Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Biochim Biophys Acta
2009 May 01;17905:326-38. doi: 10.1016/j.bbagen.2009.01.012.
Show Gene links
Show Anatomy links
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
.
???displayArticle.abstract???
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 (AâC), 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 (AâD) and stage 18 (EâG), 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).
Bachiller,
The organizer factors Chordin and Noggin are required for mouse forebrain development.
2000, Pubmed
Bachiller,
The organizer factors Chordin and Noggin are required for mouse forebrain development.
2000,
Pubmed
Cao,
The BMP signaling and in vivo bone formation.
2005,
Pubmed
Chambers,
Self-renewal of teratocarcinoma and embryonic stem cells.
2004,
Pubmed
Chen,
A knockout mouse approach reveals that TCTP functions as an essential factor for cell proliferation and survival in a tissue- or cell type-specific manner.
2007,
Pubmed
Chitpatima,
Nucleotide sequence of a major messenger RNA for a 21 kilodalton polypeptide that is under translational control in mouse tumor cells.
1988,
Pubmed
Cho,
Molecular nature of Spemann's organizer: the role of the Xenopus homeobox gene goosecoid.
1991,
Pubmed
,
Xenbase
Chomczynski,
Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction.
1987,
Pubmed
De Robertis,
Dorsal-ventral patterning and neural induction in Xenopus embryos.
2004,
Pubmed
,
Xenbase
Fainsod,
On the function of BMP-4 in patterning the marginal zone of the Xenopus embryo.
1994,
Pubmed
,
Xenbase
Ferrari,
Ectopic expression of Msx-2 in posterior limb bud mesoderm impairs limb morphogenesis while inducing BMP-4 expression, inhibiting cell proliferation, and promoting apoptosis.
1998,
Pubmed
Fujise,
Regulation of apoptosis and cell cycle progression by MCL1. Differential role of proliferating cell nuclear antigen.
2000,
Pubmed
Furuta,
Bone morphogenetic proteins (BMPs) as regulators of dorsal forebrain development.
1997,
Pubmed
Gibson,
A novel method for real time quantitative RT-PCR.
1996,
Pubmed
Gomes,
Msx-2 and p21 mediate the pro-apoptotic but not the anti-proliferative effects of BMP4 on cultured sympathetic neuroblasts.
2001,
Pubmed
Graham,
The signalling molecule BMP4 mediates apoptosis in the rhombencephalic neural crest.
1994,
Pubmed
Graidist,
Fortilin binds Ca2+ and blocks Ca2+-dependent apoptosis in vivo.
2007,
Pubmed
Graidist,
Antiapoptotic protein partners fortilin and MCL1 independently protect cells from 5-fluorouracil-induced cytotoxicity.
2004,
Pubmed
Gross,
cDNA sequence coding for a translationally controlled human tumor protein.
1989,
Pubmed
Harland,
In situ hybridization: an improved whole-mount method for Xenopus embryos.
1991,
Pubmed
,
Xenbase
Hawley,
Disruption of BMP signals in embryonic Xenopus ectoderm leads to direct neural induction.
1995,
Pubmed
,
Xenbase
Heid,
Real time quantitative PCR.
1996,
Pubmed
Hemmati-Brivanlou,
Ventral mesodermal patterning in Xenopus embryos: expression patterns and activities of BMP-2 and BMP-4.
1995,
Pubmed
,
Xenbase
Hsu,
Drosophila TCTP is essential for growth and proliferation through regulation of dRheb GTPase.
2007,
Pubmed
Jones,
Nodal-related signals induce axial mesoderm and dorsalize mesoderm during gastrulation.
1995,
Pubmed
,
Xenbase
Kao,
The entire mesodermal mantle behaves as Spemann's organizer in dorsoanterior enhanced Xenopus laevis embryos.
1988,
Pubmed
,
Xenbase
Kawasome,
Targeted disruption of p70(s6k) defines its role in protein synthesis and rapamycin sensitivity.
1998,
Pubmed
Kingsley,
The TGF-beta superfamily: new members, new receptors, and new genetic tests of function in different organisms.
1994,
Pubmed
Kozopas,
MCL1, a gene expressed in programmed myeloid cell differentiation, has sequence similarity to BCL2.
1993,
Pubmed
Lazebnik,
Cleavage of poly(ADP-ribose) polymerase by a proteinase with properties like ICE.
1994,
Pubmed
Lee,
Interaction between fortilin and transforming growth factor-beta stimulated clone-22 (TSC-22) prevents apoptosis via the destabilization of TSC-22.
2008,
Pubmed
Li,
Characterization of fortilin, a novel antiapoptotic protein.
2001,
Pubmed
Liu,
Stabilization and enhancement of the antiapoptotic activity of mcl-1 by TCTP.
2005,
Pubmed
Marazzi,
Msx2 is a transcriptional regulator in the BMP4-mediated programmed cell death pathway.
1997,
Pubmed
McKendry,
LEF-1/TCF proteins mediate wnt-inducible transcription from the Xenopus nodal-related 3 promoter.
1997,
Pubmed
,
Xenbase
McMahon,
Noggin-mediated antagonism of BMP signaling is required for growth and patterning of the neural tube and somite.
1998,
Pubmed
McMahon,
Ectopic expression of the proto-oncogene int-1 in Xenopus embryos leads to duplication of the embryonic axis.
1989,
Pubmed
,
Xenbase
Panchision,
Sequential actions of BMP receptors control neural precursor cell production and fate.
2001,
Pubmed
Piccolo,
Dorsoventral patterning in Xenopus: inhibition of ventral signals by direct binding of chordin to BMP-4.
1996,
Pubmed
,
Xenbase
Reynolds,
BCL-2 and MCL-1 expression in Chinese hamster ovary cells inhibits intracellular acidification and apoptosis induced by staurosporine.
1996,
Pubmed
Reynolds,
Mcl-1, a member of the Bcl-2 family, delays apoptosis induced by c-Myc overexpression in Chinese hamster ovary cells.
1994,
Pubmed
Sasai,
Xenopus chordin: a novel dorsalizing factor activated by organizer-specific homeobox genes.
1994,
Pubmed
,
Xenbase
Smith,
Expression cloning of noggin, a new dorsalizing factor localized to the Spemann organizer in Xenopus embryos.
1992,
Pubmed
,
Xenbase
Smith,
A nodal-related gene defines a physical and functional domain within the Spemann organizer.
1995,
Pubmed
,
Xenbase
Stocker,
Rheb is an essential regulator of S6K in controlling cell growth in Drosophila.
2003,
Pubmed
Tewari,
Yama/CPP32 beta, a mammalian homolog of CED-3, is a CrmA-inhibitable protease that cleaves the death substrate poly(ADP-ribose) polymerase.
1995,
Pubmed
Tuynder,
Biological models and genes of tumor reversion: cellular reprogramming through tpt1/TCTP and SIAH-1.
2002,
Pubmed
Watabe,
Molecular mechanisms of Spemann's organizer formation: conserved growth factor synergy between Xenopus and mouse.
1995,
Pubmed
,
Xenbase
Wilson,
Induction of epidermis and inhibition of neural fate by Bmp-4.
1995,
Pubmed
,
Xenbase
Winnier,
Bone morphogenetic protein-4 is required for mesoderm formation and patterning in the mouse.
1995,
Pubmed
Ying,
BMP induction of Id proteins suppresses differentiation and sustains embryonic stem cell self-renewal in collaboration with STAT3.
2003,
Pubmed
Zhang,
Physical and functional interaction between myeloid cell leukemia 1 protein (MCL1) and Fortilin. The potential role of MCL1 as a fortilin chaperone.
2002,
Pubmed
Zimmerman,
The Spemann organizer signal noggin binds and inactivates bone morphogenetic protein 4.
1996,
Pubmed
,
Xenbase
