CAPPELLO LAB
Developmental Neurobiology
Developmental Neurobiology
STEPS OF HUMAN BRAIN DEVELOPMENT
STEPS OF HUMAN BRAIN DEVELOPMENT
Neurogenesis, neuronal migration & neuronal maturation in the cerebral cortex occurs primarily during development .
Neurogenesis, neuronal migration & neuronal maturation in the cerebral cortex occurs primarily during development .
NEUROGENESIS IN MOUSE & HUMAN
NEUROGENESIS IN MOUSE & HUMAN
During the first stage, the preplate stage, the first early generated neurons migrate from the ventricular zone (VZ), where they have been produced by asymmetric cell division from neural stem cells (NSC). These neurons are called the Cajal-Retzius cells. As neurogenesis progresses, groups of postmitotic neurons (N) exit the proliferative ventricular and subventricular zones (VZ and SVZ) and migrate radially in an inside-out manner toward the pial surface to later form the organized cortical layers. The interneurons migrate from the proliferative zone of the ventral telencephalon in a tangentially oriented manner toward the cerebral cortex and intermingle with the excitatory neurons generated directly in the cortex.
During the first stage, the preplate stage, the first early generated neurons migrate from the ventricular zone (VZ), where they have been produced by asymmetric cell division from neural stem cells (NSC). These neurons are called the Cajal-Retzius cells. As neurogenesis progresses, groups of postmitotic neurons (N) exit the proliferative ventricular and subventricular zones (VZ and SVZ) and migrate radially in an inside-out manner toward the pial surface to later form the organized cortical layers. The interneurons migrate from the proliferative zone of the ventral telencephalon in a tangentially oriented manner toward the cerebral cortex and intermingle with the excitatory neurons generated directly in the cortex.
MALFORMATIONS OF THE DEVELOPING CORTEX
MALFORMATIONS OF THE DEVELOPING CORTEX
Genetic mutations has been associated to malformations of cortical development and these are often associated to developmental delay, intellectually disability and often to epilepsy.
Genetic mutations has been associated to malformations of cortical development and these are often associated to developmental delay, intellectually disability and often to epilepsy.
HOW DO WE TACKLE THE CAUSE OF NEURO-DEVELOPMENTAL DISORDERS
HOW DO WE TACKLE THE CAUSE OF NEURO-DEVELOPMENTAL DISORDERS
Malformations of the human neocortex due to defects in neuronal positioning are present in >1% of the general population and represent a major cause of developmental disabilities and severe epilepsies. In order to understand the biological mechanisms and therefore identify potential therapies for cortical malformations, we need to first discover the regulation of all processes of cortical development. We therefore need available mouse models that mimic the human disorders and an in vitro/in vivo approach that enable us to translate the finding into human cells/brain. Once we know whether the cellular and molecular mechanisms are maintained between the two species, we can address the circuitry and connectivity and identify the common regulators and seek for candidate molecules to use for potential therapy.
Malformations of the human neocortex due to defects in neuronal positioning are present in >1% of the general population and represent a major cause of developmental disabilities and severe epilepsies. In order to understand the biological mechanisms and therefore identify potential therapies for cortical malformations, we need to first discover the regulation of all processes of cortical development. We therefore need available mouse models that mimic the human disorders and an in vitro/in vivo approach that enable us to translate the finding into human cells/brain. Once we know whether the cellular and molecular mechanisms are maintained between the two species, we can address the circuitry and connectivity and identify the common regulators and seek for candidate molecules to use for potential therapy.
In order to achieve this we want to identify novel genes responsible for cortical malformations by mapping the genome of patients that do not have mutations in the ‘usual suspect’ genes to then generate mouse models to investigate the molecular and cellular mechanisms underlying these diseases by gain and loss of function .
In order to achieve this we want to identify novel genes responsible for cortical malformations by mapping the genome of patients that do not have mutations in the ‘usual suspect’ genes to then generate mouse models to investigate the molecular and cellular mechanisms underlying these diseases by gain and loss of function .
Moreover, we will characterize the functional aspects of these disorders by using our mouse models of cortical malformations (Cappello et al., Neuron 2012; Cappello et al., Nature Genetics 2013; Schimd et al., Frontiers in Neuroscience 2014) to address long-standing questions that are very difficult to be directly addressed in human patients: how connectivity between heterotopias is established and what is the neuronal composition as well as behavior and electrophysiological proprieties of the ectopic neurons.
Moreover, we will characterize the functional aspects of these disorders by using our mouse models of cortical malformations (Cappello et al., Neuron 2012; Cappello et al., Nature Genetics 2013; Schimd et al., Frontiers in Neuroscience 2014) to address long-standing questions that are very difficult to be directly addressed in human patients: how connectivity between heterotopias is established and what is the neuronal composition as well as behavior and electrophysiological proprieties of the ectopic neurons.
HUMAN DERIVED NEURONS & CEREBRAL ORGANOIDS
HUMAN DERIVED NEURONS & CEREBRAL ORGANOIDS
Finally we will study the molecular, cellular and functional proprieties of human reprogrammed neural stem cells and neurons derived from patients and generate cerebral organoids to mimic the human brain.
Finally we will study the molecular, cellular and functional proprieties of human reprogrammed neural stem cells and neurons derived from patients and generate cerebral organoids to mimic the human brain.
In this way we will be able to screen for several candidate genes identified from human patients as well as from known mouse models and assemble a network of genes and possibly pathways responsible for cortical malformations.
In this way we will be able to screen for several candidate genes identified from human patients as well as from known mouse models and assemble a network of genes and possibly pathways responsible for cortical malformations.
With these methods we will also be able to significantly contribute to identify strategies towards therapeutic approaches, like for instance the re-expression of mutant genes or modulation of the cytoskeleton stability and develop a genetic screening to know at a very early stage which patients could be more susceptible to epilepsy.
With these methods we will also be able to significantly contribute to identify strategies towards therapeutic approaches, like for instance the re-expression of mutant genes or modulation of the cytoskeleton stability and develop a genetic screening to know at a very early stage which patients could be more susceptible to epilepsy.
Performing RNA Sequencing and proteomics of different populations of human cells (e.g. neural stem cells versus neurons, or control versus mutant reprogrammed neurons) will ultimately enable us to define gene networks and pathways. This approach together with an appropriate functional analysis of the mouse models (e.g. functional MRI) will then give us new ideas in order to develop new targets for drug therapies.
Performing RNA Sequencing and proteomics of different populations of human cells (e.g. neural stem cells versus neurons, or control versus mutant reprogrammed neurons) will ultimately enable us to define gene networks and pathways. This approach together with an appropriate functional analysis of the mouse models (e.g. functional MRI) will then give us new ideas in order to develop new targets for drug therapies.
