Departments of Biochemistry and Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15201, USA.
Development. 2021 Oct 1;148(19). doi: 10.1242/dev.199867. Epub 2021 Oct 4.
Birth defects result from interactions between genetic and environmental factors, but the mechanisms remain poorly understood. We find that mutations and teratogens interact in predictable ways to cause birth defects by changing target cell sensitivity to Hedgehog (Hh) ligands. These interactions converge on a membrane protein complex, the MMM complex, that promotes degradation of the Hh transducer Smoothened (SMO). Deficiency of the MMM component MOSMO results in elevated SMO and increased Hh signaling, causing multiple birth defects. In utero exposure to a teratogen that directly inhibits SMO reduces the penetrance and expressivity of birth defects in Mosmo-/- embryos. Additionally, tissues that develop normally in Mosmo-/- embryos are refractory to the teratogen. Thus, changes in the abundance of the protein target of a teratogen can change birth defect outcomes by quantitative shifts in Hh signaling. Consequently, small molecules that re-calibrate signaling strength could be harnessed to rescue structural birth defects.
出生缺陷是由遗传和环境因素相互作用引起的，但其中的机制仍知之甚少。我们发现，突变和致畸剂以可预测的方式相互作用，通过改变靶细胞对 Hedgehog（Hh）配体的敏感性来导致出生缺陷。这些相互作用集中在一个膜蛋白复合物上，即 MMM 复合物，该复合物促进 Hh 转导 Smoothened（SMO）的降解。MMM 成分 MOSMO 的缺乏会导致 SMO 升高和 Hh 信号增加，从而导致多种出生缺陷。在宫内暴露于直接抑制 SMO 的致畸剂会降低 Mosmo-/-胚胎出生缺陷的外显率和表现度。此外，在 Mosmo-/-胚胎中正常发育的组织对致畸剂具有抗性。因此，致畸剂的靶蛋白丰度的变化可以通过 Hh 信号的定量变化来改变出生缺陷的结果。因此，重新校准信号强度的小分子可以被利用来挽救结构出生缺陷。
