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The primary cilium is a signaling center critical for proper embryonic development. Previous studies have demonstrated that mice lacking  Ttc21b  have impaired retrograde trafficking within the cilium and multiple organogenesis phenotypes, including microcephaly. Interestingly, the severity of the microcephaly in  Ttc21b   aln/aln   homozygous null mutants is considerably affected by the genetic background and mutants on an FVB/NJ (FVB) background develop a forebrain significantly smaller than mutants on a C57BL/6J (B6) background. We performed a Quantitative Trait Locus (QTL) analysis to identify potential genetic modifiers and identified two regions linked to differential forebrain size:  modifier of alien QTL1 (Moaq1)  on chromosome 4 at 27.8 Mb and  Moaq2  on chromosome 6 at 93.6 Mb. These QTLs were validated by constructing congenic strains. Further analysis of  Moaq1  identified an orphan G-protein coupled receptor (GPCR),  Gpr63 , as a candidate gene. We identified a SNP that is polymorphic between the FVB and B6 strains in  Gpr63  and creates a missense mutation predicted to be deleterious in the FVB protein. We used CRISPR-Cas9 genome editing to create two lines of FVB congenic mice: one with the B6 sequence of  Gpr63  and the other with a deletion allele leading to a truncation of the GPR63 C-terminal tail. We then demonstrated that  Gpr63  can localize to the cilium  in vitro . These alleles affect ciliary localization of GPR63  in vitro  and genetically interact with  Ttc21b   aln/aln   as  Gpr63;Ttc21b  double mutants show unique phenotypes including spina bifida aperta and earlier embryonic lethality. This validated  Gpr63  as a modifier of multiple  Ttc21b  neural phenotypes and strongly supports  Gpr63  as a causal gene (i.e., a quantitative trait gene, QTG) within the  Moaq1  QTL.

Gpr63 is a modifier of microcephaly in Ttc21b mouse mutants