Loss of the Max-interacting protein Mnt in mice results in decreased viability, defective embryonic growth and craniofacial defects: relevance to Miller-Dieker syndrome.
The Mnt gene encodes a Mad-family bHLH transcription factor located on human 17p13.3. Mnt is one of 20 genes deleted in a heterozygous fashion in Miller-Dieker syndrome (MDS), a contiguous gene syndrome that consists of severe neuronal migration defects and craniofacial dysmorphic features. Mnt can inhibit Myc-dependent cell transformation and is hypothesized to counterbalance the effects of c-Myc on growth and proliferation in vivo by competing with Myc for binding to Max and by repressing target genes activated by Myc : Max heterodimers. Unlike the related Mad family members, Mnt is expressed ubiquitously and Mnt/Max heterodimers are found in proliferating cells that contain Myc/Max heterodimers, suggesting a unique role for Mnt during proliferation. To examine the role of Mnt in vivo, we produced mice with null (Mnt(KO)) and loxP-flanked conditional knock-out (Mnt(CKO)) alleles of Mnt. Virtually all Mnt(KO/KO) mutants in a mixed (129S6 x NIH Black Swiss) or inbred (129S6) genetic background died perinatally. Mnt-deficient embryos exhibited small size throughout development and showed reduced levels of c-Myc and N-Myc. In addition, 37% of the mixed background mutants displayed cleft palate as well as retardation of skull development, a phenotype not observed in the inbred mutants. These results demonstrate an important role for Mnt in embryonic development and survival, and suggest that Mnt may play a role in the craniofacial defects displayed by MDS patients.
Toyo-oka
Kazuhito
K
Department of Pediatrics, UCSD Cancer Center, University of California, San Diego School of Medicine, La Jolla 92093-0627, USA.
Hirotsune
Shinji
S
Gambello
Michael J
MJ
Zhou
Zi-Qiang
ZQ
Olson
Lorin
L
Rosenfeld
Michael G
MG
Eisenman
Robert
R
Hurlin
Peter
P
Wynshaw-Boris
Anthony
A
D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D050976:Basic-Leucine Zipper Transcription Factors; D002972:Cleft Palate / Q000196:embryology / Q000235:genetics; D019465:Craniofacial Abnormalities / Q000196:embryology / Q000209:etiology* / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D047108:Embryonic Development; D005317:Fetal Growth Retardation / Q000209:etiology* / Q000235:genetics; D005804:Genes, Lethal; D008334:Mandible / Q000002:abnormalities / Q000196:embryology; D051379:Mice; D018345:Mice, Knockout; D009777:Occipital Bone / Q000002:abnormalities / Q000196:embryology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D013577:Syndrome; D014157:Transcription Factors / Q000378:metabolism
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D050976:Basic-Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; C484561:Mnt protein, mouse; C067850:Myc associated factor X; D016271:Proto-Oncogene Proteins c-myc; D012097:Repressor Proteins; D014157:Transcription Factors; C068422:Max protein, mouse