Tracy S. Tran, PhD
Federated Department of Biological Sciences
Diverse Mechanisms of Semaphorin-Neuropilin Signaling During Development and in the Adult Nervous System Influencing Complex Behaviors
The proper development of neuronal axon projections and dendritic morphologies are critical for patterning of synaptic connections and transmission, which affect circuit activity, and ultimately impact behavior. The overarching goal of my lab is to elucidate the molecular mechanisms underlying how neuronal connections are formed during development and how they are maintained in the adult animal.
The proper wiring of the nervous system is largely regulated by guidance cues signaling through specific receptors on the surface of developing neurons. The Semaphorins are a large family of cues that signal through the Plexin family of receptors directly, or through heteromeric complexes with the Neuropilins to mediate axon guidance events. Using genetic mouse models, we demonstrated that members of the class 3 secreted semaphorins (Sema3s) signaling through their obligated binding receptor Neuropilin 2 (Nrp2) is required for specific subtypes of spinal commissural axon pathfinding (Tran et al., 2013, Neural Dev; Hernandez-Enriquez et al., 2015, Genes Dev). However, the final synaptic targets of spinal commissural axons remain ill defined. Our goal is to map the synaptic targets of ascending spinal commissural axon projections using the iDisco whole-embryo immunostaining technique combined with 3D reconstruction software.
Interestingly, Sema3F-Nrp2 signaling also was demonstrated to regulate dendritic spine number, size and distribution in layer 5 cortical neurons and granule cells of the hippocampus in the adult animal (Tran et al., 2009, Nature). The loss of Nrp2 enhanced excitatory synaptic transmission in both cortical and hippocampal neurons. We conducted the first behavioral study of mice harboring a mutation of the Nrp2 gene, focusing on behaviors known to depend on cortical and hippocampal circuitry. Nrp2-/- mutants showed autism-associated behavior impairments in object recognition memory, no preference for social novelty, and increased grooming behavior compared to age-matched controls (Shiflett et al., 2015, Transl Psychiatry). Furthermore, our results show Nrp2-/- animals have abnormal corticostriatal circuit activity. Currently, we are investigating the role of Sema3F-Nrp2 signaling in corticostriatal circuit function, which is known to underlie goal-directed learning and behavior. Toward this end, we employ instrumental learning paradigms, in combination with anatomical and electrophysiological analyses of mice deficient in Sema3F-Nrp2 signaling.
Collectively, our research has pointed to key molecular pathways that regulate how axonal connections are established during development, which may contribute to better understanding and strategies for spinal cord repair following injury. Moreover, our studies of Sema3F-Nrp2 signaling in the adult nervous system highlighted the diverse functions of guidance cues and our results suggest that loss of Nrp2 leads to aberrant processing within hippocampal and corticostriatal networks that may contribute to neurodevelopmental disease mechanisms.