Fig. 7. Mekk1, Jnk1 and Jnk2 gene doses are crucial for embryonic eyelid closure. (A) M1^+/KDJ1^+/-J2^+/- triple heterozygous mice have EOB phenotype at postnatal day 1, with a partially exposed ocular surface at E16.5; by contrast, the M1^+/+ J1^+/- J2^+/- mice had closed eyelids at E16.5 and P1. The developing eye at E15.5 shows less phosphorylation of JNK and c-Jun (green) in the eyelid epithelium (arrowheads) of the triple hemizygous compared with the double hemizygous fetuses. (B) Diagram illustrating the signaling pathways in the control of eyelid epithelial morphogenesis. The signal is initiated from the eyelid morphogenetic factor activin B, which leads to the activation of MEKK1, a tissue-specific and rate-limiting determinant for transmitting the activin B signals. MEKK1 activates MKK4, which in turn phosphorylates JNK1 and JNK2. Because of the intrinsic variable sequence difference between the JNK isoforms, JNK1 is more effectively phosphorylated than JNK2. The total phospho-JNK determines the nuclear transcription factor c-Jun phosphorylation and induction of gene expression, such as PAI1. The endpoint of this pathway activation is the induction of epithelial cell migration, and eyelid epithelial morphogenesis and closure.