TGF Signaling Regulates the Timing of CNS Myelination by Modulating Oligodendrocyte Progenitor Cell Cycle Exit through SMAD3/4/FoxO1/Sp1
Copyright policy )TGF Signaling Regulates the Timing of CNS Myelination by Modulating Oligodendrocyte Progenitor Cell Cycle Exit through SMAD3/4/FoxO1/Sp1
Research on myelination has focused on identifying molecules capable of inducing oligodendrocyte (OL) differentiation in an effort to develop strategies that promote functional myelin regeneration in demyelinating disorders. Here, we show that transforming growth factor β (TGFβ) signaling is crucial for allowing oligodendrocyte progenitor (OP) cell cycle withdrawal, and therefore, for oligodendrogenesis and postnatal CNS myelination. Enhanced oligodendrogenesis and subcortical white matter (SCWM) myelination was detected after TGFβ gain of function, while TGFβ receptor II (TGFβ-RII) deletion in OPs prevents their development into mature myelinating OLs, leading to SCWM hypomyelination in mice. TGFβ signaling modulates OP cell cycle withdrawal and differentiation through the transcriptional modulation of c-myc and p21 gene expression, mediated by the interaction of SMAD3/4 with Sp1 and FoxO1 transcription factors. Our study is the first to demonstrate an autonomous and crucial role of TGFβ signaling in OL development and CNS myelination, and may provide new avenues in the treatment of demyelinating diseases.
- Stony Brook University United States
- Complutense University of Madrid Spain
Central Nervous System, 2407 Biología Celular, 612.8, Proliferation, Immunoglobulins, Bioquímica (Biología), Mice, Transgenic, Dioxoles, Myelination, TGFβ, Mice, Neurociencias (Biológicas), Animals, Smad3 Protein, 577.1, Cells, Cultured, Myelin Sheath, Oligodendrocyte progenitor, 2403 Bioquímica, Forkhead Box Protein O1, Stem Cells, Biología molecular (Biología), Cell Cycle, Age Factors, Gene Expression Regulation, Developmental, Forkhead Transcription Factors, Oligodendrocyte, Mice, Inbred C57BL, Oligodendroglia, 591.18, Animals, Newborn, 2490 Neurociencias, Benzamides, SMAD, Signal Transduction
Central Nervous System, 2407 Biología Celular, 612.8, Proliferation, Immunoglobulins, Bioquímica (Biología), Mice, Transgenic, Dioxoles, Myelination, TGFβ, Mice, Neurociencias (Biológicas), Animals, Smad3 Protein, 577.1, Cells, Cultured, Myelin Sheath, Oligodendrocyte progenitor, 2403 Bioquímica, Forkhead Box Protein O1, Stem Cells, Biología molecular (Biología), Cell Cycle, Age Factors, Gene Expression Regulation, Developmental, Forkhead Transcription Factors, Oligodendrocyte, Mice, Inbred C57BL, Oligodendroglia, 591.18, Animals, Newborn, 2490 Neurociencias, Benzamides, SMAD, Signal Transduction
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