GDF11 expressed in the adult brain negatively regulates hippocampal neurogenesis

Abstract

Growth differentiation factor 11 (GDF11) is a transforming factor-β superfamily member that functions as a negative regulator of neurogenesis during embryonic development. However, when recombinant GDF11 (rGDF11) is administered systemically in aged mice, it promotes neurogenesis, the opposite of its role during development. The goal of the present study was to reconcile this apparent discrepancy by performing the first detailed investigation into the expression of endogenous GDF11 in the adult brain and its effects on neurogenesis. Using quantitative histological analysis, we observed that Gdf11 is highly expressed in adult neurogenic niches and non-neurogenic regions within the hippocampus, choroid plexus, thalamus, habenula, and cerebellum. To investigate the role of endogenous GDF11 during adult hippocampal neurogenesis, we generated a tamoxifen inducible mouse that allowed us to reduce GDF11 levels. Depletion of Gdf11 during adulthood increased proliferation of neural progenitors and decreased the number of newborn neurons in the hippocampus, suggesting that endogenous GDF11 remains a negative regulator of hippocampal neurogenesis in adult mice. These findings further support the idea that circulating systemic GDF11 and endogenously expressed GDF11 in the adult brain have different target cells or mechanisms of action. Our data describe a role for GDF11-dependent signaling in adult neurogenesis that has implications for how GDF11 may be used to treat CNS disease.

Blood-to-brain communication in aging and rejuvenation

“…Although the age-related dynamics of its abundance in blood are under debate 83,108 , GDF11 reproduced some of the beneficial effects of heterochronic parabiosis on the aged brain by increasing vascular density and CBF, ultimately leading to enhanced adult neurogenesis in the SVZ and the DG and increased markers of neuronal activity in the hippocampus and cortex 10,109 . Surprisingly, increased GDF11 expression within the adult hippocampus inhibits neurogenesis 110 . These disparate findings were reconciled when biotinylation experiments determined that circulating GDF11 is unable to cross the BBB 109 , suggesting that systemic GDF11 exerts its rejuvenating effect on the aged brain by signaling through BECs.…”

Systemic GDF11 attenuates depression-like phenotype in aged mice via stimulation of neuronal autophagy

“…These results agree with initial reports that demonstrate GDF11 taking part in a feedback inhibitory signal that limits neurogenesis in the embryonic olfactory epithelium 18,20,38 . Moreover, it was recently reported that GDF11 is a negative regulator of adult hippocampal neurogenesis by depletion of endogenous GDF11 in a tamoxifen-inducible mouse model 23 . Therefore, the observed effects on neurogenesis after systemic GDF11 administration seem to be indirect, potentially through activation of other factors in the periphery.…”

“…The role of GDF11 in the developing central nervous system regulates the progression of neurogenesis as well as differentiation of neural subtypes [19][20][21][22] . In adults, GDF11 was recently shown to negatively regulate neurogenesis 23 . Because circulating levels of GDF11 decline with age 24,25 , supplementation with recombinant GDF11 (rGDF11) in aged mice was previously shown to rejuvenate neurogenesis in both the subventricular zone and hippocampal dentate gyrus (DG) and improve cerebral vasculature 8,26 .…”

The emerging translational potential of GDF11 in chronic wound healing

“…As a critical regulator of numerous physiological processes, endogenous GDF11 in the central nervous system suppresses the proliferation of adult neural progenitor through the ALK5 receptor [ 49 ]; And GDF11 expressed in embryonic pancreatic epithelium regulate NGN3 + islet progenitor cell differentiation in parallel or downstream of the Notch pathway [ 50 ]; Besides, studies has shown that Cor-1 ​cells express a TGFβ receptor complex containing ActRIIB/ALK5 subunits, which was regarded as natural ligand for GDF11, providing transcriptional basis for GDF11 regulation in neural stem cell transcription [ 51 ]. GDF11 also shows impact in cancer biology.…”