Our previous study has shown that Gpr177 is required for Wnt3-mediated establishment of the body axis (Fu et al., 2009
). By creating a conditional null allele, we are able to overcome the early lethality associated with the Gpr177 knockout, leading to an investigation of its role in other developmental processes involving the Wnt pathway. Using genetic analysis, we demonstrate that Gpr177 is essential for development of the mammalian head mediated by Wnt1. The loss of Gpr177 in the Wnt1-expressing cells not only impairs brain development, but also causes severe craniofacial deformities. These developmental defects are much more severe than the Wnt1 knockout (McMahon and Bradley, 1990a
; Thomas and Capecchi, 1990
), but highly reminiscent to phenotypes caused by the double knockout of Wnt1 and Wnt3a (Ikeya et al., 1997
), and the β-catenin deletion in the Wnt1-expressing cells (Brault et al., 2001
). Because the deletion of Gpr177 is likely to affect all Wnt productions in the Wnt1-expressing cells, the Gpr177Wnt1
phenotype thus reflects the impaired regulation of Wnt1 plus other Wnt(s). Our findings support the theory for the availability and the ability of other family members capable of compensating the loss of Wnt1. Gpr177-mediated regulation of Wnt is indispensable for craniofacial and brain development.
Although the loss of Gpr177 causes defects in craniofacial development mediated by neural crest cells, their induction and migration do not seem to be affected in the Gpr177Wnt1
mutants. Fate mapping study has suggested that the Wnt1-expressing cells are precursors of the cranial neural crest (Chai et al., 2000
; Jiang et al., 2000
). However, Wnt1 is not expressed in the migrating and post-migratory neural crest cells, implying that Wnt signaling is repressed during the migratory process. This is consistent with our finding that Gpr177 is dispensable for neural crest cell migration. However, the development of post-migratory neural crest cells requires Gpr177, suggesting that Wnt signaling is essential for subsequent developmental processes during craniofacial morphogenesis.
In the course of preparing this paper, Carpenter et al. reports the generation of a conditional null allele (Carpenter et al., 2010
) similar to the one created by us. The difference between these two alleles is the targeting strategy where they insert two loxP sites flanking exon 1. It is not clear whether the loxP site insertion at the 5′ untranslated region interferes with the production of Gpr177. Indeed, the phenotypic defects associated with the Wnt1-Cre-mediated deletion described by Carpenter and colleagues seem more severe than those described in our study. In their mutants, the Gpr177 deletion induces a secondary defect in the telencephalon (Carpenter et al., 2010
). Another possibility is that their analysis is performed in the heterozygous background where one copy of Gpr177
has been inactivated in all cells (Carpenter et al., 2010
). In our model, we inactivate Gpr177 in the Wnt1-expressing cells without manipulating its expression in cells which do not express Cre. If the differences between the two models are due to haploid deficiency, the gene dosage of Gpr177
might be an important issue for the regulation of Wnt in development and disease.
Our comprehensive survey on the expression of Gpr177 has led to a hypothesis that reciprocal regulation of Wnt and Gpr177 is essential for the Wnt-dependent development of multiple organs (Yu et al., 2010
). The Gpr177Fx mouse strain provides a powerful tool to further determine the requirement of Gpr177 in Wnt-mediated developmental and pathogenic processes. For the canonical pathway, there is now genetic evidence for the importance of Gpr177 in controlling Wnt1 and Wnt3 during mouse development. It is possible that Gpr177 is the master regulator in the signal-producing cells similar to the role of β-catenin, the master regulator in the signal-receiving cells, for the canonical Wnt pathway. Furthermore, the Wnt-producing cells are able to initiate autocrine and well as paracrine signaling effects, which add another layer of complexity to elucidate the regulatory mechanism. Whether non-canonical Wnt proteins are also regulated by Gpr177 remains an important issue to be addressed, especially by genetic analysis. Indeed, the brain and craniofacial defects exhibited in the Gpr177Wnt1
mutants are somewhat similar to the Wnt5a null phenotypes (Yamaguchi et al., 1999
). If Gpr177 modulates the production of canonical and non canonical Wnt proteins, it becomes a real challenge to dissect the phenotypic defects associated with the Gpr177 deletion. This is because that both the canonical and non canonical Wnt proteins could be expressed in the same cell. However, canonical and non canonical signaling pathways may trigger different, and sometimes opposite, effects on tissue/organ development and maintenance. Studying the genetic interaction of Gpr177 and a specific Wnt signaling pathway promises new insights into the Gpr177-mediated regulation of Wnt in development and disease.