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A growth-promoting signaling component cyclin D1 in neural stem cells has antiastrogliogenic function to execute

Norihisa Bizen¹, Toshihiro Inoue, Takeshi Shimizu

¹Department of Stem Cell Regulation, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.

Stem Cells (Dayton, Ohio)

|December 5, 2013

Abstract:

Self-renewing proliferation of neural stem cells (NSCs) is intimately linked to the inhibition of neuronal and glial differentiation, however, their molecular linkage has been poorly understood. We have proposed a model previously explaining partly this linkage, in which fibroblast growth factor 2 (FGF2) and Wnt signals cooperate to promote NSC self-renewal via β-catenin accumulation, which leads to the promotion of proliferation by lymphoid enhancer factor (LEF)/T-cell factor (TCF)-mediated cyclin D1 expression and at the same time to the inhibition of neuronal differentiation by β-catenin-mediated potentiation of Notch signaling. To fully understand the mechanisms underlying NSC self-renewal, it needs to be clarified how these growth factor signals inhibit glial differentiation as well. Here, we demonstrate that cyclin D1, a NSC growth promoting signaling component and also a common component of FGF2 and Wnt signaling pathways, inhibits astroglial differentiation of NSCs. Interestingly, this effect of cyclin D1 is mediated even though its cell cycle progression activity is blocked. Forced downregulation of cyclin D1 enhances astrogliogenesis of NSCs in culture and in vivo. We further demonstrate that cyclin D1 binds to STAT3, a transcription factor downstream of astrogliogenic cytokines, and suppresses its transcriptional activity on the glial fibrillary acidic protein (Gfap) gene. Taken together with our previous finding, we provide a novel molecular mechanism for NSC self-renewal in which growth promoting signaling components activated by FGF2 and Wnts inhibit neuronal and glial differentiation.

Insights

Fibroblast growth factor 2 (FGF2) and Wnt signals promote neural stem cell (NSC) self-renewal by inhibiting differentiation. Cyclin D1, activated by these signals, suppresses both neuronal and glial differentiation.

Area of Science:

Neuroscience
Stem Cell Biology
Molecular Biology

Background:

Neural stem cell (NSC) self-renewal involves inhibiting neuronal and glial differentiation.
Previous models implicated fibroblast growth factor 2 (FGF2) and Wnt signaling in NSC self-renewal via β-catenin and cyclin D1.
The precise mechanisms by which these signals inhibit glial differentiation remained unclear.

Purpose of the Study:

To elucidate the molecular mechanisms by which FGF2 and Wnt signaling pathways inhibit glial differentiation in NSCs.
To investigate the role of cyclin D1 in regulating astroglial differentiation.
To identify the interaction partners and downstream targets of cyclin D1 involved in glial differentiation inhibition.

Main Methods:

Investigated the effect of cyclin D1 on astroglial differentiation in NSCs, including experiments with blocked cell cycle activity.
Utilized cell culture and in vivo models to assess the impact of cyclin D1 downregulation on astrogliogenesis.
Performed co-immunoprecipitation assays to determine the binding of cyclin D1 to STAT3 and analyzed its effect on STAT3 transcriptional activity on the glial fibrillary acidic protein (Gfap) gene.

Main Results:

Cyclin D1 was identified as a key inhibitor of astroglial differentiation in NSCs, independent of its cell cycle-promoting function.
Downregulation of cyclin D1 promoted astrogliogenesis both in vitro and in vivo.
Cyclin D1 directly binds to STAT3, suppressing its transcriptional activity on the Gfap gene, thereby inhibiting glial differentiation.

Conclusions:

A novel molecular mechanism for NSC self-renewal is proposed, where components of FGF2 and Wnt signaling pathways, specifically cyclin D1, inhibit both neuronal and glial differentiation.
Cyclin D1 acts as a crucial link between growth factor signaling and the suppression of glial differentiation.
These findings provide a comprehensive understanding of how growth factor signals maintain NSC self-renewal by preventing differentiation into neurons and glia.

Read full analysis

Keywords:

Astrocyte differentiation Cyclin D1 GSK3β/β-catenin pathway Neural stem cell Self-renewal Transcriptional regulation

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