biostudies-literatureVanDusen NJNHLBI NIH HHSNIAMS NIH HHS2071-83https://www.ebi.ac.uk/biostudies/studies/S-EPMC4277501biostudies-literatureUnknown9(6)The basic-helix-loop-helix (bHLH) transcription factor Hand2 plays critical roles during cardiac morphogenesis via expression and function within myocardial, neural crest, and epicardial cell populations. Here, we show that Hand2 plays two essential Notch-dependent roles within the endocardium. Endocardial ablation of Hand2 results in failure to develop a patent tricuspid valve, intraventricular septum defects, and hypotrabeculated ventricles, which collectively resemble the human congenital defect tricuspid atresia. We show endocardial Hand2 to be an integral downstream component of a Notch endocardium-to-myocardium signaling pathway and a direct transcriptional regulator of Neuregulin1. Additionally, Hand2 participates in endocardium-to-endocardium-based cell signaling, with Hand2 mutantCell reportsHand2 is an essential regulator for two Notch-dependent functions within the embryonic endocardium.PMC4277501R01 AR0613921R01HL120920-011R0AR061392-031R01HL122123-01R01 HL122123R01 HL120920De La Pompa JLVincentz JWVanDusen NJGrego-Bessa JZeller RCasanovas JZhou BLopez-Rios JOsterwalder MShou WFirulli ABFirulli BAfalseHand2 is an essential regulator for two Notch-dependent functions within the embryonic endocardium.The basic-helix-loop-helix (bHLH) transcription factor Hand2 plays critical roles during cardiac morphogenesis via expression and function within myocardial, neural crest, and epicardial cell populations. Here, we show that Hand2 plays two essential Notch-dependent roles within the endocardium. Endocardial ablation of Hand2 results in failure to develop a patent tricuspid valve, intraventricular septum defects, and hypotrabeculated ventricles, which collectively resemble the human congenital defect tricuspid atresia. We show endocardial Hand2 to be an integral downstream component of a Notch endocardium-to-myocardium signaling pathway and a direct transcriptional regulator of Neuregulin1. Additionally, Hand2 participates in endocardium-to-endocardium-based cell signaling, with Hand2 mutant2014-01-01T00:00:00Z2014 Dec2025-05-29T21:07:55.666Z2025-05-29T21:07:55.666ZS-EPMC42775012549709710.1016/j.celrep.2014.11.021