Deficient GATA6-CXCR7 signaling leads to bicuspid aortic valve.

Piñeiro-Sabarís, RebecaMacGrogan, Donalde la Pompa, José LuisPiñeiro-Sabarís, RebecaMacGrogan, Donalde la Pompa, José Luis2024-11-282024-11-282024-09-01Dis Model Mech. 2024 Sep 1;17(9):dmm050934.https://hdl.handle.net/20.500.12105/25813This study was supported by grants PID2022-104776RB-100 and CB16/11/00399 (CIBER CV) from Ministerio de Ciencia e Innovación and Agencia Estatal de Investigación (MCIN/AEI/10.13039/501100011033), and the ’la Caixa’ Foundation (reference HR23-00084) to J.L.d.l.P. Support for this publication also came from the European Regional Development Fund. Open access funding provided by Centro Nacional de Investigaciones Cardiovasculares. Deposited in PMC for immediate release.The cardiac outflow tract (OFT) transiently links the ventricles to the aortic sac and forms the arterial valves. Abnormalities in these valves, such as bicuspid aortic valve (BAV), are common congenital anomalies. GATA6-inactivating variants cause cardiac OFT defects and BAV, but their mechanisms are unclear. We generated Gata6STOP/+ mice using CRISPR-Cas9, which show highly penetrant BAV (70%) and membranous ventricular septal defects (43%). These mice exhibited decreased proliferation and increased ISL1-positive progenitor cells in the OFT, indicating abnormal cardiovascular differentiation. Gata6 deletion with the Mef2cCre driver line recapitulated Gata6STOP/+ phenotypes, indicating a cell-autonomous role for Gata6 in the second heart field. Gata6STOP/+ mice showed reduced OFT length and caliber, associated with deficient cardiac neural crest cell contribution, which may cause valvulo-septal defects. RNA-sequencing analysis showed depletion in pathways related to cell proliferation and migration, highlighting Cxcr7 (also known as Ackr3) as a candidate gene. Reduced mesenchymal cell migration and invasion were observed in Gata6STOP/+ OFT tissue. CXCR7 agonists reduced mesenchymal cell migration and increased invasion in wild-type but not in Gata6STOP/+ explants, indicating the GATA6-dependent role of CXCR7 in OFT development and its potential link to BAV.engVoRhttp://creativecommons.org/licenses/by/4.0/ACKR3/CXCR7Bicuspid aortic valveCardiac neural crestEndocardial cushion developmentGATA6Outflow tractDeficient GATA6-CXCR7 signaling leads to bicuspid aortic valve.Attribution 4.0 International39253784179dmm050934Disease Models & Mechanismsopen access