Project Lead: Stephen Santoro How an olfactory sensory neuron's choice of odorant receptor gene determines its wiring In mammals, each olfactory sensory neuron (OSN) projects a single axon to a precise location within the olfactory bulb that depends on the single specific odorant receptor (OR) gene that the OSN `chooses' to express. A fascinating aspect of this process is that the OR protein itself plays a critical role in the guidance and refinement of the OSN axon, in part through its level of signaling activity. How OR activity regulates the expression of molecules required for the precise guidance and refinement of axons is largely unknown. We propose to study this phenomenon on two levels: First, we will test the hypothesis that transcription factors that we have identified to be expressed in an activity-dependent manner in OSNs may be involved in regulating the expression of genes that mediate the activity-dependent guidance and/or refinement of OSN axons. Second, we will use two transgenic approaches to characterize the role of axonal mRNA transport and translation in OR-dependent axon guidance/refinement. As part of this objective, we will investigate whether OR mRNAs are actively transported and translated within axon termini, where they have previously been shown to be present, along with OR proteins. Moreover, we will investigate a potential role for an intriguing set of antisense RNAs in the transport and/or regulation axonal OR mRNAs. This project is expected to help elucidate how an OSN's choice of OR gene determines its activity-dependent connectivity. More generally, this work is expected to provide insights into how neuronal activity guides the development of the nervous system and how disruption of these processes contribute neurological disorders, including autism spectrum disorders.
The precise creation and modulation of connections within the nervous system has long been known to depend on neuronal activity and, more recently, has been found to require local protein synthesis within dendrites and axons. Enhancing our understanding of the mechanisms that underlie the formation and alteration of neuronal connectivity promises to yield insights into the causes of neurodevelopmental and neurodegenerative disorders, many of which have been linked to defects in components of activity-dependent signaling pathways (Ebert and Greenberg, 2013) and axonal mRNA translation (Jung et al., 2012). Here we propose to study these processes within the mouse olfactory system, which offers a superb platform for investigating mechanisms of activity-dependent neural connectivity and plasticity. 1