JNK initiates a cytokine cascade that causes Pax2 expression and closure of the optic fissure

Abstract

The c-Jun NH₂-terminal kinase (JNK) group of mitogen-activated protein kinases is stimulated in response to a wide array of cellular stresses and proinflammatory cytokines. Mice lacking individual members of theJnkfamily (Jnk1,Jnk2, andJnk3) are viable and survive without overt structural abnormalities. Here we show that mice with a compound deficiency inJnkexpression can survive to birth, but fail to close the optic fissure (retinal coloboma). We demonstrate that JNK initiates a cytokine cascade of bone morphogenetic protein-4 (BMP4) and sonic hedgehog (Shh) that induces the expression of the paired-like homeobox transcription factor Pax2 and closure of the optic fissure. Interestingly, the role of JNK to regulate BMP4 expression during optic fissure closure is conserved inDrosophiladuring dorsal closure, a related morphogenetic process that requires JNK-regulated expression of the BMP4 ortholog Decapentaplegic (Dpp).