Embryonic lethality of fortilin-null mutant mice by BMP-pathway overactivation

Abstract

Background Fortilin negatively regulates apoptosis and is overexpressed in cancer. However, the role of fortilin in mammalian development is not clear. Methods & 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-coitum (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, including 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.

The Translational Controlled Tumour Protein TCTP: Biological Functions and Regulation

“…Since then, the anti-apoptotic activity of TCTP has been reported on numerous occasions and in a range of different settings, which will be discussed below. Major support for the cytoprotective role of TCTP came from gene-knockout studies in mice, which demonstrated that TCTP-knockout was embryonic lethal, due to excessive apoptosis at an early embryonic state (Susini et al 2008;Chen et al 2007a;Koide et al 2009). The following mechanisms have been proposed to underlie the anti-apoptotic activity of TCTP/fortilin: …”

“…The most impressive evidence for the importance of TCTP in early development was provided by TPT1-gene-knockouts in mice, which resulted in embryonic lethality (Susini et al 2008;Chen et al 2007a;Koide et al 2009). The explanation typically given for this effect was 'excessive apoptosis at an early embryonic state' (Susini et al 2008;Chen et al 2007a), whereas another report reasons that the lack of TCTP results in an overactivity of the BMP4 (bone morphogenetic protein 4) pathway, which is normally inhibited by TCTP (Koide et al 2009). The authors of this paper also show that in Xenopus embryos TCTP/fortilin is particularly important for the formation of neural tissue, even in the brain.…”

Growth-factor dependent expression of the translationally controlled tumour protein TCTP is regulated through the PI3-K/Akt/mTORC1 signalling pathway

“…This is underscored by the finding that gene knockout of TCTP in mice is embryonically lethal, due to excessive apoptosis early in embryogenesis [5][6][7]. TCTP has been found to bind to microtubules [8] and actin filaments [9], and to a range of other proteins [10].…”

Cellular Function and Regulation of the Translationally Controlled Tumour Protein TCTP

“…Complete gene knockout of TCTP in Drosophila [28] and in mice [29][30][31] is embryonic lethal, and this effect was related to excessive apoptosis during early embryonic development of these mice. Koide et al [31] provided data showing that TCTP functions as an inhibitor of the BMP pathway in the early phases of development.…”

“…The role of TCTP as an anti-apoptotic protein was highlighted in TCTP gene-knockout studies on mice [29][30][31], which demonstrated embryonic lethality due to excessive apoptosis at an early embryonic state. In 2009 two papers showed the importance of TCTP in preventing apoptotic cell death for the maintenance and development of T-cells.…”