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Research Group Dendritic Development (Dr. Marta Rosario)

The research group of Dr. Marta Rosario is interested in identifying the mechanims that prevent dendritic tree formation during the early phases of neuronal differentiation and induce and control it during later phases.

The group uses genetically modified mice and primary cell culture to identify the molecular mechanisms that regulate dendritic tree formation and maturation during the development of the mammalian neocortex.

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The neuronal dendritic tree

The neocortex is involved in processing sensory information and in maintaining cognitive function.  At the cellular level, the dendritic tree is the site of information input and processing of the neuron. The complexity and scope of this tree is neuron subtype-specific and ultimately determines the richness of neuronal interactions. The dendritic tree is formed during late cortical development, after neurons have finished migrating to their correct position in the cortex and after extension of the axon and only reaches fully maturity during adolescence. Defective formation or maturation of the dendritic tree is associated with cognitive defects in human neurodevelopmental disorders ranging from intellectual disability to neuropsychiatric conditions such as schizophrenia and autism spectrum disorders (ASD).

We are interested in identifying the mechanisms that regulate the normal timing, extent and final maturation of the dendritic tree during formation of the mammalian neocortex. Furthermore, we also investigate how defects in these mechanisms contribute to the development of neurodevelopmental disorders ranging from intellectual disability to neuropsychiatric conditions such as schizophrenia and autism spectrum disorders.

Regulation of dendritic development

An important aspect that we concentrate on is the regulation of the cellular cytoskeleton by the Rho family of small GTPases (Figure 1). Cytoskeletal dynamics is essential for permitting the branching and extension of the dendritic tree, the formation and maturation of dendritic spines and for the correct trafficking of postsynaptic molecules in the dendritic tree during the lifetime of the neuron. This dynamism is controlled by Rho proteins, a family of small GTPases that act as molecular switches by cycling through an active GTP-bound and an inactive GDP-bound state. The ability of these proteins to cycle is critical for specifying the kinetics of activation of downstream pathways and is regulated primarily by two large groups of proteins: the Guanine-nucleotide exchange factors (GEFs) that promote GDP/GTP exchange and the GTPase-activating proteins (GAPs) that promote the hydrolysis of GTP. A third group of regulators, the Guanine nucleotide dissociation inhibitors (GDIs) functions by  sequestering the GDP-bound form in the cytosol.

We have been principally interested in the GAPs for Rho GTPases, encoded by the ARHGAP genes. This is a large family of multidomain proteins that not only possess the ability to inhibit the activity of different Rho proteins but also act as signaling platforms that enable integration of the regulation of cytoskeletal dynamics with other cellular and environmental cues. For example, we identified a neuronal signaling molecule, NOMA-GAP, encoded by the ARHGAP33 gene that is an essential negative regulator of the Rho family member Cdc42, during development of the mammalian neocortex (Rosario et al., 2007; Rosario et al., 2012). Neurons lacking NOMA-GAP/ARHGAP33 show weakly branched dendritic trees possessing immature dendritic spines. Mice lacking NOMA-GAP/ARHGAP33, in turn, show specific changes in the social behaviour and recognition typical of mouse models of ASD autism (Schuster et al., 2015).

Currently, we are addressing the cellular and molecular alterations down- and up-stream of a selection of ARHGAP proteins, such as NOMA-GAP/ARHGAP33, that regulate dendritic development and maturation in the mammalian neocortex and examining their possible roles in the development of neurological diseases