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Low-density lipoprotein receptor related protein 6 ( Lrp6)  mutational effects on neurulation were examined using gain ( Crooked tail, Lrp6 Cd  ) and loss ( Lrp6  − ) of function mouse lines. Two features often associated with canonical Wnt signaling, dorsal–ventral patterning and proliferation, were no different from wild-type (WT) in the  Lrp6 Cd/Cd   neural tube.  Lrp6  −/−  embryos showed reduced proliferation and subtle patterning changes in the neural folds. Cell polarity defects in both  Lrp6 Cd/Cd   and  Lrp6  − / −  cranial folds were indicated by cell shape, centrosome displacement and failure of F-actin and GTP-RhoA accumulation at the apical surface. Mouse embryonic fibroblasts (MEFs) derived from  Lrp6 Cd/Cd   or  Lrp6  − / −  embryos exhibited elevated and decreased RhoA basal activity levels, respectively. While ligand-independent activation of canonical Wnt signaling, bypassing Lrp-Frizzled receptors, did not activate RhoA, non-canonical Wnt5a stimulation of RhoA activity was impaired in  Lrp6  − / −  MEFs. RhoA inhibition exacerbated NTDs in cultured  Lrp6  knockout embryos compared with WT littermates. In contrast, a ROCK inhibitor rescued  Lrp6 Cd/Cd   embryos from NTDs. Lrp6 co-immunoprecipitated with Disheveled-associated activator of morphogenesis 1 (DAAM1), a formin promoting GEF activity in Wnt signaling. Biochemical and cell biological data revealed intracellular accumulation of Lrp6 Cd  protein where interaction with DAAM1 could account for observed elevated RhoA activity. Conversely, null mutation that eliminates Lrp6 interaction with DAAM1 led to lower basal RhoA activity in  Lrp6  − / −  embryos. These results indicate that Lrp6 mediates not only canonical Wnt signaling, but can also modulate non-canonical pathways involving RhoA-dependent mechanisms to impact neurulation, possibly through intracellular complexes with DAAM1.

LRP6 exerts non-canonical effects on Wnt signaling during neural tube closure