jkk-1 and mek-1 regulate body movement coordination and response to heavy metals through jnk-1 in Caenorhabditis elegans

Although in vitro evidence suggests two c-Jun N-terminal kinase (JNK) kinas es, MKK4 and MKK7, transactivate JNK, in vivo confirmation is incomplete. I n fact, JNK deficiency may differ from the composite deficiency of MKK4 and MKK7 in Drosophila and mice. Recently, the Caenorhabditis elegans homolog of human JNK, jnk-1, and two MKK-7s, mek-1 and jkk-1, were cloned. Here we characterize jnk-1, which encodes two isoforms JNK-1 alpha and JNK-1 beta. A null allele,jnk-1(gk7), yielded worms with defective body movement coordi nation and modest mechanosensory deficits. Similarly to jkk-1 mutants, elim ination of GABAergic signals suppressed the jnk-1(gk7) locomotion defect. L ike mek-1 nulls, jnk-1(gk7) showed copper and cadmium hypersensitivity. Con ditional expression of JNK-1 isoforms rescued these defects, suggesting tha t they are not due to developmental errors. While jkk-1 or mek-1 inactivati on mimicked jnk-1(gk7) locomotion and heavy metal stress defects, respectiv ely, mkk-4 inactivation did not, but rather yielded defective egg laying. O ur results delineate at least two different JNK pathways through jkk-1 and mek-1 in C.elegans, and define interaction between MKK7, but not MKK4, and JNK.