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Biochim Biophys Acta
2009 May 01;17905:326-38. doi: 10.1016/j.bbagen.2009.01.012.
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Embryonic lethality of fortilin-null mutant mice by BMP-pathway overactivation.
Koide Y
,
Kiyota T
,
Tonganunt M
,
Pinkaew D
,
Liu Z
,
Kato Y
,
Hutadilok-Towatana N
,
Phongdara A
,
Fujise K
.
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BACKGROUND: Fortilin negatively regulates apoptosis and is overexpressed in cancer. However, the role of fortilin in mammalian development is not clear.
METHODS AND 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.
CONCLUSION: 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.
GENERAL SIGNIFICANCE: Abnormalities in the fortilin gene may be associated with early pregnancy loss.
Fig. 5.
Xenopus embryos exhibit robust fortilin expression in animal pole. (A) Stage 6 lateral view, (B) Stage 8 animal pole view; circle, the area of fortilin expression, (C) Stage 10 lateral view; an, animal pole; ve, vegetal pole. (D) Stage 10 sagittal section; an, animal pole; ve, vegetal pole. (E) Stage 12 dorsal view; a, anterior; p, posterior; arrowheads, the area of fortilin expression. (F) Stage 15 dorsal view; a, anterior; p, posterior; arrowheads, the area of fortilin expression.
Fig. 6.
Fortilin overexpression enhances, but fortilin deficiency retards, the head development in Xenopus. The overexpressions of Xenopus (xFortilin) and human (hFortilin) fortilin induced the partial secondary body axis indicated by arrows (B and C) but not the ectopic expressions of goosecoid (gsc) and Xnr3 indicated by arrow heads (G and H). Controls are shown in A. Fortilin RNA was injected into the ventral marginal zone of four-cell stage embryos, and the phenotype was observed at stage 35 or whole mount in situ hybridization was performed using stage 10 embryos. Fortilin MO inhibited the head formation (E) and this phenotype was rescued by co-injection with human fortilin (F). MO was injected into the ventral marginal zone of four-cell stage embryos and control MO was used as a negative control. Table showed the summary of injection experiments. Fortilin MO partially depleted endogenous Xenopus fortilin protein in stage 10 embryos (I). DAI, dorsoanterior index.
Fig. 7.
Fortilin is a BMP4 inhibitor in Xenopus development. In the animal cap assay, Xenopus fortilin (xFortilin) inhibited the expression of direct targets of BMP signaling, Vent1, Vent2 and Msx1 (A–C), and induced the expression of neural markers, NCAM and Sox2 (E, F). In addition, other markers, Xbra, goosecoid, Xnr3 and cardiac actin (D and G), were not induced by xFortilin. The gene expression was tested by quantitative real time RT-PCR at stage 10 (A–D) and stage 18 (E–G), and ODC (ornithine decarboxylase) expression was used to normalize the samples. Noggin was used as a positive control of a BMP inhibitor. The same experiments were performed three times, the means of which are depicted along with standard deviations (SDs).
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