Special Issue Research Article
MESD is essential for apical localization of megalin/LRP2 in the visceral endoderm
Article first published online: 8 NOV 2010
Copyright © 2010 Wiley-Liss, Inc.
Special Issue: Special Focus on Endoderm
Volume 240, Issue 3, pages 577–588, March 2011
How to Cite
Lighthouse, J. K., Zhang, L., Hsieh, J.-C., Rosenquist, T. and Holdener, B. C. (2011), MESD is essential for apical localization of megalin/LRP2 in the visceral endoderm. Dev. Dyn., 240: 577–588. doi: 10.1002/dvdy.22477
- Issue published online: 17 FEB 2011
- Article first published online: 8 NOV 2010
- Manuscript Accepted: 5 OCT 2010
- NIH. Grant Numbers: GM053964, CA095407, CA123071
- low-density lipoprotein receptor-related protein;
- visceral endoderm;
Deletion of the Mesd gene region blocks gastrulation and mesoderm differentiation in mice. MESD is a chaperone for the Wnt co-receptors: low-density lipoprotein receptor-related protein (LRP) 5 and 6 (LRP5/6). We hypothesized that loss of Wnt signaling is responsible for the polarity defects observed in Mesd-deficient embryos. However, because the Mesd-deficient embryo is considerably smaller than Lrp5/6 or Wnt3 mutants, we predicted that MESD function extends more broadly to the LRP family of receptors. Consistent with this prediction, we demonstrated that MESD function in vitro was essential for maturation of the β-propeller/EGF domain common to LRPs. To begin to understand the role of MESD in LRP maturation in vivo, we generated a targeted Mesd knockout and verified that loss of Mesd blocks WNT signaling in vivo. Mesd mutants continue to express the pluripotency markers Oct4, Nanog, and Sox2, suggesting that Wnt signaling is essential for differentiation of the epiblast. Moreover, we demonstrated that MESD was essential for the apical localization of the related LRP2 (Megalin/MEG) in the visceral endoderm, resulting in impaired endocytic function. Combined, our results provide evidence that MESD functions as a general LRP chaperone and suggest that the Mesd phenotype results from both signaling and endocytic defects resulting from misfolding of multiple LRP receptors. Developmental Dynamics 240:577–588, 2011. © 2010 Wiley-Liss, Inc.