Bmi-1 cooperates with Foxgl to maintain neural stem cell self-renewal in the forebrain

Christopher A. Fasano, Timothy N. Phoenix, Erzsebet Kokovay, Natalia Lowry, Yechiel Elkabetz, John T. Dimos, Ihor R. Lemischka, Lorenz Studer, Sally Temple

Research output: Contribution to journalArticlepeer-review

129 Scopus citations

Abstract

Neural stem cells (NSCs) persist throughout life in two forebrain areas: the subventricular zone (SVZ) and the hippocampus. Why forebrain NSCs self-renew more extensively than those from other regions remains unclear. Prior studies have shown that the polycomb factor Bmi-1 is necessary for NSC self-renewal and that it represses the cell cycle inhibitors pl6, pl9, and p21. Here we show that overexpression of Bmi-1 enhances self-renewal of forebrain NSCs significantly more than those derived from spinal cord, demonstrating a regional difference in responsiveness. We show that forebrain NSCs require the forebrain-specific transcription factor Foxgl for Bmi-1-dependent self-renewal, and that repression of p21 is a focus of this interaction. Bmi-1 enhancement of NSC self-renewal is significantly greater with increasing age and passage. Importantly, when Bmi-1 is overexpressed in cultured adult forebrain NSCs, they expand dramatically and continue to make neurons even after multiple passages, when control NSCs have become restricted to glial differentiation. Together these findings demonstrate the importance of Bmi-1 and Foxgl cooperation to maintenance of NSC multipotency and self-renewal, and establish a useful method for generating abundant forebrain neurons ex vivo, outside the neurogenic niche.

Original languageEnglish (US)
Pages (from-to)561-574
Number of pages14
JournalGenes and Development
Volume23
Issue number5
DOIs
StatePublished - Mar 1 2009

Keywords

  • Adult stem cells
  • Bmil
  • Neural stem cells
  • SVZ
  • Self-renewal

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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