Ectopic Hoxa-1 induces rhombomere transformation in mouse hindbrain.
Homeobox genes are expressed with a specific spatial and temporal order, which is essential for pattern formation during the early development of both invertebrates and vertebrates. Here we show that widespread ectopic expression of the Hoxa-1 (Hox 1.6) gene directed by a human beta-actin promoter in transgenic mice is embryolethal and produces abnormal phenotypes in a subset of domains primarily located in anterior regions. Interestingly, this abnormal development in the Hoxa-1 transgenic mice is associated with ectopic expression of the Hoxb-1 (Hox 2.9) gene in select hindbrain regions. At gestation day 9.5, two domains of strong Hoxb-1 expression are found in the anterior region of the hindbrains of Hoxa-1 transgenic embryos. One region represents the normal pattern of Hoxb-1 expression in rhombomere 4 and its associated migrating neural crest cells, while another major domain of Hoxb-1 expression consistently appears in rhombomere 2. Similar ectopic domains of beta-galactosidase activity are detected in dual transgenic embryos containing both beta-actin/Hoxa-1 transgene and a Hoxb-1/lacZ reporter construct. Expression of another lacZ reporter gene that directs beta-galactosidase activity predominantly in rhombomere 2 is suppressed in the Hoxa-1 transgenic embryos. We have also detected weaker and variable ectopic Hoxb-1 expression in rhombomeres 1, 3 and 6. No ectopic Hoxb-1 expression is detected in rhombomere 5 and the expression of Hoxa-3 and Krox-20 in this region is unchanged in the Hoxa-1 transgenic embryos. While no obvious change in the morphology of the trigeminal or facial-acoustic ganglia is evident, phenotypic changes do occur in neurons that emanate from rhombomeres 2 and 3 in the Hoxa-1 transgenic embryos. Additionally, alterations in the pattern of Hoxa-2 and Hoxb-1 expression in a subpopulation of neural crest cells migrating from the rhombomere 2 region are detected in these transgenics. Taken together, these data suggest that ectopic Hoxa-1 expression can reorganize select regions of the developing hindbrain by inducing partial transformations of several rhombomeres into a rhombomere-4-like identity.
Department of Toxicology and Pathology, Roche Research Center, Hoffmann-La Roche, Nutley, New Jersey 07110.
M
M
Zhang
H J
HJ
Kim
H
H
Marshall
M
M
Gendron-Maguire
D A
DA
Lucas
A
A
Baron
L J
LJ
Gudas
T
T
Gridley
R
R
Krumlauf
J F
JF
Grippo
D000199:Actins / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D005786:Gene Expression Regulation; D005801:Genes, Homeobox; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009024:Morphogenesis / Q000235:genetics; D009420:Nervous System / Q000196:embryology; D009432:Neural Crest / Q000166:cytology; D011401:Promoter Regions, Genetic; D012249:Rhombencephalon / Q000196:embryology*; D014170:Transformation, Genetic
D000199:Actins