Mice mutant for both Hoxa1 and Hoxb1 show extensive remodeling of the hindbrain and defects in craniofacial development.
The analysis of mice mutant for both Hoxa1 and Hoxb1 suggests that these two genes function together to pattern the hindbrain. Separately, mutations in Hoxa1 and Hoxb1 have profoundly different effects on hindbrain development. Hoxa1 mutations disrupt the rhombomeric organization of the hindbrain, whereas Hoxb1 mutations do not alter the rhombomeric pattern, but instead influence the fate of cells originating in rhombomere 4. We suggest that these differences are not the consequences of different functional roles for these gene products, but rather reflect differences in the kinetics of Hoxa1 and Hoxb1 gene expression. In strong support of the idea that Hoxa1 and Hoxb1 have overlapping functions, Hoxa1/Hoxb1 double mutant homozygotes exhibit a plethora of defects either not seen, or seen only in a very mild form, in mice mutant for only Hoxa1 or Hoxb1. Examples include: the loss of both rhombomeres 4 and 5, the selective loss of the 2(nd) branchial arch, and the loss of most, but not all, 2(nd) branchial arch-derived tissues. We suggest that the early role for both of these genes in hindbrain development is specification of rhombomere identities and that the aberrant development of the hindbrain in Hoxa1/Hoxb1 double mutants proceeds through two phases, the misspecification of rhombomeres within the hindbrain, followed subsequently by size regulation of the misspecified hindbrain through induction of apoptosis.
Rossel
M
M
Howard Hughes Medical Institute, Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah 84112, USA.
Capecchi
M R
MR
D000818:Animals; D017209:Apoptosis; D030161:Avian Proteins; D001934:Branchial Region / Q000002:abnormalities / Q000196:embryology; D019465:Craniofacial Abnormalities / Q000235:genetics* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D051767:Early Growth Response Protein 2; D005314:Embryonic and Fetal Development; D005326:Fetal Proteins / Q000096:biosynthesis; D005838:Genotype; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics*; D051258:MafB Transcription Factor; D051379:Mice; D008817:Mice, Mutant Strains; D009046:Motor Neurons / Q000502:physiology; D009154:Mutation; D015513:Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis; D036122:Receptor, EphA4; D018168:Receptors, Retinoic Acid / Q000096:biosynthesis; D012249:Rhombencephalon / Q000002:abnormalities / Q000196:embryology* / Q000473:pathology; D050656:Transcription Factor AP-2; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D000099261:Homeobox A1 Protein
D030161:Avian Proteins; D004268:DNA-Binding Proteins; D051767:Early Growth Response Protein 2; D005326:Fetal Proteins; D018398:Homeodomain Proteins; D051258:MafB Transcription Factor; D015513:Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D036122:Receptor, EphA4; D018168:Receptors, Retinoic Acid; D050656:Transcription Factor AP-2; D014157:Transcription Factors; D000099261:Homeobox A1 Protein; C497327:Egr2 protein, mouse; C101121:HOXB1 homeodomain protein; C490111:Hoxb2 protein, mouse; C490406:Mafb protein, mouse; C082927:retinoic acid binding protein I, cellular