Transcriptional Basis for the Inhibition of Neural Stem Cell Proliferation and Migration by the TGFβ-Family Member GDF11

Abstract

Signalling through EGF, FGF and endocannabinoid (eCB) receptors promotes adult neurogenesis, and this can be modelled in culture using the Cor-1 neural stem cell line. In the present study we show that Cor-1 cells express a TGFβ receptor complex composed of the ActRIIB/ALK5 subunits and that a natural ligand for this receptor complex, GDF11, activates the canonical Smad2/3 signalling cascade and significantly alters the expression of ∼4700 gene transcripts within a few hours of treatment. Many of the transcripts regulated by GDF11 are also regulated by the EGF, FGF and eCB receptors and by the MAPK pathway – however, in general in the opposite direction. This can be explained to some extent by the observation that GDF11 inhibits expression of, and signalling through, the EGF receptor. GDF11 regulates expression of numerous cell-cycle genes and suppresses Cor-1 cell proliferation; interestingly we found down-regulation of Cyclin D2 rather than p27kip1 to be a good molecular correlate of this. GDF11 also inhibited the expression of numerous genes linked to cytoskeletal regulation including Fascin and LIM and SH3 domain protein 1 (LASP1) and this was associated with an inhibition of Cor-1 cell migration in a scratch wound assay. These data demonstrate GDF11 to be a master regulator of neural stem cell transcription that can suppress cell proliferation and migration by regulating the expression of numerous genes involved in both these processes, and by suppressing transcriptional responses to factors that normally promote proliferation and/or migration.

Growth differentiation factor 11 worsens hepatocellular injury and liver regeneration after liver ischemia reperfusion injury

“…Differences may be a result of the tissue specificity of GDF11 expression, and the function of GDF11 may be cell type specific. This antiproliferative effect of GDF11 has been supported by other observations that have shown that GDF11 inhibited neural stem-cell proliferation and migration (43), olfactory progenitor-cell proliferation (7), and osteoblast and myoblast differentiation (20). Conflicting findings may also have been a result of the different sources and quality of recombinant GDF11, varying sources of animals, and diverse experimental models used in each study.…”

Vinculin network–mediated cytoskeletal remodeling regulates contractile function in the aging heart

“…Although the intrinsic molecular causes of vinculin overexpression in the aging heart remain unclear, upstream regulators and activating reagents have been identified that could be used for therapeutic vinculin overexpression. For example, growth differentiation factor 11 (GDF-11), a transforming growth factor–β family protein, positively regulates vinculin expression in the brain (39), and its overexpression can reverse pathophysiological hypertrophy in aged mice (3). However, GDF-11 declines with age in mice, and humans have lower concentrations of GDF-11 than mice at all ages (3), implying that reduced GDF-11 is not the underlying cause of vinculin overexpression in aging patients.…”

GDF11 exhibits tumor suppressive properties in hepatocellular carcinoma cells by restricting clonal expansion and invasion

“…Cells were exposed to 50 ng/ml GDF11 [20] for different times. GDF11 was added to culture media every 24 h and cells were recovered after 72 h for experiments, as depicted in supplementary figure 1A.…”