NRX CODE

Deciphering the neurexin code in neuronal circuitry

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 Obiettivo del progetto (Objective)

'Networks of neurons, joined together by synaptic connections, represent basic functional units of the brain. Neuronal cells are very heterogeneous. Even a small unit of the nervous system such as the retina contains more than 50 physiologically and morphologically distinct neuron types where each type is tied with stereotyped connectivity into the neuronal network and is dedicated to specific aspects of information processing. Moreover, within a morphologically recognizable class of neurons sub-specializations exist that can be appreciated through analysis of the molecular repertoire of the cells. Understanding the developmental and molecular mechanisms contributing to the unique morphological and functional properties, as well as the specific synaptic connectivity of neurons represents one of the key questions in current neurobiological research.One hypothesis is that neuronal cell populations carry molecular recognition tags that contribute to targeted growth, selective wiring, and specific synaptic properties. Such tags would have to be highly polymorphic with different isoforms mediating cellular recognition events through binding partners. At the same time, such recognition tags should couple such extracellular interactions to a common cellular response. The recent development of new technologies for genome-wide proteomic and transcriptional analysis in combination with transgenic technologies provide a unique opportunity for unraveling molecular codes of neuronal identity. The goal of this project is to further develop such approaches and to apply them to the dissection and interpretation of neuronal identity in the mammalian central nervous system. In particular in this project I will focus on one highly polymorphic class of neuronal cell surface receptors called neurexins (NRXN) which show a remarkable molecular diversity with over 3,000 variants generated through alternative splicing and which are prime candidates to encode some aspect of neuronal identity'

Introduzione (Teaser)

Elucidation of molecular mechanisms behind the heterogeneity of neurons is crucial for our understanding of the nervous system. Insight into such mechanisms has important implications for the development of therapeutic interventions. With this in mind, a European study concentrated on the role of the different variants of important neuronal proteins, neurexins.

Descrizione progetto (Article)

Neuronal cells are responsible for reception, transmission, and integration of information in the central and peripheral nervous systems. They are morphologically and physiologically heterogeneous, and connected in a precise way through synapses, forming complex neuronal networks. Neurobiological research is trying to shed light into molecular mechanisms underlying proper formation of neuronal circuits.

The scope of the EU-funded 'Deciphering the neurexin code in neuronal circuitry' (NRX CODE) project was to delineate the role of the surface receptors neurexins (NRXNs) in neuronal identity. NRXNs are cell-adhesion molecules known for their capacity to induce formation and organise neuronal synapses. Mutations in NRXN genes show strong correlation with neuropsychiatric disorders, including schizophrenia, autism and addiction.

NRX CODE scientists wished to investigate the diversity of NRXNs created through alternative splicing at mRNA and protein levels. Using next-generation sequencing they revealed the content of NRXN mRNA transcripts in the adult mouse brain and demonstrated that NRXN repertoires correlate with cellular diversity of different brain areas. They observed that certain alternatively spliced sequences are responsible for the regulation of some NRXN variants at the mRNA level and thus gained important insight into the regulation of these genes.

Additionally, NRX CODE scientists established selected reaction monitoring mass spectrometry assays, which allow relative and absolute quantification of different NRXN protein variants in different biological samples. This methodology capable of monitoring different NRXN splice variants at the protein level is an important step to further understand the role of NRX variants in vivo.

Taken together, the experimental findings of the NRX CODE study provide fundamental insight into the diversification of NRXN gene by alternative splicing helping to understand the fundaments of neuronal diversity. Given the medical importance of NRXN gene mutations, the results and the tools of this study could be utilised for the clinical diagnosis of neuropsychiatric disorders.