Development of the vertebrate hindbrain involves specification of the neural epithelium into lineage-restricted compartments known as rhombomeres. The identity of each rhombomere is controlled, at least in part, by Hox genes which encode positional values along the anterior- posterior axis. Recent studies identified a family of receptor tyrosine kinases (Eph RTK) with restricted segmental expression during rhombomere formation. In addition, these Eph receptors mediate repulsive cell-cell interaction in axonal guidance, and a dominant-negative form of Eph receptor sek-1 disrupts the establishment of sharp rhombomere boundary in zebrafish and Xenopus. These data suggest that Eph receptor tyrosine kinases play an important role in hindbrain patterning. Our hypotheses are: 1) Eph receptor tyrosine kinases participate in establishment of segmental identity and/or rhombomere boundaries, and 2) they are regulated by Hox genes. To test these hypotheses, we will: (1) determine whether secreted Eph-Fc proteins can block rhombomere cell sorting in vitro and hindbrain patterning in embryo culture; (2) overexpress inhibitors of Eph RTKs in transgenic mice and characterize their phenotypes; and (3) investigate whether and how Hox genes are involved in regulating Eck expression in rhombomere 4.Understanding of normal mammalian hindbrain developmental processes will contribute to the better understanding of the mechanism of the central nervous system and craniofacial defects in humans.
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