Lrp4 Modulates Extracellular Integration of Cell Signaling Pathways in Development

Abstract

The extent to which cell signaling is integrated outside the cell is not currently appreciated. We show that a member of the low-density receptor-related protein family, Lrp4 modulates and integrates Bmp and canonical Wnt signalling during tooth morphogenesis by binding the secreted Bmp antagonist protein Wise. Mouse mutants of Lrp4 and Wise exhibit identical tooth phenotypes that include supernumerary incisors and molars, and fused molars. We propose that the Lrp4/Wise interaction acts as an extracellular integrator of epithelial-mesenchymal cell signaling. Wise, secreted from mesenchyme cells binds to BMP's and also to Lrp4 that is expressed on epithelial cells. This binding then results in the modulation of Wnt activity in the epithelial cells. Thus in this context Wise acts as an extracellular signaling molecule linking two signaling pathways. We further show that a downstream mediator of this integration is the Shh signaling pathway.

A role for suppressed incisor cuspal morphogenesis in the evolution of mammalian heterodont dentition

“…4 D-F). Interestingly, Lrp4 expression was also observed in the primary enamel knot in the molars (8). These results suggest that the role of Lrp4 in incisors is probably similar to that in molars.…”

“…S2) (8). It has been shown that the extra incisor tooth germs grow from endogenous incisor tooth germs (22).…”

“…The LDL receptor was first identified as an endocytic receptor that transports the lipoprotein LDL into cells by receptormediated endocytosis. More recent findings have shown that LDL receptor family members can also function as direct signal transducers or modulators for a broad range of cellular signaling pathways (6)(7)(8)(9).…”

Secreted and Transmembrane Wnt Inhibitors and Activators

“…Not only secreted Wise is able to inhibit Wnt signaling, but endoplasmic reticulum (ER)-retained Wise is also able to do so by reducing cell surface LRP6 (Guidato and Itasaki 2007). Wise also binds the LRP4 receptor (Ohazama et al 2008), which is able to modulate Wnt signaling mediated by LRP5 and -6 (Ohazama et al 2008;Li et al 2010).…”

Determining the Role of Sost and Sostdc1 During Fracture Healing

“…Sostdc1 has been described as both a Bmp and a Wnt antagonist in a contextdependent manner [182], and it interacts with Lpr4, 5, and 6 Wnt co-receptors and with Bmp ligands [3,103,[182][183][184], in vivo. While Sostdc1 shares 55% protein sequence homology to its paralog Sost, it reportedly displays higher specificity for the Lrp4 coreceptor [183], in contrast to the preferred binding to the Lrp5 and 6 co-receptors by Sost [85,137]. Mesenchyme-derived Sostdc1 inhibits Wnt signaling in the epithelium through the activation of Hedgehog signaling, which in turn suppresses Wnt signaling via Sostdc1 up-regulation in the mesenchyme [185,186].…”