Han Zhe, Yi Peng, Li Xiumin, Olson Eric N
Department of Molecular Biology, University of Texas Southwestern Medical Center at Dallas, TX 75390, USA.
Development. 2006 Mar;133(6):1175-82. doi: 10.1242/dev.02285. Epub 2006 Feb 8.
The Hand gene family encodes highly conserved basic helix-loop-helix (bHLH) transcription factors that play crucial roles in cardiac and vascular development in vertebrates. In Drosophila, a single Hand gene is expressed in the three major cell types that comprise the circulatory system: cardioblasts, pericardial nephrocytes and lymph gland hematopoietic progenitors, but its function has not been determined. Here we show that Drosophila Hand functions as a potent transcriptional activator, and converting it into a repressor blocks heart and lymph gland formation. Disruption of Hand function by homologous recombination also results in profound cardiac defects that include hypoplastic myocardium and a deficiency of pericardial and lymph gland hematopoietic cells, accompanied by cardiac apoptosis. Targeted expression of Hand in the heart completely rescued the lethality of Hand mutants, and cardiac expression of a human HAND gene, or the caspase inhibitor P35, partially rescued the cardiac and lymph gland phenotypes. These findings demonstrate evolutionarily conserved functions of HAND transcription factors in Drosophila and mammalian cardiogenesis, and reveal a previously unrecognized requirement of Hand genes in hematopoiesis.
Hand基因家族编码高度保守的碱性螺旋-环-螺旋（bHLH）转录因子，这些转录因子在脊椎动物的心脏和血管发育中发挥关键作用。在果蝇中，单个Hand基因在构成循环系统的三种主要细胞类型中表达：成心肌细胞、心包肾细胞和淋巴腺造血祖细胞，但其功能尚未确定。在这里，我们表明果蝇Hand作为一种强大的转录激活因子发挥作用，将其转化为阻遏因子会阻碍心脏和淋巴腺的形成。通过同源重组破坏Hand功能也会导致严重的心脏缺陷，包括心肌发育不全以及心包和淋巴腺造血细胞缺乏，并伴有心脏细胞凋亡。在心脏中靶向表达Hand完全挽救了Hand突变体的致死性，而人类HAND基因或半胱天冬酶抑制剂P35在心脏中的表达部分挽救了心脏和淋巴腺表型。这些发现证明了HAND转录因子在果蝇和哺乳动物心脏发生过程中的进化保守功能，并揭示了Hand基因在造血过程中以前未被认识到的需求。
