The pluripotency of mouse embryonic stem cells (mESCs) is controlled by a network of transcription factors, mi-RNAs, and signaling pathways. Here, we present a new regulatory circuit that connects miR-335, Oct4, and the Retinoblastoma pathway to control mESC self-renewal and differentiation. Oct4 drives the expression of Nipp1 and Ccnf that inhibit the activity of the protein phosphatase 1 (PP1) complex to establish hyperphosphorylation of the retinoblastoma protein 1 (pRb) as a hallmark feature of self-renewing mESCs. The Oct4-Nipp1/Ccnf-PP1-pRb axis promoting mESC self-renewal is under control of miR-335 that regulates Oct4 and Rb expression. During mESC differentiation, miR-335 upregulation co-operates with the transcriptional repression of Oct4 to facilitate the collapse of the Oct4-Nipp1/Ccnf-PP1-pRb axis, pRb dephosphorylation, the exit from self-renewal, and the establishment of a pRb-regulated cell cycle program. Our results introduce Oct4-dependent control of the Rb pathway as novel regulatory circuit controlling mESC self-renewal and differentiation.

An Oct4-pRB axis, controlled by MiR-335, integrates stem cell self-renewal and cell cycle control

SCHOEFTNER, Stefan;SCAROLA, MICHELE;COMISSO, ELISA;SCHNEIDER, CLAUDIO;
2013-01-01

Abstract

The pluripotency of mouse embryonic stem cells (mESCs) is controlled by a network of transcription factors, mi-RNAs, and signaling pathways. Here, we present a new regulatory circuit that connects miR-335, Oct4, and the Retinoblastoma pathway to control mESC self-renewal and differentiation. Oct4 drives the expression of Nipp1 and Ccnf that inhibit the activity of the protein phosphatase 1 (PP1) complex to establish hyperphosphorylation of the retinoblastoma protein 1 (pRb) as a hallmark feature of self-renewing mESCs. The Oct4-Nipp1/Ccnf-PP1-pRb axis promoting mESC self-renewal is under control of miR-335 that regulates Oct4 and Rb expression. During mESC differentiation, miR-335 upregulation co-operates with the transcriptional repression of Oct4 to facilitate the collapse of the Oct4-Nipp1/Ccnf-PP1-pRb axis, pRb dephosphorylation, the exit from self-renewal, and the establishment of a pRb-regulated cell cycle program. Our results introduce Oct4-dependent control of the Rb pathway as novel regulatory circuit controlling mESC self-renewal and differentiation.
File in questo prodotto:
Non ci sono file associati a questo prodotto.
Pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11368/2834908
Citazioni
  • ???jsp.display-item.citation.pmc??? 32
  • Scopus 42
  • ???jsp.display-item.citation.isi??? 41
social impact