FBXL12-mediated degradation of ALDH3 is essential for trophoblast differentiation during placental development

Masaaki Nishiyama, Akihiro Nita, Kanae Yumimoto, Keiichi I. Nakayama

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

How stem cells maintain their stemness or initiate exit from the stem cell state for differentiation remains largely unknown. Aldehyde dehydrogenase (ALDH) activity is a hallmark of stem cells - including embryonic, adult tissue, and cancer stem cells - and is essential for their maintenance. The mechanisms by which ALDH activity is regulated in stem cells have remained poorly understood, however. We now show that the ubiquitin-dependent degradation of ALDH3 mediated by FBXL12 (F box and leucine-rich repeat protein 12) is essential for execution of the differentiation program of trophoblast stem cells (TSCs). FBXL12 is present only in eutherian mammals, and its expression is largely restricted to the placenta during mouse embryogenesis. FBXL12 was found to interact specifically with members of the ALDH3 family and to mediate their polyubiquitylation. Most mice deficient in FBXL12 died during the embryonic or perinatal period probably as a result of abnormal development of the placenta, characterized by impaired formation of the junctional zone. ALDH3 accumulated in the FBXL12-deficient placenta, and forced expression of ALDH3 in wild-type TSCs phenocopied the differentiation defect of FBXL12-deficient TSCs. Conversely, inhibition of ALDH3 activity by gossypol rescued the phenotype of FBXL12 deficiency. Our results suggest that FBXL12 plays a key role in the downregulation of ALDH3 activity in TSCs and thereby initiates trophoblast differentiation during placental development.

Original languageEnglish
Pages (from-to)3327-3340
Number of pages14
JournalSTEM CELLS
Volume33
Issue number11
DOIs
Publication statusPublished - Nov 2015

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Developmental Biology
  • Cell Biology

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