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FoxG1 promotes the survival of postmitotic neurons.

ABSTRACT: The transcription factor FoxG1 regulates neurogenesis in the embryonic telencephalon as well as a number of other neurodevelopmental processes. While FoxG1 continues to be expressed in neurons postnatally and through adulthood, its role in fully differentiated neurons is not known. The current study demonstrates that FoxG1 promotes the survival of postmitotic neurons. In cerebellar granule neurons primed to undergo apoptosis, FoxG1 expression is reduced. Ectopic expression of FoxG1 blocks neuronal death, whereas suppression of its expression induces death in otherwise healthy neurons. The first 36 residues of FoxG1 are necessary for its survival-promoting effect, while the C-terminal half of the protein is dispensable. Mutation of Asp219, a residue necessary for DNA binding, abrogates survival promotion by FoxG1. Survival promotion is also eliminated by mutation of Thr271, a residue phosphorylated by Akt. Pharmacological inhibition of Akt blocks the survival effects of wild-type FoxG1 but not forms in which Thr271 is replaced with phosphomimetic residues. Treatment of neurons with IGF-1, a neurotrophic factor that promotes neuronal survival by activating Akt, prevents the apoptosis-associated downregulation of FoxG1 expression. Moreover, the overexpression of dominant-negative forms of FoxG1 blocks the ability of IGF-1 to maintain neuronal survival suggesting that FoxG1 is a downstream mediator of IGF-1/Akt signaling. Our study identifies a new and important function for FoxG1 in differentiated neurons.

SUBMITTER: Dastidar SG

PROVIDER: S-EPMC4640444 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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FoxG1 promotes the survival of postmitotic neurons.

Dastidar Somasish Ghosh SG Landrieu Paul Michael Zagala PM D'Mello Santosh R SR

The Journal of neuroscience : the official journal of the Society for Neuroscience 20110101 2

The transcription factor FoxG1 regulates neurogenesis in the embryonic telencephalon as well as a number of other neurodevelopmental processes. While FoxG1 continues to be expressed in neurons postnatally and through adulthood, its role in fully differentiated neurons is not known. The current study demonstrates that FoxG1 promotes the survival of postmitotic neurons. In cerebellar granule neurons primed to undergo apoptosis, FoxG1 expression is reduced. Ectopic expression of FoxG1 blocks neuron ...[more]

PMID: 21228151

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Project description:Foxg1, a winged-helix transcription factor, promotes the development of anterior neural structures; in mice lacking Foxg1, development of the cerebral hemispheres and olfactory epithelium (OE) is severely reduced. It has been suggested that Foxg1 acts by positively regulating the expression of growth factors, such as Fgf8, which support neurogenesis. However, Foxg1 also binds Smad transcriptional complexes, allowing it to negatively regulate the effects of TGFbeta family ligands. Here, we provide evidence that this latter effect explains much of the ability of Foxg1 to drive neurogenesis in the OE. We show that Foxg1 is expressed in developing OE at the same time as the gene encoding growth differentiation factor 11 (Gdf11), a TGFbeta family member that mediates negative-feedback control of OE neurogenesis. Mutations in Gdf11 rescue, to a considerable degree, the major defects in Foxg1(-/-) OE, including the early, severe loss of neural precursors and olfactory receptor neurons, and the subsequent collapse of both neurogenesis and nasal cavity formation. Rescue is gene-dosage dependent, with loss of even one allele of Gdf11 restoring substantial neurogenesis. Notably, we find no evidence for a disruption of Fgf8 expression in Foxg1(-/-) OE. However, we do observe both a failure of expression of follistatin (Fst), which encodes a secreted Gdf11 antagonist normally expressed in and around OE, and an increase in the expression of Gdf11 itself within the remaining OE in these mutants. Fst expression is rescued in Foxg1(-/-);Gdf11(-/-) and Foxg1(-/-);Gdf11(+/-) mice. These data suggest that the influence of Foxg1 on Gdf11-mediated negative feedback of neurogenesis may be both direct and indirect. In addition, defects in development of the cerebral hemispheres in Foxg1(-/-) mice are not rescued by mutations in Gdf11, nor is Gdf11 expressed at high levels within these structures. Thus, the pro-neurogenic effects of Foxg1 are likely to be mediated through different signaling pathways in different parts of the nervous system.

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FoxG1 promotes the survival of postmitotic neurons.

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FoxG1 promotes the survival of postmitotic neurons.

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