| Actin dynamics is critical for muscle development and function,and mutations leading to deregulation of actin dynamics cause various forms of inheritable muscle diseases.As a major co-factor of the actin depolymerizing factor(ADF)/cofilin,AIP1(called WDR1 in mammals),promotes ADF/cofilin-mediated actin disassembly.But,its function in vertebrate muscle has not been studied.To investigate the functional roles of WDR1 in myocardium,we generated conditional knockout(cKO)mice and deleted Wdrl(encoding WDR1)specifically in cardiomyocytes(cKO)by αMHC-Cre transgenic mice.Wdrl cKO mice began to die at postnatal day 13(P13)and none survived past P24.cKO mice displayed cardiac hypertrophy,impaired contraction of left ventricle at P12.Actin filament(F-actin)accumulations began at P10 and became prominent at P12 in the myocardium of cKO mice.Within regions of myofibrils where F-actin accumulated,the sarcomeric components α-actinin and Tropomodulin1(Tmod1)showed disrupted patterns,indicating that F-actin accumulations caused by Wdrl deletion resulted in disruption of sarcomeric structure.Interestingly,ectopic cofilin colocalized with F-actin aggregates.Lastly,Wdr1 deletion in adult heart resulted in similar but much milder phenotypes of mice lethality,heart hypertrophy and F-actin accumulations within myofibrils.Taken together,these results demonstrate that WDR1-regulated actin dynamics plays essential roles in heart function in mice.The heart originates from two main sources of heart progenitors in anterior splanchnic mesoderm:the first and the second heart fields(FHF and SHF,respectively).The progenitor cells of SHF deploy from the pharyngeal and splanchnic mesoderm to the elongated heart tube,and contribute to the outflow tract(OFT)and right ventricle(RV)at the arterial pole,as well as the atrial myocardium at the venous pole.Perturbation of SHF development results in a shorter heart tube that fails to remodel correctly,leading to a spectrum of morphological anomalies.Understanding how progressive deployment and migration of SHF cells is regulated is therefore an important step towards deciphering the origins of congenital heart defects.Unfortunately,so far the detailed mechanisms that regulate the deployment and migration of the SHF progenitor cells to the OFT,RV remain largely unknown.Actin dynamics plays important roles in cell migration,whether disruption of actin dynamics affects the deployment of SHF,and how actin dynamics governs the deployment and migration process of the SHF,are both not clear yet.Here,we deleted Wdrl in the Mef2c-expressing SHF progenitors(shfKO)using Mef2c-AHF-Cre,to investigate WDR1 mediated actin dynamics in the deployment and differentiation of this progenitor pool.We found that the shKCO mice died after embryonic day 10.5(E10.5).In shfKO mice,the length of OFT was not altered,but the size of RV,and the conus part of OFT(proximal OFT)was dramatically reduced.The pool of the Mef2c-expressing SHF progenitor cells in SpM was similar between control and shfKO embryos,and the proliferation and apoptosis of SHF progenitor cells in SpM and distal OFT were not changed.Histological data indicated that the apico-basal polarization,adherens junction,and tight junction of SHF progenitor cells in distal OFT were not affected in Wdrl shfKO embryos;this suggest that the deployment of the Mef2c-expressing derivatives to distal OFT was not affected.Primary studies revealed that the morphogenesis and myofibrillogenesis of the proximal OFT and RV myocardium were impaired as the sarcomeric structure and cellular arrangement were damaged,and the number of mitotic cells in the proximal OFT and RV was also decreased.We speculated that the disrupted processes of differentiation,morphogenesis and mitosis of SHF progenitor cells in the proximal OFT and RV,lead to the failure of the proximal OFT and RV expansion.In summary,our data indicated that WDR1 mediated actin dynamics plays indispensible roles in the Mef2c-expressiong progenitors for OFT and RV development. |
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