Fibroblast-derived Hgf controls recruitment and expansion of muscle during morphogenesis of the mammalian diaphragm.
Fibroblast-derived Hgf controls recruitment and expansion of muscle during morphogenesis of the mammalian diaphragm.
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DOI：
10.7554/elife.74592
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发表时间：
2022-09-26
期刊：
影响因子：
7.7
通讯作者：
Kardon G
中科院分区：
文献类型：
--
作者：
Sefton EM;Gallardo M;Tobin CE;Collins BC;Colasanto MP;Merrell AJ;Kardon G
横膈膜是哺乳动物胸部和腹部之间的一块圆顶状肌肉，对呼吸至关重要。横膈膜的发育需要肌肉、结缔组织和神经的协调发育，它们来源于不同的胚胎来源。横膈膜发育缺陷是一种常见的致命性出生缺陷，即先天性膈疝。横膈膜肌化需要HGF/MET信号，但HGF的来源和该途径在肌肉祖细胞中的具体功能以及对膈神经的影响尚未得到明确的测试。通过小鼠条件诱变和MET的药理学抑制，我们证明了胸膜腹膜折叠（PPFs），即在横膈膜中产生结缔组织的瞬态胚胎结构，是横膈膜肌肉化的关键HGF的来源。ppf衍生的HGF是将MET+肌祖细胞募集到膈肌所直接需要的，也是膈神经初级分支所间接需要的（通过其对肌肉发育的影响）。此外，HGF是持续需要的维持和运动的祖细胞池，使充分的肌肉化。HGF在膈肌前缘的定位指导肌肉的背侧和腹侧扩张，并调节其整体大小和形状。令人惊讶的是，HGF和Met突变体的大的无肌肉区域不会导致疝气。虽然这些区域可能更容易发生CDH，但肌肉损失不足以引起CDH。
The diaphragm is a domed muscle between the thorax and abdomen essential for breathing in mammals. Diaphragm development requires the coordinated development of muscle, connective tissue, and nerve, which are derived from different embryonic sources. Defects in diaphragm development cause the common and often lethal birth defect, congenital diaphragmatic hernias (CDH). HGF/MET signaling is required for diaphragm muscularization, but the source of HGF and the specific functions of this pathway in muscle progenitors and effects on phrenic nerve have not been explicitly tested. Using conditional mutagenesis in mice and pharmacological inhibition of MET, we demonstrate that the pleuroperitoneal folds (PPFs), transient embryonic structures that give rise to the connective tissue in the diaphragm, are the source of HGF critical for diaphragm muscularization. PPF-derived HGF is directly required for recruitment of MET+ muscle progenitors to the diaphragm and indirectly (via its effect on muscle development) required for phrenic nerve primary branching. In addition, HGF is continuously required for maintenance and motility of the pool of progenitors to enable full muscularization. Localization of HGF at the diaphragm’s leading edges directs dorsal and ventral expansion of muscle and regulates its overall size and shape. Surprisingly, large muscleless regions in HGF and Met mutants do not lead to hernias. While these regions are likely more susceptible to CDH, muscle loss is not sufficient to cause CDH.