SHH and cleft palate: Inactivation of Hand2 in the palatal mesenchyme had no effect on palatal development while elimination of Hand2 in the palatal epithelium led to cleft palate resulted from premature death of periderm cells in the MEE and reduced mesenchymal proliferation via modulating Shh expression (Morikawa et al., 2007; Xiong et al., 2009).