Inactivation of Palb2 gene leads to mesoderm differentiation defect and early embryonic lethality in mice.
Mutations of the PALB2 tumor suppressor gene in humans are associated with hereditary predisposition to breast and also some other cancers. In the present study, we have characterized mice deficient in Palb2. The data show that the Palb2((+/-)) mice are normal and fertile, and lack macroscopic tumors when followed up till the age of 8 months. Homozygous (HO) Palb2((-/-)) mice present with embryonic lethality and die at E9.5 at the latest. The mutant embryos are smaller in size, developmentally retarded and display defective mesoderm differentiation after gastrulation. In Palb2((-/-)) embryos, the expression of cyclin-dependent kinase inhibitor p21 is increased, and Palb2((-/-)) blastocysts show a growth defect in vitro. Hence, the phenotype of the Palb2((-/-)) mice in many regards resembles those previously reported for Brca1 and Brca2 knockout mice. The similarity in the phenotypes between Palb2, Brca1 and Brca2 knockout mice further supports the functional relationship shown in vitro for these three proteins. Accordingly, our data in vivo suggest that a key function for PALB2 is to interact with and to build up appropriate communication between BRCA1 and BRCA2, thereby licensing the successful performance of the physiological tasks mediated by these two proteins, particularly in homologous recombination and in proper DNA damage response signaling.
Rantakari
Pia
P
Department of Physiology, Turku Center for Disease Modeling, Institute of Biomedicine, University of Turku, FIN-20520 Turku, Finland.
Nikkilä
Jenni
J
Jokela
Heli
H
Ola
Roxana
R
Pylkäs
Katri
K
Lagerbohm
Heidi
H
Sainio
Kirsi
K
Poutanen
Matti
M
Winqvist
Robert
R
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001755:Blastocyst / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D020964:Embryo Loss / Q000235:genetics* / Q000473:pathology; D004622:Embryo, Mammalian / Q000378:metabolism / Q000473:pathology; D047108:Embryonic Development; D000076164:Fanconi Anemia Complementation Group N Protein; D018507:Gene Expression Regulation, Developmental; D020868:Gene Silencing; D006579:Heterozygote; D008648:Mesoderm / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D009154:Mutation / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism
D015415:Biomarkers; D050759:Cyclin-Dependent Kinase Inhibitor p21; D000076164:Fanconi Anemia Complementation Group N Protein; C552932:Palb2 protein, mouse; D025521:Tumor Suppressor Proteins