Gene-environment interactions underlie the complex aetiology of many developmental disorders; but the underlying mechanisms are poorly understood. Two new studies highlight gene-environment interactions that influence Hedgehog (Hh) morphogen signalling, a crucial pathway for embryonic development. In their study, Robert Krauss and colleagues reveal that THC, the psychoactive ingredient in cannabis, can induce developmental disorders in genetically susceptible Cdon–/–mice, which have reduced Hh signalling. Using a combination of in vivo genetics and in vitro cell biology, they show that THC can directly bind to the Hh effector protein, Smoothened, and prevent its translocation to the primary cilium, thereby attenuating Hh signalling. Exposing pregnant mice to THC is sufficient to cause developmental defects in developing Cdon-/- embryos, including holoprosencephaly and neural tube mispatterning. This study has important implications, providing evidence that cannabis could increase the risk of developmental disorders in genetically predisposed individuals. How might the Hh pathway be sensitive to environmental influences? Rajat Rohatgi and colleagues reveal the role of MOSMO, a previously uncharacterised modulator of Smoothened. Using Mosmo-/- mutant mice, they show that Hh signalling activity increases in the absence of MOSMO resulting in developmental defects in multiple organs. They demonstrate that MOSMO interacts with MEGF8 and MGRN1, forming a membrane-bound E3 ubiquitin ligase complex (termed the MMM complex) that promotes Smoothened degradation at the cell surface. Partial inhibition of Smoothened via the teratogen vismodegib alleviates defect phenotypes in some Mosmo-/- tissues. Mosmo-/- tissues are also partially protected against the teratogenic effects of vismodegib. These data indicate that the MMM complex refines tissue-specific Hh gradients, making the pathway robust to environmental influences. Taken together, these two studies show how an environmental exposure can have divergent effects on development depending on the presence of specific genetic mutations.
