An LDL-receptor-related protein mediates Wnt signalling in mice

Abstract

Wnt genes comprise a large family of secreted polypeptides that are expressed in spatially and tissue-restricted patterns during vertebrate embryonic development. Mutational analysis in mice has shown the importance of Wnts in controlling diverse developmental processes such as patterning of the body axis, central nervous system and limbs, and the regulation of inductive events during organogenesis. Although many components of the Wnt signalling pathway have been identified, little is known about how Wnts and their cognate Frizzled receptors signal to downstream effector molecules. Here we present evidence that a new member of the low-density lipoprotein (LDL)-receptor-related protein family, LRP6 (ref. 3), is critical for Wnt signalling in mice. Embryos homozygous for an insertion mutation in the LRP6 gene exhibit developmental defects that are a striking composite of those caused by mutations in individual Wnt genes. Furthermore, we show a genetic enhancement of a Wnt mutant phenotype in mice lacking one functional copy of LRP6. Together, our results support a broad role for LRP6 in the transduction of several Wnt signals in mammals.

The ups and downs of Wnt signaling in prevalent neurological disorders

“…Nonetheless, LRP1 levels decline normally in the aging population and are drastically reduced in AD brains (Kang et al, 2000), suggesting that once LRP1 is absent other receptors might become important in modulating the effects of APOE. In recent years it has become clear that the highly homologous LRP5 LRP6 (Brown et al, 1998) proteins are crucial for reception of the Wnt signal transduction pathway (Pinson et al, 2000;Tamai et al, 2000;Wehrli et al, 2000). Although we lack conclusive evidence regarding the interaction between LRP5/6 and APOE at the cellular and molecular levels, it has been proposed that LRP5/6 may recognize and be involved in APOE catabolism (Kim et al, 1998;Magoori et al, 2003).…”

Bone mass is inversely proportional to Dkk1 levels in mice

“…LRP6 plays an essential role during embryogenesis and the severe developmental defects in Lrp6 −/− mice prevent the study of postnatal bone [53]. However, heterozygous Lrp6 +/− and hypomorphic ringelshwanz Lrp6 mutant mice exhibit delays in ossification and decreased bone mass in adults [11,54].…”

Function and biological roles of the Dickkopf family of Wnt modulators

“…The phenotype of Lrp6 null mutant mice with loss of caudal somites is very similar (Pinson et al, 2000). In the hypomorphic Lrp6 mutant ringelschwanz (rs), a-p polarity of the somites is affected, and no discrete somite a-p compartments are established from the lumbar region onwards (Kokubu et al, 2004).…”