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

Yuichi Koide, Tomomi Kiyota, Moltira Tonganunt, Decha Pinkaew, Zhihe Liu, Yoichi Kato, Nongporn Hutadilok-Towatana, Amornrat Phongdara, Kenichi Fujise

Research output: Contribution to journalArticle

23 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)326-338
Number of pages13
JournalBiochimica et Biophysica Acta - General Subjects
Volume1790
Issue number5
DOIs
StatePublished - May 2009
Externally publishedYes

Fingerprint

Fibroblasts
Embryonic Structures
Genes
DNA
Cell death
Transcription
Small Interfering RNA
DNA Fragmentation
Brain
Tissue
Apoptosis
Trophoblasts
Blastocyst
Xenopus
Cell Death
Pregnancy
Growth
Neoplasms

Keywords

  • Apoptosis
  • BMP
  • Fortilin
  • Knockout
  • Msx2
  • Targeted gene disruption

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

Cite this

Embryonic lethality of fortilin-null mutant mice by BMP-pathway overactivation. / Koide, Yuichi; Kiyota, Tomomi; Tonganunt, Moltira; Pinkaew, Decha; Liu, Zhihe; Kato, Yoichi; Hutadilok-Towatana, Nongporn; Phongdara, Amornrat; Fujise, Kenichi.

In: Biochimica et Biophysica Acta - General Subjects, Vol. 1790, No. 5, 05.2009, p. 326-338.

Research output: Contribution to journalArticle

Koide, Y, Kiyota, T, Tonganunt, M, Pinkaew, D, Liu, Z, Kato, Y, Hutadilok-Towatana, N, Phongdara, A & Fujise, K 2009, 'Embryonic lethality of fortilin-null mutant mice by BMP-pathway overactivation', Biochimica et Biophysica Acta - General Subjects, vol. 1790, no. 5, pp. 326-338. https://doi.org/10.1016/j.bbagen.2009.01.012
Koide, Yuichi ; Kiyota, Tomomi ; Tonganunt, Moltira ; Pinkaew, Decha ; Liu, Zhihe ; Kato, Yoichi ; Hutadilok-Towatana, Nongporn ; Phongdara, Amornrat ; Fujise, Kenichi. / Embryonic lethality of fortilin-null mutant mice by BMP-pathway overactivation. In: Biochimica et Biophysica Acta - General Subjects. 2009 ; Vol. 1790, No. 5. pp. 326-338.
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AU - Liu, Zhihe

AU - Kato, Yoichi

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