The absence of Prep1 causes p53-dependent apoptosis of mouse pluripotent epiblast cells.
Disruption of mouse Prep1, which codes for a homeodomain transcription factor, leads to embryonic lethality during post-implantation stages. Prep1(-/-) embryos stop developing after implantation and before anterior visceral endoderm (AVE) formation. In Prep1(-/-) embryos at E6.5 (onset of gastrulation), the AVE is absent and the proliferating extra-embryonic ectoderm and epiblast, marked by Bmp4 and Oct4, respectively, are reduced in size. At E.7.5, Prep1(-/-) embryos are small and very delayed, showing no evidence of primitive streak or of differentiated embryonic lineages. Bmp4 is expressed residually, while the reduced number of Oct4-positive cells is constant up to E8.5. At E6.5, Prep1(-/-) embryos retain a normal mitotic index but show a major increase in cleaved caspase 3 and TUNEL staining, indicating apoptosis. Therefore, the mouse embryo requires Prep1 when undergoing maximal expansion in cell number. Indeed, the phenotype is partially rescued in a p53(-/-), but not in a p16(-/-), background. Apoptosis is probably due to DNA damage as Atm downregulation exacerbates the phenotype. Despite this early lethal phenotype, Prep1 is not essential for ES cell establishment. A differential embryonic expression pattern underscores the unique function of Prep1 within the Meis-Prep family.
Fernandez-Diaz
Luis C
LC
IFOM, FIRC Institute of Molecular Oncology Foundation, IFOM-IEO Campus, via Adamello 16, Milan, Italy.
Laurent
Audrey
A
Girasoli
Sara
S
Turco
Margherita
M
Longobardi
Elena
E
Iotti
Giorgio
G
Jenkins
Nancy A
NA
Fiorenza
Maria Teresa
MT
Copeland
Neal G
NG
Blasi
Francesco
F
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015139:Blotting, Southern; D017931:DNA Primers / Q000235:genetics; D024202:Electrophoretic Mobility Shift Assay; D047108:Embryonic Development / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D005838:Genotype; D005855:Germ Layers / Q000166:cytology*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D020287:In Situ Nick-End Labeling; D051379:Mice; D018345:Mice, Knockout; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D017931:DNA Primers; D018398:Homeodomain Proteins; C491412:Pknox1 protein, mouse; D016159:Tumor Suppressor Protein p53