{"doi":"10.1101/2024.03.25.586641","title":"Tcf21 as a Founder Transcription Factor in Specifying Foxd1 Cells to the Juxtaglomerular Cell Lineage","abstract":"ABSTRACT Renin is crucial for blood pressure regulation and electrolyte balance, and its expressing cells arise from Foxd1+ stromal progenitors. However, factors guiding these progenitors toward renin-secreting cell fate remain unclear. Tcf21, a basic helix-loop-helix (bHLH) transcription factor, is essential in kidney development. Utilizing Foxd1 Cre/+ ;Tcf21 f/f and Ren1 dCre/+ ;Tcf21 f/f mouse models, we investigated the role of Tcf21 in the differentiation of Foxd1+ progenitor cells into juxtaglomerular (JG) cells. Immunostaining and in-situ hybridization demonstrated fewer renin-positive areas and altered renal arterial morphology, including the afferent arteriole, in Foxd1 Cre/+ ;Tcf21 f/f kidneys compared to controls, indicating Tcf21’s critical role in the emergence of renin-expressing cells. However, Tcf21 inactivation in renin-expressing cells ( Ren1 dCre/+ ;Tcf21 f/f ) did not recapitulate this phenotype, suggesting Tcf21 is dispensable once renin cell identity is established. Using an integrated analysis of single-cell RNA sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) on GFP+ cells (stromal lineage) from E12, E18, P5, and P30 Foxd1 Cre/+ ;Rosa26 mTmG control kidneys, we analyzed the temporal dynamics of Tcf21 expression in cells comprising the JG lineage ( n =2,054). A pseudotime trajectory analysis revealed that Tcf21 expression is highest in metanephric mesenchyme and stromal cells at early developmental stages (E12), with a decline in expression as cells mature into renin-expressing JG cells. Motif enrichment analyses supported Tcf21’s significant involvement in early kidney development. These findings underscore the critical role of Tcf21 in Foxd1+ cell differentiation into JG cells during early stages of kidney development, offering insights into the molecular mechanisms governing JG cell differentiation and highlight Tcf21’s pivotal role in kidney development. NEW & NOTEWORTHY This manuscript provides novel insights into the role of Tcf21 in the differentiation of Foxd1+ cells into JG cells. Utilizing integrated scRNA-seq and scATAC-seq, the study reveals that Tcf21 expression is crucial during early embryonic stages, with its peak at embryonic day 12. The findings demonstrate that inactivation of Tcf21 leads to fewer renin-positive areas and altered renal arterial morphology, underscoring the importance of Tcf21 in the specification of renin-expressing JG cells and kidney development.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":496074,"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":0.9567,"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":321066,"name":"Jason P. Smith","orcid":"0000-0002-2688-0988","position":1,"is_corresponding":false},{"id":407344,"name":"Alexandre G. Martini","orcid":"0000-0003-3169-014X","position":2,"is_corresponding":false},{"id":283291,"name":"George Yacu","orcid":null,"position":3,"is_corresponding":false},{"id":680515,"name":"Silvia Medrano","orcid":"0000-0003-3967-2800","position":4,"is_corresponding":false},{"id":329355,"name":"R. Ariel Gómez","orcid":"0000-0002-5124-8255","position":5,"is_corresponding":false},{"id":407345,"name":"Maria Luisa S. Sequeira-Lόpez","orcid":"0000-0002-4459-7940","position":6,"is_corresponding":false},{"id":245996,"name":"Susan E. Quaggin","orcid":"0000-0002-3706-5727","position":7,"is_corresponding":false},{"id":917230,"name":"Gal Finer","orcid":"0000-0002-1488-9985","position":8,"is_corresponding":false},{"id":1343001,"name":"Hina Anjum","orcid":null,"position":0,"is_corresponding":true}],"reference_count":26,"raw_metadata":null,"created_at":"2026-07-19T02:09:23.333150Z","pmid":"38585851","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":[]}