Knockout Of Pdgfrα In Mouse Cardiac Progenitor Cells Leads To Noncompaction Of The Ventricular Myocardium

The heart is the first organ during the embryonic development and its occurrence and development requires a variety of transcription factors and growth factors.For example,the morphogenesis of the embryonic heart requires specific spatiotemporal expression of platelet-derived growth factor（PDGF）and platelet-derived growth factor receptor（PDGFR）.The PDGFs family comprises four tyrosine kinase namely PDGF-A,PDGF-B,PDGF-C and PDGF-D.Specific ligand receptor binding spectrum in PDGFs lead to formation of dimers including PDGF-AA,PDGF-BB,PDGF-CC and PDGF-DD and a heterodimer PDGF-AB.The PDGFs signal through two type III tyrosine kinase receptors namely PDGFRαand PDGFRβ.A previous study utilizing Pdgfrαconventional knockout mice reported cardiac malformations consisting of noncompaction of the ventricular myocardium.This mouse line embryos die by E11.5 due to embryonic lethality,rendering them difficult to investigate the details.To elucidate the underlying mechanism,in this study,we revisited this observation by generation of specific ablation of Pdgfrαin in mouse cardiac progenitor cells by Nkx2.5^cre/+at E7.5,using a Nkx2.5^cre/+;Pdgfrα^flox/floxconditional mouse line.Firstly,we tracked Pdgfrαexpression in NKX2.5 cell lineages in the heart of Nkx2.5^cre/+;R26R^{m Tm G}mice at E7.75-9.5.The results showed that Pdgfrαwas strongly expressed in the cardiac progenitor cells during early mouse embryonic heart development.To analyze the cell types of NKX2.5⁺/PDGFRα⁺cells in the embryonic heart,we performed immunofluorescence staining of mouse embryos with c Tn T,α-SMA and CD31 antibodies and found that these cells were cardiac progenitor cells,cardiomyocytes and endocardial cells.Subsequently,we observed that Pdgfrαwould continue to be expressed only in endocardial cells at E10.5-15.5.Finally,we constructed Nkx2.5^cre/+;Pdgfrα^flox/floxconditional knockout mice,which exhibited abnormal ventricular conduction and noncompaction of the ventricular myocardium.Further studies revealed that conditional knockout of Pdgfrαaffected cell proliferation,apoptosis,and disturbed CD31 and CollagenⅢexpression,which may lead to noncompaction of expression,which may lead to noncompaction of the ventricular myocardium.In summary,we traced the expression of Pdgfrαin NKX2.5⁺cardiac progenitor cells and their derived cells,and constructed Nkx2.5^cre/+;Pdgfrα^flox/floxmice,which Pdgfrαwas conditionally knocked out in cardiac progenitor cells,to explore the role in heart development.Nkx2.5^cre/+;Pdgfrα^flox/floxmice could be used to understand the molecular mechanism of Pdgfrαin the development and function maintaining of heart,providing a theoretical basis for further understand the role of this signal in heart and a mouse pathological model for noncompaction of the ventricular myocardium.