GENETIC INTERACTIONS BETWEEN HOXA1 AND HOXB1 REVEAL NEW ROLES IN REGULATION OF EARLY HINDBRAIN PATTERNING

In the developing vertebrate hindbrain Hoxa1 and Hoxb1 play important roles in patterning segmental units (rhombomeres). In this study, gene tic analysis of double mutants demonstrates that both Hoxa1 and Hoxb1 participate in the establishment and maintenance of Hoxb1 expression i n rhombomere 4 through auto- and pararegulatory interactions. The gene ration of a targeted mutation in a Hoxb1 3' retinoic acid response ele ment (RARE) shows that it is required for establishing early high leve ls of Hoxb1 expression in neural ectoderm. Double mutant analysis with this Hoxb1(3'RARE) allele and other targeted loss-of-function alleles from both Hoxa1 and Hoxb1 reveals synergy between these genes. In the absence of both genes, a territory appears in the region of r4, but t he earliest r4 marker, the Eph tyrosine kinase receptor EphA2, fails t o be activated. This suggests a failure to initiate rather than mainta in the specification of r4 identity and defines new roles for both Hox b1 and Hoxa1 in early patterning events in r4. Our genetic analysis sh ows that individual members of the vertebrate labial-related genes hav e multiple roles in different steps governing segmental processes in t he developing hindbrain.