%0 Journal Article
%T Loss of muscleblind-like 1 promotes invasive mesenchyme formation in endocardial cushions by stimulating autocrine TGF¦Â3
%A LeMasters Kathryn E
%A Blech-Hermoni Yotam
%A Stillwagon Samantha J
%A Vajda Natalie A
%J BMC Developmental Biology
%D 2012
%I BioMed Central
%R 10.1186/1471-213x-12-22
%X Background Valvulogenesis and septation in the developing heart depend on the formation and remodeling of endocardial cushions in the atrioventricular canal (AVC) and outflow tract (OFT). These cushions are invaded by a subpopulation of endocardial cells that undergo an epithelial-mesenchymal transition in response to paracrine and autocrine transforming growth factor ¦Â (TGF¦Â) signals. We previously demonstrated that the RNA binding protein muscleblind-like 1 (MBNL1) is expressed specifically in the cushion endocardium, and knockdown of MBNL1 in stage 14 embryonic chicken AVC explants enhances TGF¦Â-dependent endocardial cell invasion. Results In this study, we demonstrate that the effect of MBNL1 knockdown on invasion remains dependent on TGF¦Â3 after it is no longer required to induce basal levels of invasion. TGF¦Â3, but not TGF¦Â2, levels are elevated in medium conditioned by MBNL1-depleted AVC explants. TGF¦Â3 is elevated even when the myocardium is removed, indicating that MBNL1 modulates autocrine TGF¦Â3 production in the endocardium. More TGF¦Â3-positive cells are observed in the endocardial monolayer following MBNL1 knockdown. Addition of exogenous TGF¦Â3 to AVC explants recapitulates the effects of MBNL1 knockdown. Time course experiments demonstrate that knockdown of MBNL1 induces precocious TGF¦Â3 secretion, and early exposure to excess TGF¦Â3 induces precocious invasion. MBNL1 expression precedes TGF¦Â3 in the AVC endocardium, consistent with a role in preventing precocious autocrine TGF¦Â3 signaling. The stimulatory effects of MBNL1 knockdown on invasion are lost in stage 16 AVC explants. Knockdown of MBNL1 in OFT explants similarly enhances cell invasion, but not activation. TGF¦Â is necessary and sufficient to mediate this effect. Conclusions Taken together, these data support a model in which MBNL1 negatively regulates cell invasion in the endocardial cushions by restricting the magnitude and timing of endocardial-derived TGF¦Â3 production.
%K Muscleblind-like 1
%K Alternative splicing
%K TGF¦Â
%K Endocardial cushions
%K Epithelial-mesenchymal transition
%K Cell invasion
%U http://www.biomedcentral.com/1471-213X/12/22