Fibroblast-derived Hgf controls recruitment and expansion of muscle during morphogenesis of the mammalian diaphragm.

Autor:	Sefton EM; Department of Human Genetics, University of Utah, Salt Lake City, United States., Gallardo M; Department of Human Genetics, University of Utah, Salt Lake City, United States., Tobin CE; Department of Human Genetics, University of Utah, Salt Lake City, United States., Collins BC; Department of Human Genetics, University of Utah, Salt Lake City, United States., Colasanto MP; Department of Human Genetics, University of Utah, Salt Lake City, United States., Merrell AJ; Ambys Medicines, South San Francisco, United States., Kardon G; Department of Human Genetics, University of Utah, Salt Lake City, United States.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2022 Sep 26; Vol. 11. Date of Electronic Publication: 2022 Sep 26.
DOI:	10.7554/eLife.74592
Abstrakt:	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. Competing Interests: ES, MG, CT, BC, MC, AM, GK No competing interests declared (© 2022, Sefton et al.)
Databáze:	MEDLINE
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