Ovca1, a candidate gene of the genetic modifier of Tp53, Mop2, affects mouse embryonic lethality.
In this study, we show genetic modifier genes of Tp53 that can exacerbate embryonic abnormalities. Using a mouse model in which CE/J mice were crossed with the Tp53-null 129/Sv (129-Trp53(tm1 Tyj)) mice, a subset of Tp53+/- and -/- male and female embryos died during gestation. Our hypothesis, based on the genotypes of survivors, is that two genetic modifiers and a Tp53 null allele lead to an increase in embryonic lethality. We previously identified a recessive modifier (Mop1) from CE/J mice on chromosome 11 centromeric to Tp53. We have uncovered a dominant modifier (Mop2) from 129/Sv mice telomeric to Tp53. We discovered a polymorphic change (321P-->321S) of Ovca1 within the Mop2 locus of CE/J mice. This polymorphism increased both mRNA and protein levels of OVCA1 in various tissues. CE/J primary cells cultured from different tissues proliferated more rapidly than 129/Sv cells. In addition, CE/J cells cycled while 129/Sv cells had a higher arrest in the G1 phase. Transfection of Ovca1 containing the 321P polymorphism into CE/J cells caused a higher G1 arrest. The pattern of OVCA1 expression also changed from being diffuse throughout the cytoplasm in 129/Sv cells to being punctuate in the cytoplasm of CE/J cells. Tp53+/- abnormal embryos had more proliferating cells than normal embryos, but no obvious difference in differentiated neuronal cells. Tp53-/- small embryos had less differentiated neuronal cells and proliferating cells than normal embryos. Thus, a polymorphism of Ovca1, combined with Mop1, genetically modifies embryonic lethality in Tp53 deficient mice.
Liang
Min
M
Department of Chemistry and Biochemistry, Ohio University, Athens, OH 45701, USA.
Ayanga
Bernard
B
Du
Shuhua
S
Godwin
Andrew K
AK
Hartsock
Jennifer K
JK
Evans
Susan C
SC
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D015153:Blotting, Western; D002453:Cell Cycle; D049109:Cell Proliferation; D002874:Chromosome Mapping; D005260:Female; D005455:Fluorescent Antibody Technique; D005804:Genes, Lethal; D005819:Genetic Markers; D005838:Genotype; D016864:Li-Fraumeni Syndrome / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D015778:Minor Histocompatibility Antigens; D016297:Mutagenesis, Site-Directed; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D005819:Genetic Markers; D015778:Minor Histocompatibility Antigens; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D000099162:Endothelial PAS Domain-Containing Protein 1; C121987:DPH1 protein, human