.
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