Sefton Elizabeth M, Gallardo Mirialys, Kardon Gabrielle
Department of Human Genetics University of Utah, Salt Lake City, UT 84112, USA.
Dev Biol. 2018 Aug 15;440(2):64-73. doi: 10.1016/j.ydbio.2018.04.010. Epub 2018 Apr 19.
The diaphragm is a mammalian skeletal muscle essential for respiration and for separating the thoracic and abdominal cavities. Development of the diaphragm requires the coordinated development of muscle, muscle connective tissue, tendon, nerves, and vasculature that derive from different embryonic sources. However, defects in diaphragm development are common and the cause of an often deadly birth defect, Congenital Diaphragmatic Hernia (CDH). Here we comprehensively describe the normal developmental origin and complex spatial-temporal relationship between the different developing tissues to form a functional diaphragm using a developmental series of mouse embryos genetically and immunofluorescently labeled and analyzed in whole mount. We find that the earliest developmental events are the emigration of muscle progenitors from cervical somites followed by the projection of phrenic nerve axons from the cervical neural tube. Muscle progenitors and phrenic nerve target the pleuroperitoneal folds (PPFs), transient pyramidal-shaped structures that form between the thoracic and abdominal cavities. Subsequently, the PPFs expand across the surface of the liver to give rise to the muscle connective tissue and central tendon, and the leading edge of their expansion precedes muscle morphogenesis, formation of the vascular network, and outgrowth and branching of the phrenic nerve. Thus development and morphogenesis of the PPFs is critical for diaphragm formation. In addition, our data indicate that the earliest events in diaphragm development are critical for the etiology of CDH and instrumental to the evolution of the diaphragm. CDH initiates prior to E12.5 in mouse and suggests that defects in the early PPF formation or their ability to recruit muscle are an important source of CDH. Also, the recruitment of muscle progenitors from cervical somites to the nascent PPFs is uniquely mammalian and a key developmental innovation essential for the evolution of the muscularized diaphragm.
横膈膜是一种哺乳动物骨骼肌，对呼吸以及分隔胸腔和腹腔至关重要。横膈膜的发育需要肌肉、肌肉结缔组织、肌腱、神经和血管的协调发育，这些组织来源于不同的胚胎来源。然而，横膈膜发育缺陷很常见，是一种通常致命的出生缺陷——先天性膈疝（CDH）的病因。在这里，我们全面描述了正常发育起源以及不同发育组织之间复杂的时空关系，以使用一系列经过基因和免疫荧光标记并进行整体分析的小鼠胚胎来形成功能性横膈膜。我们发现最早的发育事件是肌肉祖细胞从颈节迁出，随后是膈神经轴突从颈神经管投射。肌肉祖细胞和膈神经靶向胸腹皱襞（PPF），这是在胸腔和腹腔之间形成的短暂的金字塔形结构。随后，PPF在肝脏表面扩展，形成肌肉结缔组织和中央腱，其扩展的前缘先于肌肉形态发生、血管网络形成以及膈神经的生长和分支。因此，PPF的发育和形态发生对于横膈膜的形成至关重要。此外，我们的数据表明，横膈膜发育的最早事件对于CDH的病因至关重要，并且对横膈膜的进化具有重要作用。CDH在小鼠胚胎第12.5天之前开始发生，这表明早期PPF形成缺陷或其募集肌肉的能力是CDH的一个重要来源。而且，从颈节向新生PPF募集肌肉祖细胞是哺乳动物特有的，是肌肉化横膈膜进化所必需的关键发育创新。
