Lrp6, a single-span transmembrane protein, together with its vertebrate subfamily member Lrp5 and the fly ortholog Arrow, is known as the coreceptor for canonical Wnt/β-catenin signaling and has key roles in development and disease (He et al.,2004; Logan and Nusse,2004). Lrp6 has functional redundancy with Lrp5 in gastrulation (Kelly et al.,2004). Human Lrp5 mutations are associated with familial osteoporosis, high bone density syndromes, and ocular disorders (Gong et al.,2001), and Lrp5-deficient mice are viable and fertile (Kato et al.,2002). In contrast, Lrp6 mutant mice are embryonic or perinatal lethal with broad defects (Pinson et al.,2000), including abnormalities in embryonic brain, neural tube, and limbs. In addition, mutations in the human Lrp6 gene have recently been implicated in late-onset Alzheimer's disease, and familial coronary artery disease associated with diabetes and osteoporosis (De Ferrari et al.,2007; Mani et al.,2007). These implications suggest a crucial but pleiotropic role of Lrp6 in developmental disorders or genetic disease. We have previously demonstrated that Lrp6 mutants have multiple defects in forebrain structures and may be implicated in the pathogenesis of lissencephaly, schizophrenia, and related mental retardation (Zhou et al.,2004a,b,2006). Recently we have further found that Lrp6 is responsible for ocular birth defects including microphthalmia, coloboma, and dorsoventral neuroretina patterning defects (Zhou et al.,2008). Additionally, Lrp6 mutants have severe defects in other systems, particularly in embryonic hearts (Bryja et al.,2009; Song et al.,2009b).
Because of the significance of Lrp6 in organogenesis and the association of Lrp6 mutants with multiple birth defects, we have for the first time, generated a loxP-floxed Lrp6 mutant mouse line for conditional gene-targeting analyses. We obtained the Lrp6-floxdel mice with the CMV-Cre to delete the Lrp6 gene ubiquitously. We show the evidence of the identical phenotypes in external organs of the homozygous Lrp6-floxdel mice as seen in conventional Lrp6 mutant mice. We also report new phenotypes including the cleft palate and agenesis of external genitalia in Lrp6-floxdel mice. Combined with tissue-specific or inducible Cre mouse lines, the conditional Lrp6 mouse line will allow us to model and dissect specific types of birth defects for mechanisms and prevention studies.