Lrp5 Knockout mouse models

Lrp5, the mouse ortholog of human LRP5, encodes a single-pass LDL receptor-related Wnt co-receptor whose extracellular region comprises four beta-propeller and EGF module pairs; upon Wnt binding it is brought together with Frizzled, and CK1gamma and Gsk3 phosphorylation of reiterated PPPSPXS motifs in its cytoplasmic tail creates the Axin docking site that disables the beta-catenin destruction complex. The first propeller is the binding surface for the antagonists Dkk1 and Sost, which explains why the Gly171Val high bone mass substitution acts by escaping sclerostin inhibition rather than by increasing intrinsic activity, while loss-of-function alleles cause osteoporosis-pseudoglioma syndrome and familial exudative vitreoretinopathy. Nulls are viable with low bone mass and persistent hyaloid vasculature, so germline and conditional alleles are both practical, and the high bone mass knockin or a humanized propeller is the correct design for sclerostin antibody and Dkk1 blockade studies. Lrp6 overlaps functionally, so compound alleles reveal masked skeletal phenotypes.

Whole body loss of Lrp5 gives the clearest readout when the question is whether the gene is required at all. Follow up tissue work can still move to a conditional allele if lethality or compensation appears.