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Development of the Striatum in Health and Disease

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The mammalian striatum serves as interface connecting the cerebral cortex with the basal ganglia and the limbic system. Its highly complex structure is organized in multiple functional levels that reflect the relay function the striatum has within neuronal circuitries in the forebrain. Firstly, the striatum ...

The mammalian striatum serves as interface connecting the cerebral cortex with the basal ganglia and the limbic system. Its highly complex structure is organized in multiple functional levels that reflect the relay function the striatum has within neuronal circuitries in the forebrain. Firstly, the striatum can be divided into a dorsal caudate-putamen that links the basal ganglia with the cerebral cortex and the ventral accumbens nucleus that interacts with the limbic system. A second organizational level can be defined amongst the striatal projection neurons, referred to as medium spiny neurons (MSN) which can be grouped into direct and indirect pathway based on their target projections, peptide co-transmitter and dopamine-receptor expression. A third level of differentiation is the so-called striosome-matrix subdivision associated with the origin of the cortical input and is based on striatal ontogeny.
Molecular mechanisms underlying the patterning processes in the fetal forebrain are of crucial interest to understand cellular interaction in the basal ganglia. Ontogenetically, the striatum derives from the ganglionic eminence, a structure located in the fetal ventral telencephalon. A large number of extrinsic and intrinsic factors involved in striatal ontogeny have recently been identified. Notwithstanding, there remain many unresolved questions concerning inductive signals, genetic interactions, cell migration and target projections underlying the complex organization and cellular diversity of the adult striatum.
Striatal differentiation of pluripotent embryonic stem cells (ESC) can serve as source for cell replacement in neurodegenerative disorders affecting the striatum such as Huntington’s disease (HD). The recent discovered conversion of somatic cells into neurons opens new perspectives for cell replacement therapies which have been previously validated using primary cells. Differentiation of ESCs provides the opportunity to investigate current models of striatal neurogenesis. Understanding the genetic interactions of striatal neurogenesis is essential, as it allows developing strategies against neurodegeneration caused by mutations in the human Huntingtin (HTT) gene. ESCs, respectively induced pluripotent stem cells (iPS) carrying the HTT gene mutations allow studying HTT gene function, especially the impact the mutation has on neurogenesis. Furthermore, in vitro disease models offer a good background to study cellular and molecular processes of HD, providing a tool for drug screening with the potential of improving on currently available disease management options.


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