{"doi":"10.1101/2022.09.05.506659","title":"Self-assembly of cellular neighborhoods converts stochastic signaling into sustained olfactory neurogenesis","abstract":"SUMMARY Olfactory neurogenesis occurs continuously throughout the lives of vertebrates, including in humans, and relies on the rapid, unceasing differentiation and integration of neurons into a complex multicellular network. The system-wide regulation of this intricate choreography is poorly understood; in particular, it is unclear how progenitor cells convert stochastic fluctuations in cell-cell signaling, over both space and time, into streamlined fate decisions. Here, we track single-cell level multicellular dynamics in the developing zebrafish olfactory epithelium, perturb signaling pathways with temporal specificity, and find that the continuous generation of neurons is driven by the spatially-restricted self-assembly of transient groups of progenitor cells, i.e. cellular neighborhoods. Stochastic modeling and validation of the underlying genetic circuit reveals that neighborhood self-assembly is driven by a tightly regulated bistable toggle switch between Notch signaling and the transcription factor Insulinoma-associated 1a that is responsive to inter-organ retinoic acid signaling. Newly differentiating neurons emerge from neighborhoods and, in response to brain-derived neurotrophic factor signaling, migrate across the olfactory epithelium to take up residence as apically-located, mature sensory neurons. After developmental olfactory neurogenesis is complete, inducing injury results in a robust expansion of neighborhoods, followed by neuroregeneration. Taken together, these findings provide new insights into how stochastic signaling networks spatially pattern and regulate a delicate balance between progenitors and their neuronal derivatives to drive sustained neurogenesis during both development and regeneration.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2022,"id":311194,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9466,"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":1007837,"name":"Joseph N. Lombardo","orcid":null,"position":1,"is_corresponding":false},{"id":791302,"name":"Lynne M. Nacke","orcid":null,"position":2,"is_corresponding":false},{"id":410289,"name":"Farid Manuchehrfar","orcid":null,"position":3,"is_corresponding":false},{"id":611281,"name":"Kaelan Wong","orcid":null,"position":4,"is_corresponding":false},{"id":1007838,"name":"Jocelyn Garcia","orcid":null,"position":5,"is_corresponding":false},{"id":408721,"name":"Jie Liang","orcid":"0000-0002-2773-6427","position":6,"is_corresponding":false},{"id":790667,"name":"Ankur Saxena","orcid":"0000-0001-8646-2887","position":7,"is_corresponding":false},{"id":790665,"name":"Sriivatsan G. Rajan","orcid":"0000-0002-1414-0747","position":0,"is_corresponding":true}],"reference_count":66,"raw_metadata":null,"created_at":"2026-07-19T00:33:28.480200Z","pmid":null,"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":[]}