Development of a lethal congenital heart defect in the splotch (Pax3) mutant mouse
Development of a lethal congenital heart defect in the splotch (Pax3) mutant mouse
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DOI：
10.1016/s0008-6363(97)00172-7
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发表时间：
1997-11-01
影响因子：
10.8
通讯作者：
Copp, AJ
中科院分区：
文献类型：
--
作者：
Conway, SJ;Henderson, DJ;Copp, AJ
目的：Spotch（Sp（2 H））突变破坏Pax 3基因，在纯合子中具有致死性。本研究的目的是调查致死的原因，方法和结果：使用斑点（Sp（2 H））小鼠突变体，我们证明了大约60%的Sp（2 H）纯合子在妊娠13.5-14.5天子宫内死亡。所有这些胚胎都有心脏畸形，包括流出道部分或完全分隔失败。虽然子宫内死亡的原因还不清楚，但死亡的胚胎是水肿的，它们的上级腔静脉过度扩张，胎儿肝脏增大并充血，所有这些都是心力衰竭的迹象。剩余的Sp（2 H）纯合子在出生时死亡，这些胚胎具有非常正常的心脏。所有Sp（2 H）纯合子都有神经管缺陷，脊柱裂，露脑畸形，或两者兼而有之。虽然这些缺陷显然不会导致子宫内死亡，但它们很可能是存活至妊娠晚期的纯合子围产期死亡的原因。有无心脏缺陷与神经管缺陷的类型之间没有相关性。另一方面，心脏缺陷的存在与作为神经嵴衍生物的背根神经节的减少或缺失之间存在显著的相关性。结论：在本文中，我们表明，致死率有一个双相模式，数据强烈表明，中期妊娠致死是由于心脏缺陷，而不是相关的神经管缺陷。这一发现支持了这样一种观点，即涉及心室流出道的“圆锥干”心脏缺陷是由于“心脏”神经嵴未能在妊娠中期胚胎的发育中的心脏中定植而发展的，并且由此产生的心脏缺陷是观察到的死亡率的唯一原因。(C)1997年Elsevier Science B.V.
Objective: The splotch (Sp(2H)) mutation disrupts the Pax3 gene and is lethal in homozygotes. The aim of the present study was to investigate the cause of lethality, Methods and results: Using the splotch (Sp(2H)) mouse mutant, we demonstrated that approximately 60% of Sp(2H) homozygotes die in utero at 13.5-14.5 days of gestation. All these embryos have cardiac malformations involving partial or complete failure of septation of the outflow tract. Although the cause of death in utero is unknown, the dying embryos are edematous, their superior caval veins are over-expanded, and the fetal liver is enlarged and engorged with blood, all signs of cardiac failure. The remaining Sp(2H) homozygotes die around the time of birth, and these embryos have grossly normal hearts. All Sp(2H) homozygotes have neural tube defects, either spina bifida, exencephaly, or both. Although these defects clearly do not cause death in utero, they are Very likely responsible for the perinatal death of homozygotes that survive to late gestation. There is no correlation between the presence or absence of a cardiac defect and the type of neural tube defect. On the other hand, there is a striking correlation between presence of a cardiac defect and reduction or absence of dorsal root ganglia, which are derivatives of the neural crest. Conclusions: In this paper, we show that the lethality has a biphasic pattern, and the data strongly suggests that mid-gestation lethality is due to cardiac defects and not the associated neural tube defects. This finding supports the idea that 'conotruncal' cardiac defects involving the ventricular outflow tracts develop as a result of failure of the 'cardiac' neural crest to colonise the developing heart in the mid-gestation embryo, and that the resulting heart defects are solely responsible for the observed mortality. (C) 1997 Elsevier Science B.V.