During development, neurons connect with a remarkable degree of specificity, forming synapses with only a fraction of the potential partners they encounter. Neurons accomplish this feat by expressing particular cell surface receptor and adhesion proteins that enable differential target selection in addition to axon and dendrite guidance mechanisms. Two members of a conserved family of transmembrane cell surface proteins, the Teneurins, play critical roles in the formation of such specific connections during Drosophila neural development2,8. There are four Teneurin genes in the mammalian genome, one of which is linked to susceptibility to bipolar disorder4, and two of which are located in genomic regions associated with intellectual disability3. Understanding how mammalian Teneurins function during neural development may thus provide new insights into the mechanisms that generate specific synaptic connectivity, and how perturbations in this process result in cognitive impairment. The mouse olfactory system is a valuable system for studying mechanisms that generate specific synaptic connectivity due to its stereotyped, macroscopic synaptic glomeruli, and the exquisite genetic control afforded by the mutually exclusive expression of odorant receptor molecules. I have found that Teneurins are expressed in distinct patterns in the mammalian olfactory system, suggesting specific roles in the development of olfactory connectivity. In this proposal, I will use novel genetic tools to study the function of Teneurins during olfactory system development. This work will provide insight into Teneurin function, enhance our understanding of the development and organization of the olfactory system, and potentially shed light on the developmental processes that, when disrupted, lead to disorders of the nervous system. In addition, the genetic tools generated as part of this project will be useful for researchers studying Teneurin proteins throughout the nervous system.
The function of the nervous system depends on the patterns of connectivity formed during development, and impairment of developmental wiring processes may lead to neurodevelopmental and psychiatric disorders. The research proposed here focuses on the function of a family of proteins, the Teneurins, hypothesized to instruct the development of specific connections in the developing olfactory system. Teneurin genes are linked to bipolar disorder and are potentially associated with several intellectual disabilities4,5 thus, characterizing the function of Teneurin proteins may provide insight into the mechanistic underpinnings of neurodevelopmental disorders.
|Berns, Dominic S; DeNardo, Laura A; Pederick, Daniel T et al. (2018) Teneurin-3 controls topographic circuit assembly in the hippocampus. Nature 554:328-333|
|DeNardo, Laura A; Berns, Dominic S; DeLoach, Katherine et al. (2015) Connectivity of mouse somatosensory and prefrontal cortex examined with trans-synaptic tracing. Nat Neurosci 18:1687-1697|