Embryonic lethality of fortilin-null mutant mice by BMP-pathway overactivation.
BACKGROUND
Fortilin negatively regulates apoptosis and is overexpressed in cancer. However, the role of fortilin in mammalian development is not clear.


RESULTS
In order to evaluate the physiological role of fortilin in vivo, we performed a targeted disruption of the fortilin gene in mice. Fortilin(+/-) mice have the ability to survive and exhibit normal growth, while fortilin(-/-) mice are embryonically lethal around the 3.5 days post-coital (dpc). Cultured blastocysts from fortilin(+/-) embryos undergo normal outgrowth to produce inner cell mass (ICM) and trophoblasts (TB), while ICM of fortilin(-/-) embryos either fails to outgrow or prematurely disintegrates. Mouse embryonic fibroblasts (MEF) derived from fortilin(+/-) embryos are more susceptible to noxious stimuli than are wild type embryos. It has been consistently shown in Xenopus embryos that the depletion of fortilin's message severely compromises the formation of neural tissue, even in the brain, while overexpression of fortilin induces the partial double body axis in embryos and is capable of blocking BMP4-induced transcription of Vent1, Vent2, and Msx1 genes. This suggests that fortilin is an inhibitor of the BMP pathway. Strikingly, when fortilin levels are reduced by siRNA, BMP4 causes MEF to undergo extensive DNA-fragmentation, while DNA fragmentation is minimal in the presence of fortilin. In addition, BMP4 induces more Msx2 in the absence of fortilin than in its presence. Furthermore, Msx2 overexpression causes MEF to undergo apoptotic cell death.


CONCLUSIONS
We conclude that in early phase of development, fortilin functions as an inhibitor of the BMP pathway. The presence of fortilin in the very early stages of development is required for the survival of embryos.


CONCLUSIONS
Abnormalities in the fortilin gene may be associated with early pregnancy loss.
Research Center for Cardiovascular Diseases, Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, Houston, TX 77030, USA.
Yuichi
Y
Koide
Tomomi
T
Kiyota
Moltira
M
Tonganunt
Decha
D
Pinkaew
Zhihe
Z
Liu
Yoichi
Y
Kato
Nongporn
N
Hutadilok-Towatana
Amornrat
A
Phongdara
Ken
K
Fujise
D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D001755:Blastocyst / Q000166:cytology / Q000378:metabolism; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D003433:Crosses, Genetic; D020964:Embryo Loss / Q000378:metabolism* / Q000473:pathology; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D005298:Fertility; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006262:Health; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D015398:Signal Transduction; D016019:Survival Analysis; D000090324:Tumor Protein, Translationally-Controlled 1; D014981:Xenopus / Q000196:embryology; D001616:beta-Galactosidase / Q000378:metabolism
D014408:Biomarkers, Tumor; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D000090324:Tumor Protein, Translationally-Controlled 1; D001616:beta-Galactosidase