Firulli Beth A, Ferguson Chloe A, de Gier-de Vries Corrie, Podicheti Ram, Rusch Douglas B, Christoffels Vincent M, Rubart-von der Lohe Michael, Firulli Anthony B
Herman B Wells Center for Pediatric Research Department of Pediatrics, Anatomy, Biochemistry, and Medical and Molecular Genetics, Indiana University School of Medicine, 1044 W. Walnut Street, Indianapolis, IN 46202-5225, USA.
Department of Medical Biology, Academic Medical Center, University of Amsterdam, 22660, 1100 DD Amsterdam, The Netherlands.
Development. 2025 Oct 1;152(19). doi: 10.1242/dev.204963. Epub 2025 Oct 14.
The bHLH transcription factors HAND1 and HAND2 are expressed in partially overlapping patterns during development. Studies have established evidence for significant functional redundancy between HAND1 and HAND2. To test redundancy fully, we engineered a Hand1 allele in which we directly replaced the Hand1 exons and intron with those of Hand2. The results show that 2% of Hand1Hand2/Hand2 mice are viable and fertile. The remaining Hand1Hand2/Hand2 embryos exhibit neonatal lethality due to omphalocele accompanied by ventricular septal defects and conduction anomalies. Omphalocele can occur due to altered gut rotation. Our transcriptomic expression analysis reveals that established gene expression patterns associated with normal gut rotation are compromised. Interrogation of cardiac function in surviving Hand1Hand2/Hand2 mice reveals QRS abnormalities and cardiac morphogenic defects. These data support previous findings that HAND factors exhibit extensive functional overlap but also reveals that HAND1 protein has unique functions within the Hand1 expression domain and is required for normal embryonic development.
bHLH转录因子HAND1和HAND2在发育过程中以部分重叠的模式表达。研究已证实HAND1和HAND2之间存在显著的功能冗余。为了全面测试冗余性，我们构建了一个Hand1等位基因，其中我们直接用Hand2的外显子和内含子替换了Hand1的外显子和内含子。结果表明，2%的Hand1Hand2/Hand2小鼠是存活且可育的。其余的Hand1Hand2/Hand2胚胎由于脐膨出伴室间隔缺损和传导异常而表现出新生儿致死性。脐膨出可能由于肠道旋转改变而发生。我们的转录组表达分析表明，与正常肠道旋转相关的既定基因表达模式受到损害。对存活的Hand1Hand2/Hand2小鼠的心脏功能进行检测发现QRS异常和心脏形态发生缺陷。这些数据支持了之前的研究结果，即HAND因子表现出广泛的功能重叠，但也表明HAND1蛋白在Hand1表达域内具有独特功能，是正常胚胎发育所必需的。
