Abstract
The Low-density lipoprotein receptor-Related Protein (LRP) family members are essential for diverse processes ranging from the regulation of gastrulation to the modulation of lipid homeostasis. Receptors in this family bind and internalize a diverse array of ligands in the extracellular matrix (ECM). As a consequence, LRPs regulate a wide variety of cellular functions including, but not limited to lipid metabolism, membrane composition, cell motility, and cell signaling. Not surprisingly, mutations in single human LRPs are associated with defects in cholesterol metabolism and development of atherosclerosis, abnormalities in bone density, or aberrant eye vasculature, and may be a contributing factor in development of Alzheimer’s disease. Often, members of this diverse family of receptors perform overlapping roles in the same tissues, complicating the analysis of their function through conventional targeted mutagenesis. Here, we describe development of a mouse Mesd (Mesoderm Development) conditional knockout allele, and demonstrate that ubiquitous deletion of Mesd using Cre-recombinase blocks gastrulation, as observed in the traditional knockout and albino-deletion phenotypes. This conditional allele will serve as an excellent tool for future characterization of the cumulative contribution of LRP members in defined tissues.
Highlights
MESD is an endoplasmic reticulum (ER) chaperone whose function is specialized for folding the b-propeller/Epidermal Growth Factor (EGF) module characteristically found in the extracellular domains of the Low-density lipoprotein receptorRelated Protein (LRP) family [1,2,3]
Since the signal peptide directing the MESD protein into the endoplasmic reticulum (ER) and the N-terminal a-helical region essential for folding the LRP b-propeller/EGF motif are encoded by exon 1 [3], we predicted that Cre-recombinase mediated deletion of Mesd exon 1 (Mesd-LoxP) would result in the loss of MESD function
Mesd-LoxP heterozygotes were crossed to Mesd-KO, Mesd-3YPSD, or Mesd-LoxP heterozygotes, and embryo phenotypes were examined at E 7.5 and E 8.5
Summary
MESD is an endoplasmic reticulum (ER) chaperone whose function is specialized for folding the b-propeller/Epidermal Growth Factor (EGF) module characteristically found in the extracellular domains of the Low-density lipoprotein receptorRelated Protein (LRP) family [1,2,3]. Ten mammalian LRPs contain the b-propeller/EGF module: Low Density Lipoprotein Receptor (LDLR), Very Low Density Lipoprotein Receptor (VLDLR), LDLR-Related Protein 1 and 1b (LRP1 and LRP1b), Megalin (LRP2), Apolipoprotein E Receptor 2 (ApoER2), LDLRRelated Protein 4 (LRP4 or Megf7), LDLR-Related Protein 5 and 6 (LRP5 and 6), and Sorting receptor related (SorLA) [4,5,6]. Because of their diverse roles in cell signaling and endocytosis, mutations in LRPs lead to phenotypes ranging from developmental defects to elevated serum lipids in the adult [7,8,9]. Given the variable efficiency of infection and recombination achieved through delivery of adCre, we recommend that future studies evaluating LRP function in hepatocytes use inherited tissue specific Cre-recombinase transgenes
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