Roles of Hoxa1 and Hoxa2 in patterning the early hindbrain of the mouse.
Early in its development, the vertebrate hindbrain is transiently subdivided into a series of compartments called rhombomeres. Genes have been identified whose expression patterns distinguish these cellular compartments. Two of these genes, Hoxa1 and Hoxa2, have been shown to be required for proper patterning of the early mouse hindbrain and the associated neural crest. To determine the extent to which these two genes function together to pattern the hindbrain, we generated mice simultaneously mutant at both loci. The hindbrain patterning defects were analyzed in embryos individually mutant for Hoxa1 and Hoxa2 in greater detail and extended to embryos mutant for both genes. From these data a model is proposed to describe how Hoxa1, Hoxa2, Hoxb1, Krox20 (Egr2) and kreisler function together to pattern the early mouse hindbrain. Critical to the model is the demonstration that Hoxa1 activity is required to set the anterior limit of Hoxb1 expression at the presumptive r3/4 rhombomere boundary. Failure to express Hoxb1 to this boundary in Hoxa1 mutant embryos initiates a cascade of gene misexpressions that result in misspecification of the hindbrain compartments from r2 through r5. Subsequent to misspecification of the hindbrain compartments, ectopic induction of apoptosis appears to be used to regulate the aberrant size of the misspecified rhombomeres.
Barrow
J R
JR
Howard Hughes Medical Institute, Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
Stadler
H S
HS
Capecchi
M R
MR
D000818:Animals; D017209:Apoptosis; D019521:Body Patterning / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics; D051767:Early Growth Response Protein 2; D005314:Embryonic and Fetal Development; D005326:Fetal Proteins / Q000235:genetics; D038681:Follistatin; D018507:Gene Expression Regulation, Developmental; D006023:Glycoproteins / Q000235:genetics; D049452:Green Fluorescent Proteins; D006133:Growth Substances / Q000235:genetics; D018398:Homeodomain Proteins / Q000032:analysis / Q000235:genetics* / Q000502:physiology; D008164:Luminescent Proteins / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020890:Neuregulin-1 / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D036122:Receptor, EphA4; D012249:Rhombencephalon / Q000196:embryology*; D014157:Transcription Factors / Q000032:analysis / Q000235:genetics* / Q000502:physiology; D000099261:Homeobox A1 Protein
D004268:DNA-Binding Proteins; D051767:Early Growth Response Protein 2; D005326:Fetal Proteins; D038681:Follistatin; D006023:Glycoproteins; D049452:Green Fluorescent Proteins; D006133:Growth Substances; D018398:Homeodomain Proteins; D008164:Luminescent Proteins; D020890:Neuregulin-1; D020794:Receptor Protein-Tyrosine Kinases; D036122:Receptor, EphA4; D014157:Transcription Factors; D000099261:Homeobox A1 Protein; C497327:Egr2 protein, mouse; C101121:HOXB1 homeodomain protein; C489833:Hoxa2 protein, mouse; C080331:Hoxa3 protein, mouse