Cell disorientation by loss of SHH-dependent mechanosensation causes cyclopia.

The physical causes of organ malformation remain largely unclear in most cases due to a lack of information on tissue/cell dynamics. Here, we address this issue by considering onset of cyclopia in sonic hedgehog (SHH)-inhibited chick embryos. We show that ventral forebrain-specific self-organization ability driven by SHH-dependent polarized patterns in cell shape, phosphorylated myosin localization, and collective cell motion promotes optic vesicle elongation during normal development. Stress loading tests revealed that these polarized dynamics result from mechanical responses. In particular, stress and active tissue deformation satisfy orthogonality, defining an SHH-regulated morphogenetic law. Without SHH signaling, cells cannot detect the direction of stress and move randomly, leading to insufficient optic vesicle elongation and consequently a cyclopia phenotype. Since polarized tissue/cell dynamics are common in organogenesis, cell disorientation caused by loss of mechanosensation could be a pathogenic mechanism for other malformations.