HOX GROUP-3 PARALOGOUS GENES ACT SYNERGISTICALLY IN THE FORMATION OF SOMITIC AND NEURAL CREST-DERIVED STRUCTURES

Hox genes encode transcription factors that are used to regionalize th e mammalian embryo. Analysis of mice carrying targeted mutations in in dividual and multiple Hox genes is beginning to reveal a complex netwo rk of interactions among these closely related genes which is responsi ble for directing the formation of spatially restricted tissues and st ructures. In this report we present an analysis of the genetic interac tions between all members of the third paralogous group, Hoxa3, Hoxb3, and Hoxd3. Previous analysis has shown that although mice homozygous for loss-of-function mutations in either Hoxa3 or Hoxd3 have no defect s in common, mice mutant for both genes demonstrate that these two gen es strongly interact in a dosage-dependent manner. To complete the ana lysis of this paralogous gene family, mice with a targeted disruption of the Hoxb3 gene were generated. Homozygous mutants have minor defect s at low penetrance in the formation of both the cervical vertebrae an d the IXth cranial nerve. Analysis and comparison of all double-mutant combinations demonstrate that all three members of this paralogous gr oup interact synergistically to affect the development of both neurona l and mesenchymal neural crest-derived structures, as well as semitic mesoderm-derived structures. Surprisingly, with respect to the formati on of the cervical vertebrae, mice doubly mutant for Hoxa3 and Hoxd3 o r Hoxb3 and Hoxd3 show an indistinguishable defect, loss of the entire atlas. This suggests that the identity of the specific Hox genes that are functional in a given region may not be as critical as the total number of Hox genes operating in that region. (C) 1997 Academic Press.