{"doi":"10.1083/jcb.202110167","title":"Transcytosis and trans-synaptic retention by postsynaptic ErbB4 underlie axonal accumulation of NRG3","abstract":"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.","journal":"The Journal of Cell Biology","year":2022,"id":269606,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":15,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9533,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":932782,"name":"Detlef Vullhorst","orcid":"0000-0002-7947-8044","position":1,"is_corresponding":false},{"id":932783,"name":"Rituparna Kundu Chaudhuri","orcid":"0000-0002-7450-5007","position":2,"is_corresponding":false},{"id":251543,"name":"Carlos M. Guardia","orcid":"0000-0002-4662-9360","position":3,"is_corresponding":false},{"id":932784,"name":"Nisha Chaudhary","orcid":"0000-0001-5630-938X","position":4,"is_corresponding":false},{"id":933304,"name":"Irina Karavanova","orcid":null,"position":5,"is_corresponding":false},{"id":62801,"name":"Juan S. Bonifacino","orcid":"0000-0002-5673-6370","position":6,"is_corresponding":false},{"id":372238,"name":"Andrés Buonanno","orcid":"0000-0003-4651-9134","position":7,"is_corresponding":false},{"id":932781,"name":"Tanveer Ahmad","orcid":"0000-0002-8384-5273","position":0,"is_corresponding":true}],"reference_count":103,"raw_metadata":null,"created_at":"2026-07-19T00:27:22.602796Z","pmid":"35579602","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}