The class A repeats of Lrp5 are required for normal development of bone, retinal vasculature, and mammary gland in vivo

Low-density lipoprotein-related receptor 5 (LRP5) is an LDLR family member with well-defined roles in mediating Wnt signaling. Its domain structure includes 4 LDLR class B and 3 LDLR class A repeats. Class B repeats mediate binding with Wnt ligands and other effectors, while the role of the LRP5 class A repeats, known to interact with apolipoproteins within the LDLR, is unclear. Complete loss of the LRP5 gene in humans causes osteoporosis pseudoglioma, a syndrome characterized by early-onset osteoporosis and changes in retinal vascularization. We and others have previously created mice and rats completely deficient for Lrp5 and reported the presence of bone and retinal vascularization defects. In this study, we created an allele of Lrp5 in mice where the entire protein except for the class A repeats is present and expressed from the endogenous locus. Unlike in vitro studies using ectopic overexpression of LRP5, our in vivo data demonstrate that the class A repeats are essential for several normal LRP5 functions, including bone homeostasis, retinal vascularization, and mammary gland development—phenotypes similar to those observed in Lrp5-null mice.