Posterior transformation, neurological abnormalities, and severe hematopoietic defects in mice with a targeted deletion of the bmi-1 proto-oncogene.
The bmi-1 proto-oncogene has been implicated in B-cell lymphomagenesis in E mu-myc transgenic mice. Distinct domains of the Bmi-1 protein are highly conserved within the Drosophila protein Posterior Sex Combs, a member of the Polycomb group involved in maintaining stable repression of homeotic genes during development. We have inactivated the bmi-1 gene in the germ line of mice by homologous recombination in ES cells. Null mutant mice display three phenotypic alterations: (1) a progressive decrease in the number of hematopoietic cells and an impaired proliferative response of these cells to mitogens; (2) neurological abnormalities manifested by an ataxic gait and sporadic seizures; and (3) posterior transformation, in most cases along the complete anteroposterior axis of the skeleton. The observations indicate that Mbi-1 plays an important role in morphogenesis during embryonic development and in hematopoiesis throughout pre- and postnatal life. Furthermore, these data provide the first evidence of functional conservation of a mammalian Polycomb group homolog.
van der Lugt
N M
NM
Department of Molecular Genetics, The Netherlands Cancer Institute, Amsterdam.
Domen
J
J
Linders
K
K
van Roon
M
M
Robanus-Maandag
E
E
te Riele
H
H
van der Valk
M
M
Deschamps
J
J
Sofroniew
M
M
van Lohuizen
M
M
D000818:Animals; D001259:Ataxia / Q000235:genetics; D001854:Bone Marrow Cells; D001921:Brain / Q000002:abnormalities*; D005314:Embryonic and Fetal Development; D005260:Female; D018507:Gene Expression Regulation, Developmental; D018390:Gene Targeting; D018095:Germ-Line Mutation / Q000502:physiology; D006413:Hematopoietic System / Q000002:abnormalities* / Q000166:cytology; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008934:Mitogens / Q000494:pharmacology; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D063150:Polycomb Repressive Complex 1; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D011519:Proto-Oncogenes; D011995:Recombination, Genetic; D012097:Repressor Proteins; D012272:Ribs / Q000002:abnormalities; D012640:Seizures / Q000235:genetics; D013131:Spine / Q000002:abnormalities*; D013154:Spleen / Q000166:cytology; D013950:Thymus Gland / Q000166:cytology
C489421:Bmi1 protein, mouse; D008934:Mitogens; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D063150:Polycomb Repressive Complex 1