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Unique Identity at the Level of Single Neurons Supports Self-Recognition During the Assembly of Neural Circuits

  • Author(s): Miura, Satoru
  • Advisor(s): Zipursky, Stephen L
  • et al.
Abstract

From hunting preys, avoiding predators, to more complex social interactions, our behaviors depend on precise connectivity patterns of the nervous system. Nervous systems comprise numerous cell types exhibiting diverse morphologies and surprisingly stereotypical connection patterns, as Ramón y Cajal had noted more than a century ago. Its development encompasses tasks that are each enormously complex, such as cell fate determination, cell migration, axon guidance, branch ramification, and synaptic matching. How such a feat is achieved at the molecular level continues to be a fascinating question in neurobiology. Over the last few decades, advances have been made in understanding the logic underlying how neurites are guided to their correct targets. As initially proposed by Cajal and later by Roger Sperry, the interactions of neurites with their environment are mediated by cell recognition molecules. Drosophila Dscam1 encodes a set of such molecules. The gene is unique, in that it is able to generate a tremendous number of isoforms, each with unique binding specificity, from a single locus. Through mutually exclusive alternative splicing at multiple exon clusters, it has the potential to generate 19,008 extracellular domains, tethered to the membrane with one of two single-pass transmembrane domains. Extensive biochemistry has shown that each extracellular domain isoform exhibits isoform-specific homophilic binding, with little to no heterophilic binding. Genetic studies show that these isoforms mediate self-avoidance, the tendency of neurites from the same neuron to repel each other. They also suggest that neighboring neurons express distinct sets of Dscam1 isoforms, allowing the neurites to discriminate self from non-self. How is this achieved? And more importantly, could unique Dscam1 identities contribute to the assembly of neural circuits by mediating specific interactions between different neurons? To answer these questions, we developed splicing reporters to visualize the splicing pattern of one of the alternatively spliced exon clusters in vivo. Our results demonstrate that the splicing in neurons identified by their unique anatomical locations is different in different animals and that it does not occur in a cell-type specific fashion. The data argue that neurons acquire unique Dscam1 identity through probabilistic splicing. In fact, probabilistic splicing was observed throughout the nervous system, suggesting that Dscam1 isoforms are unlikely to specify connectivity between different neurons. Rather, the major role of Dscam1 in the assembly of the neural circuits is to mediate self-recognition.

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