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We asked whether key morphogenetic signaling pathways interact with 22q11 gene dosage to modulate the severity of cranial or cardiac anomalies in DiGeorge/22q1 deletion syndrome (22q11DS). Sonic hedgehog ( Shh ) and retinoic acid (RA) signaling is altered in the brain and heart—clinically significant 22q11DS phenotypic sites—in  LgDel  mouse embryos, an established 22q11DS model.  LgDel  embryos treated with cyclopamine, an  Shh  inhibitor, or carrying mutations in  Gli3  Xtj , an Shh-signaling effector, have morphogenetic anomalies that are either not seen, or seen at significantly lower frequencies in control or single-mutant embryos. Similarly, RA exposure or genetic loss of RA function via heterozygous mutation of the RA synthetic enzyme  Raldh2  induces novel cranial anomalies and enhances cardiovascular phenotypes in  LgDel  but not other genotypes. These changes are not seen in heterozygous  Tbx1  mutant embryos—a 22q11 gene thought to explain much of 22q11DS pathogenesis—in which  Shh  or RA signaling has been similarly modified. Our results suggest that full dosage of 22q11 genes beyond  Tbx1  establish an adaptive range for morphogenetic signaling via Shh and RA. When this adaptive range is constricted by diminished dosage of 22q11 genes, embryos are sensitized to otherwise benign changes in Shh and RA signaling. Such sensitization, in the face of environmental or genetic factors that modify Shh or RA signaling, may explain variability in 22q11DS morphogenetic phenotypes.

22q11 Gene dosage establishes an adaptive range for sonic hedgehog and retinoic acid signaling during early development