THE EXPRESSION PATTERN OF THE MOUSE RECEPTOR TYROSINE KINASE GENE MDK1 IS CONSERVED THROUGH EVOLUTION AND REQUIRES HOXA-2 FOR RHOMBOMERE-SPECIFIC EXPRESSION IN MOUSE EMBRYOS

Segmentation of the hindbrain has been conserved throughout the verteb rate species and results in the transient formation of rhombomeres, wh ich are lineage-restricted compartments. Studies on the molecular mech anisms underlying the segmentation process have revealed that rhombome ric boundaries coincide with the expression limits of several evolutio nary conserved genes such as the zinc-finger transcription factor Krox -20 and homeobox genes which are expressed in a specific spatial and t emporal order and have been shown to be important regulators of segmen tal identity. In addition to Krox-20 and Hox genes, several members of the Eph subfamily of receptor protein tyrosine kinase (RTK) genes are also expressed in a segment-restricted manner in the hindbrain, sugge sting that these receptors may act in concert with Hox genes to establ ish regional identity. In the cascade of regulatory interactions leadi ng to segmental identity, Krox-20 appears to act ''upstream'' of Hox g enes, but the identity of the ''downstream'' effecters has not yet bee n identified. We report here the isolation of the zebrafish orthologue of the mouse RTK gene MDK1 which belongs to the Eph receptor subfamil y and show that the major expression domains of the mouse and the zebr afish genes have been conserved through evolution. Since the coinciden t spatial and temporal expression of Hoxa-2 and MDK1 in the mouse hind brain suggested a possible regulatory link between them, we analyzed t he expression of the MDK1 in Hoxa-2 null mutant embryos. A selective l ack of MDK1 expression in rhombomere 3 of Hoxa-2 mutant hindbrains tog ether with an overall altered expression pattern in the other rhombome res was observed, thus demonstrating that MDK1 lies downstream of Hoxa -2 in the morphogenetic signaling cascade. (C) 1996 Academic Press, In c.