Neuregulins (NRGs) are EGF-like ligands associated with cognitive disorders. Unprocessed proNRG3 is cleaved by BACE1 to generate the mature membrane-bound NRG3 ligand, but the subcellular site of proNRG3 cleavage, mechanisms underlying its transport into axons, and presynaptic accumulation remain unknown. Using an optogenetic proNRG3 cleavage reporter (LA143-NRG3), we investigate the spatial-temporal dynamics of NRG3 processing and sorting in neurons. In dark conditions, unprocessed LA143-NRG3 is retained in the trans-Golgi network but, upon photoactivation, is cleaved by BACE1 and released from the TGN. Mature NRG3 then emerges on the somatodendritic plasma membrane from where it is re-endocytosed and anterogradely transported on Rab4+ vesicles into axons via transcytosis. By contrast, the BACE1 substrate APP is sorted into axons on Rab11+ vesicles. Lastly, by a mechanism we denote “trans-synaptic retention,” NRG3 accumulates at presynaptic terminals by stable interaction with its receptor ErbB4 on postsynaptic GABAergic interneurons. We propose that trans-synaptic retention may account for polarized expression of other neuronal transmembrane ligands and receptors.
Transcytosis and trans-synaptic retention by postsynaptic ErbB4 underlie axonal accumulation of NRG3
- Award Id(s): ZIA-HD001607,ZIA-HD000711
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Tanveer Ahmad, Detlef Vullhorst, Rituparna Chaudhuri, Carlos M. Guardia, Nisha Chaudhary, Irina Karavanova, Juan S. Bonifacino, Andres Buonanno; Transcytosis and trans-synaptic retention by postsynaptic ErbB4 underlie axonal accumulation of NRG3. J Cell Biol 4 July 2022; 221 (7): e202110167. doi: https://doi.org/10.1083/jcb.202110167
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