Targeted disruption of the DM domain containing transcription factor Dmrt2 reveals an essential role in somite patterning.
Dmrt2 is expressed in the dermomyotome of developing vertebrate somites. To determine the role of Dmrt2 during mouse embryonic development, we generated a null mutation of Dmrt2 via homologous recombination in embryonic stem cells. Dmrt2 heterozygous mice derived from these cells are phenotypically normal. However, Dmrt2 homozygotes die soon after birth. The cause of death is likely due to abnormal rib and sternal development, leading to an inability to breathe. Loss of Dmrt2 leads to embryonic somite patterning defects, first evidenced at embryonic day (E) 10.5 and more pronounced by E11.5. Notably, both the dermomyotome and myotome fail to adopt a normal epithelial morphology in the absence of Dmrt2. Accompanying these morphological defects are alterations in the expression patterns of dermomyotomal and myotomal transcription factors including Pax3, Paraxis, Myf5, myogenin, Mrf4 and MyoD. Despite these defects, embryos harvested from E13.5 onwards exhibited relatively normal muscle pattern and mass, suggesting that early myotomal defects are corrected by a Dmrt2-independent mechanism. Taken together, our results define an essential function for Dmrt2 in somite development and provide evidence that DM domain genes have been co-opted into other critical developmental pathways distinct from that of sex determination or differentiation.
Seo
Kwang Won
KW
Department of Biochemistry and Molecular Biology, University of Texas, MD Anderson Cancer Center, Houston, 77030, USA.
Wang
Yingdi
Y
Kokubo
Hiroki
H
Kettlewell
Jae R
JR
Zarkower
David A
DA
Johnson
Randy L
RL
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D019521:Body Patterning; D001842:Bone and Bones / Q000002:abnormalities; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020964:Embryo Loss; D047108:Embryonic Development; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006066:Gonads / Q000196:embryology / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D017570:MyoD Protein / Q000378:metabolism; D051787:Myogenic Regulatory Factor 5 / Q000378:metabolism; D018006:Myogenic Regulatory Factors / Q000378:metabolism; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors / Q000378:metabolism; D017434:Protein Structure, Tertiary; D012733:Sex Differentiation; D019170:Somites / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D017570:MyoD Protein; D051787:Myogenic Regulatory Factor 5; D018006:Myogenic Regulatory Factors; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors; D014157:Transcription Factors; C486538:Dmrt2 protein, mouse; C497418:Myf5 protein, mouse; C057363:MyoD1 myogenic differentiation protein; C093234:Tcf15 protein, mouse; C063403:myogenic factor 6; C068686:Pax3 protein, mouse