Firulli Beth A, 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 St., Indianapolis, IN, 46202-5225, USA.
Pediatr Cardiol. 2019 Oct;40(7):1339-1344. doi: 10.1007/s00246-019-02162-8. Epub 2019 Jul 23.
Hand1 is a basic Helix-loop-Helix transcription factor that exhibits post-translationally regulated dimer partner choice that allows for a diverse set of Hand1 transcriptional complexes. Indeed, when Hand1 phosphoregulation is altered, conditionally activated hypophorylation (Hand1) and phosphorylation mimic (Hand1) Hand1 alleles disrupt both craniofacial and limb morphogenesis with 100% penetrance. Interestingly, activation of conditional Hand1 Phosphomutant alleles within post-migratory neural crest cells produce heart defects that include ventricular septal defects, double-outlet right ventricle, persistent truncus arteriosus with partial penetrance. Single versus double-lobed thymus is a distinguishing feature between Wnt1-Cre;Hand1 and Wnt1-Cre;Hand1 mice. These data show that although Hand1 dimer regulation plays critical and consistent roles in disrupting craniofacial and limb morphogenesis, Hand1 dimer regulation during cardiac outflow track formation is less critical for normal morphogenesis. This review will present the OFT phenotypes observed in Hand1 Phosphomutant mice, and discuss possible mechanisms of how penetrance differences within the same tissues within the same embryos could be variable.
Hand1是一种基本的螺旋-环-螺旋转录因子，它表现出翻译后调控的二聚体伙伴选择，从而形成多种Hand1转录复合体。事实上，当Hand1的磷酸化调节发生改变时，条件性激活的低磷酸化（Hand1）和磷酸化模拟（Hand1）Hand1等位基因会以100%的外显率破坏颅面和肢体形态发生。有趣的是，在迁移后神经嵴细胞内激活条件性Hand1磷酸突变等位基因会产生心脏缺陷，包括室间隔缺损、右心室双出口、部分外显率的永存动脉干。单叶胸腺与双叶胸腺是Wnt1-Cre;Hand1和Wnt1-Cre;Hand1小鼠之间的一个显著特征。这些数据表明，尽管Hand1二聚体调节在破坏颅面和肢体形态发生中起着关键且一致的作用，但在心脏流出道形成过程中，Hand1二聚体调节对正常形态发生的重要性较低。本综述将介绍在Hand1磷酸突变小鼠中观察到的流出道表型，并讨论同一胚胎内相同组织中外显率差异可变的可能机制。
