Laboratory of Genetics, University of Wisconsin-Madison, Madison, WI 53706, USA.
Dev Cell. 2013 Jan 14;24(1):52-63. doi: 10.1016/j.devcel.2012.11.018.
In mammals, precise placement of organs is essential for survival. We show here that inactivation of Roundabout (Robo) receptors 1 and 2 in mice leads to mispositioning of the stomach in the thoracic instead of the abdominal cavity, which likely contributes to poor lung inflation and lethality at birth, reminiscent of congenital diaphragmatic hernia (CDH) cases in humans. Unexpectedly, in Robo mutant mice, the primary defect preceding organ misplacement and diaphragm malformation is a delayed separation of foregut from the dorsal body wall. Foregut separation is a rarely considered morphogenetic event, and our data indicate that it occurs via repulsion of Robo-expressing foregut cells away from the Slit ligand source. In humans, genomic lesions containing Robo genes have been documented in CDH. Our findings suggest that separation of the foregut from the body wall is genetically controlled and that defects in this event may contribute to CDH.
在哺乳动物中，器官的精确位置对于生存至关重要。我们在这里展示，敲除小鼠 Roundabout（Robo）受体 1 和 2 会导致胃错位到胸腔而不是腹腔，这可能导致出生时肺部充气不良和死亡，类似于人类先天性膈疝（CDH）病例。出乎意料的是，在 Robo 突变小鼠中，器官错位和膈肌畸形之前的主要缺陷是前肠与背部体壁的延迟分离。前肠分离是一个很少被考虑的形态发生事件，我们的数据表明，它是通过表达 Robo 的前肠细胞远离 Slit 配体源的排斥作用发生的。在人类中，已经在 CDH 中记录了包含 Robo 基因的基因组病变。我们的研究结果表明，前肠与体壁的分离是受遗传控制的，并且该事件的缺陷可能导致 CDH。
