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According to current paradigms, signal-dependent transcription factors (TFs), such as FGF\/MapK-activated Ets family factors, partner with lineage-determining factors to achieve regulatory specificity. However, many aspects of this model have not been rigorously investigated. One key question relates to whether lineage-determining factors dictate lineage-specific responses to inductive signals or facilitate these responses in collaboration with other inputs. We utilize the chordate model<jats:italic>Ciona robusta<\/jats:italic>to investigate mechanisms generating lineage-specific induction. Previous studies in<jats:italic>C<\/jats:italic>.<jats:italic>robusta<\/jats:italic>have shown that cardiopharyngeal progenitor cells are specified through the combined activity of FGF-activated<jats:italic>Ets1\/2<\/jats:italic>.<jats:italic>b<\/jats:italic>and an inferred ATTA-binding transcriptional cofactor. Here, we show that the homeobox TF<jats:italic>Lhx3\/4<\/jats:italic>serves as the lineage-determining TF that dictates cardiopharyngeal-specific transcription in response to pleiotropic FGF signaling. Targeted knockdown of<jats:italic>Lhx3\/4<\/jats:italic>leads to loss of cardiopharyngeal gene expression. Strikingly, ectopic expression of<jats:italic>Lhx3\/4<\/jats:italic>in a neuroectodermal lineage subject to FGF-dependent specification leads to ectopic cardiopharyngeal gene expression in this lineage. Furthermore, ectopic<jats:italic>Lhx3\/4<\/jats:italic>expression disrupts neural plate morphogenesis, generating aberrant cell behaviors associated with execution of incompatible morphogenetic programs. Based on these findings, we propose that combinatorial regulation by signal-dependent and lineage-determinant factors represents a generalizable, previously uncategorized regulatory subcircuit we term \u201ccofactor-dependent induction.\u201d Integration of this subcircuit into theoretical models will facilitate accurate predictions regarding the impact of gene regulatory network rewiring on evolutionary diversification and disease ontogeny.<\/jats:p>","DOI":"10.1371\/journal.pbio.3002169","type":"journal-article","created":{"date-parts":[[2024,1,25]],"date-time":"2024-01-25T18:20:56Z","timestamp":1706206856000},"page":"e3002169","update-policy":"https:\/\/doi.org\/10.1371\/journal.pbio.corrections_policy","source":"Crossref","is-referenced-by-count":7,"title":["Lhx3\/4 initiates a cardiopharyngeal-specific transcriptional program in response to widespread FGF signaling"],"prefix":"10.1371","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2326-5437","authenticated-orcid":true,"given":"C. 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