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

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

  • Dis Model Mech. 2025 Sep 11:dmm.052280. doi: 10.1242/dmm.052280.
Cassandra R Diegel 1,  Megan N Michalski 1,  John L Ubels 1,  Gabrielle Foxa Wiartalla 1,  Cheng-Mao Lin 2,  Zhendong A Zhong 1,  Mitchell J McDonald 1,  Nicole J Ethen 1,  Madison Brookshire 1,  Zachary B Madaj 3,  Mingxuan Xia 4,  Paul R Gavine 5,  VAI Transgenic Core,  David A Antonetti 2,  Bart O Williams 1
Affiliations

Affiliations

  • 1 Department of Cell Biology, Van Andel Institute, 333 Bostwick Ave., NE, Grand Rapids, MI 49503, USA.
  • 2 Kellogg Eye Center, Department of Ophthalmology and Visual Sciences, University of Michigan School of Medicine, 1000 Wall St, Ann Arbor, MI 48105, USA.
  • 3 Bioinformatics and Biostatistics Core, Van Andel Institute, 333 Bostwick Ave., NE, Grand Rapids, MI 49503, USA.
  • 4 Oncology Translational Research Asia, Johnson & Johnson Innovative Medicines, China.
  • 5 Oncology Discovery, Johnson & Johnson Innovative Medicines, Belgium.
PMID: 40932232 DOI: 10.1242/dmm.052280
Abstract

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.

Keywords

Bone; LDLR Type A repeats; Lrp5; Retina; Wnt.

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