{"doi":"10.1038/s42003-024-06039-2","title":"Segregation of morphogenetic regulatory function of Shox2 from its cell fate guardian role in sinoatrial node development","abstract":"Abstract Shox2 plays a vital role in the morphogenesis and physiological function of the sinoatrial node (SAN), the primary cardiac pacemaker, manifested by the formation of a hypoplastic SAN and failed differentiation of pacemaker cells in Shox2 mutants. Shox2 and Nkx2-5 are co-expressed in the developing SAN and regulate the fate of the pacemaker cells through a Shox2-Nkx2-5 antagonistic mechanism. Here we show that simultaneous inactivation of Nkx2-5 in the SAN of Shox2 mutants (dKO) rescued the pacemaking cell fate but not the hypoplastic defects, indicating uncoupling of SAN cell fate determination and morphogenesis. Single-cell RNA-seq revealed that the presumptive SAN cells of Shox2 -/- mutants failed to activate pacemaking program but remained in a progenitor state preceding working myocardium, while both wildtype and dKO SAN cells displayed normal pacemaking cell fate with similar cellular state. Shox2 thus acts as a safeguard but not a determinant to ensure the pacemaking cell fate through the Shox2-Nkx2-5 antagonistic mechanism, which is segregated from its morphogenetic regulatory function in SAN development.","journal":"Communications Biology","year":2024,"id":476555,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9516,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1281569,"name":"Qinghuang Tang","orcid":"0000-0002-9436-8628","position":1,"is_corresponding":false},{"id":521243,"name":"Tianfang Yang","orcid":null,"position":2,"is_corresponding":false},{"id":1314101,"name":"Zhengsen Wang","orcid":"0000-0002-1256-7894","position":3,"is_corresponding":false},{"id":427503,"name":"Dainan Li","orcid":null,"position":4,"is_corresponding":false},{"id":581225,"name":"Linyan Wang","orcid":"0000-0001-8316-6994","position":5,"is_corresponding":false},{"id":680642,"name":"Liwen Li","orcid":"0000-0003-3726-5013","position":6,"is_corresponding":false},{"id":1314495,"name":"Yaoyi Chen","orcid":null,"position":7,"is_corresponding":false},{"id":426609,"name":"Hai Huang","orcid":"0000-0002-6928-3198","position":8,"is_corresponding":false},{"id":1314102,"name":"Yanding Zhang","orcid":"0000-0001-7177-5039","position":9,"is_corresponding":false},{"id":520386,"name":"Yiping Chen","orcid":"0000-0002-8628-7713","position":10,"is_corresponding":false},{"id":483001,"name":"Hua Li","orcid":"0000-0003-3481-0629","position":0,"is_corresponding":true}],"reference_count":57,"raw_metadata":null,"created_at":"2026-07-19T02:06:29.605760Z","pmid":"38553636","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":[]}