PT - JOURNAL ARTICLE AU - Daniela Alfano AU - Alessandra Altomonte AU - Claudio Cortes AU - Marchesa Bilio AU - Robert G. Kelly AU - Antonio Baldini TI - <em>Tbx1</em> regulates extracellular matrix-cell interactions in the second heart field AID - 10.1101/267906 DP - 2018 Jan 01 TA - bioRxiv PG - 267906 4099 - http://biorxiv.org/content/early/2018/08/26/267906.short 4100 - http://biorxiv.org/content/early/2018/08/26/267906.full AB - Tbx1, the major candidate gene for DiGeorge or 22q11.2 deletion syndrome, is required for efficient incorporation of cardiac progenitors (CPs) of the second heart field (SHF) into the heart. However, the mechanisms by which TBX1 regulates this process are still unclear. Here, we have used two independent models, mouse embryos and cultured cells, to define the role of TBX1 in establishing morphological and dynamic characteristics of SHF in the mouse. We found that loss of TBX1 impairs extra cellular matrix (ECM)-integrin-focal adhesion (FA) signaling in both models. Mosaic analysis in embryos showed that this function is non-cell autonomous and, in cultured cells, loss of TBX1 impairs cell migration and focal adhesions. Additionally, we found that ECM-mediated outside-in integrin signaling is disrupted upon loss of TBX1. Finally, we show that interfering with the ECM-integrin-FA axis between E8.5 and E9.5 in mouse embryos, corresponding to the time window within which TBX1 is required in the SHF, causes outflow tract dysmorphogenesis. Our results demonstrate that TBX1 is required to maintain the integrity of ECM-cell interactions in the SHF, and that this interaction is critical for cardiac outflow tract development. More broadly, our data identifies a novel TBX1 downstream pathway as an important player in SHF tissue architecture and cardiac morphogenesis.Non-standard abbreviations and AcronymsCDH1E-cadherinCOLIcollagen type IEEmbryonic dayECMextracellular matrixFAfocal adhesionGFPgreen fluorescent proteinIFimmunofluorescenceNMIIBnon-muscle myosin II isoform B (MYH10)OFToutflow tractPXNPaxillinPCRpolymerase chain reactionSHFsecond heart fieldTBX1T-box transcription factor 1VCLvinculinWTwild-type