DOI: 10.1186/1471-213x-12-22. Loss of muscleblind-like 1 promotes invasive mesenchyme formation in endocardial cushions by stimulating autocrine TGFβ3

Loss of muscleblind-like 1 promotes invasive mesenchyme formation in endocardial cushions by stimulating autocrine TGFβ3

10.1186/1471-213x-12-22

Crossref journal-article

Springer Science and Business Media LLC

BMC Developmental Biology (297)

Abstract

Abstract 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 β (TGFβ) 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 TGFβ-dependent endocardial cell invasion. Results In this study, we demonstrate that the effect of MBNL1 knockdown on invasion remains dependent on TGFβ3 after it is no longer required to induce basal levels of invasion. TGFβ3, but not TGFβ2, levels are elevated in medium conditioned by MBNL1-depleted AVC explants. TGFβ3 is elevated even when the myocardium is removed, indicating that MBNL1 modulates autocrine TGFβ3 production in the endocardium. More TGFβ3-positive cells are observed in the endocardial monolayer following MBNL1 knockdown. Addition of exogenous TGFβ3 to AVC explants recapitulates the effects of MBNL1 knockdown. Time course experiments demonstrate that knockdown of MBNL1 induces precocious TGFβ3 secretion, and early exposure to excess TGFβ3 induces precocious invasion. MBNL1 expression precedes TGFβ3 in the AVC endocardium, consistent with a role in preventing precocious autocrine TGFβ3 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. TGFβ 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 TGFβ3 production.

Bibliography

LeMasters, K. E., Blech-Hermoni, Y., Stillwagon, S. J., Vajda, N. A., & Ladd, A. N. (2012). Loss of muscleblind-like 1 promotes invasive mesenchyme formation in endocardial cushions by stimulating autocrine TGFÎ²3. BMC Developmental Biology, 12(1).

Authors 5

Kathryn E LeMasters (first)
Yotam Blech-Hermoni (additional)
Samantha J Stillwagon (additional)
Natalie A Vajda (additional)
Andrea N Ladd (additional)

References 25 Referenced 18

Dates

Type	When
Created	13 years ago (Aug. 6, 2012, 8:14 a.m.)
Deposited	3 years, 11 months ago (Sept. 1, 2021, 4:04 p.m.)
Indexed	1 year ago (Aug. 5, 2024, 4:28 a.m.)
Issued	13 years ago (Aug. 6, 2012)
Published	13 years ago (Aug. 6, 2012)
Published Online	13 years ago (Aug. 6, 2012)
Published Print	12 years, 9 months ago (Dec. 1, 2012)

Funders 0

None

BibTeX

@article{LeMasters_2012, title={Loss of muscleblind-like 1 promotes invasive mesenchyme formation in endocardial cushions by stimulating autocrine TGFβ3}, volume={12}, ISSN={1471-213X}, url={http://dx.doi.org/10.1186/1471-213x-12-22}, DOI={10.1186/1471-213x-12-22}, number={1}, journal={BMC Developmental Biology}, publisher={Springer Science and Business Media LLC}, author={LeMasters, Kathryn E and Blech-Hermoni, Yotam and Stillwagon, Samantha J and Vajda, Natalie A and Ladd, Andrea N}, year={2012}, month=aug }

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  "abstract": "<jats:title>Abstract</jats:title>\n          <jats:sec>\n            <jats:title>Background</jats:title>\n            <jats:p>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 \u03b2 (TGF\u03b2) 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\u03b2-dependent endocardial cell invasion.</jats:p>\n          </jats:sec>\n          <jats:sec>\n            <jats:title>Results</jats:title>\n            <jats:p>In this study, we demonstrate that the effect of MBNL1 knockdown on invasion remains dependent on TGF\u03b23 after it is no longer required to induce basal levels of invasion. TGF\u03b23, but not TGF\u03b22, levels are elevated in medium conditioned by MBNL1-depleted AVC explants. TGF\u03b23 is elevated even when the myocardium is removed, indicating that MBNL1 modulates autocrine TGF\u03b23 production in the endocardium. More TGF\u03b23-positive cells are observed in the endocardial monolayer following MBNL1 knockdown. Addition of exogenous TGF\u03b23 to AVC explants recapitulates the effects of MBNL1 knockdown. Time course experiments demonstrate that knockdown of MBNL1 induces precocious TGF\u03b23 secretion, and early exposure to excess TGF\u03b23 induces precocious invasion. MBNL1 expression precedes TGF\u03b23 in the AVC endocardium, consistent with a role in preventing precocious autocrine TGF\u03b23 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\u03b2 is necessary and sufficient to mediate this effect.</jats:p>\n          </jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions</jats:title>\n            <jats:p>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\u03b23 production.</jats:p>\n          </jats:sec>",
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        "label": "Article History"
      }
    }
  ],
  "article-number": "22"
}