The Mdm2 gene of zebrafish (Danio rerio): preferential expression during development of neural and muscular tissues, and absence of tumor formation after overexpression of its cDNA during early embryogenesis.
The Mdm2 protein is most probably the main negative cellular regulator of the p53 tumor-suppressor protein. It was found to be overexpressed in a great number of human tumors and is considered as a potential target for anti-tumor therapies. Mdm2 is an essential gene in mice, yet its role in normal development and tissue differentiation is unknown. In order to study the role of this important protein in an evolutionary perspective, we cloned an Mdm2 cDNA from the fish Danio rerio and analyzed its expression pattern as well as the phenotypic consequences of its overexpression. The main functional domains as well as the interaction between Mdm2 and p53 are conserved in zebrafish. Moreover, we show here that the gene is expressed specifically during early development in neural and muscular tissues. Surprisingly, microinjection of Mdm2 mRNA in two-cell-stage embryos led to inhibition of cellular convergence during gastrulation. The clones derived from Mdm2 microinjected blastomeres were significantly smaller than those derived from control microinjections, and, in contrast to what was observed in Xenopus, did not develop tumors. Our results suggest that Mdm2 expression may be important during the differentiation of neural and muscular tissues of zebrafish. They also point to important differences between phyla in the susceptibility to tumor formation.
Thisse
C
C
Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, Illkirch, France.
Neel
H
H
Thisse
B
B
Daujat
S
S
Piette
J
J
D000595:Amino Acid Sequence; D000818:Animals; D001757:Blastomeres / Q000502:physiology; D002454:Cell Differentiation; D003001:Cloning, Molecular; D018076:DNA, Complementary; D005775:Gastrula / Q000502:physiology; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009024:Morphogenesis; D009132:Muscles / Q000196:embryology*; D009420:Nervous System / Q000196:embryology*; D009687:Nuclear Proteins / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000235:genetics*; D051736:Proto-Oncogene Proteins c-mdm2; D012333:RNA, Messenger / Q000235:genetics; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D029867:Xenopus Proteins; D014982:Xenopus laevis; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics; D029961:Zebrafish Proteins
D018076:DNA, Complementary; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D029867:Xenopus Proteins; D029961:Zebrafish Proteins; C497210:MDM2 protein, Xenopus; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; C497209:mdm2 protein, zebrafish