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IFN gamma regulates proliferation and neuronal differentiation by STAT1 in adult SVZ niche.

Pereira L, Medina R, Baena M, Planas AM, Pozas E - Front Cell Neurosci (2015)

Bottom Line: Interferon gamma (IFNγ) has somewhat controversially been associated with SVZ progenitor proliferation and neurogenesis.The final result is deficient recruitment of newborn neurons to the olfactory bulb (OB), indicating that IFNγ-induced stimulation of neuronal differentiation does not compensate for its antiproliferative effect.We conclude that IFNγ signaling via STAT1 in the SVZ acts dually as an antiproliferative and proneurogenic factor, and thereby regulates neurogenesis in normal adult brains.

View Article: PubMed Central - PubMed

Affiliation: Unit of Brain Ischemia, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) Barcelona, Spain ; Department of Brain Ischemia and Neurodegeneration, Institute of Biomedical Research of Barcelona, Consejo Superior de Investigaciones Científicas (CSIC) Barcelona, Spain.

ABSTRACT
The adult subventricular zone (SVZ) is the main neurogenic niche in normal adult brains of mice and rats. Interferon gamma (IFNγ) has somewhat controversially been associated with SVZ progenitor proliferation and neurogenesis. The in vivo involvement of IFNγ in the physiology of the adult SVZ niche is not fully understood and its intracellular mediators are unknown. Here we show that IFNγ, through activation of its canonical signal transducer and activator of transcription 1 (STAT1) pathway, acts specifically on Nestin+ progenitors by decreasing both progenitor proliferation and the number of cycling cells. In addition, IFNγ increases the number of neuroblasts generated without shifting glial fate determination. The final result is deficient recruitment of newborn neurons to the olfactory bulb (OB), indicating that IFNγ-induced stimulation of neuronal differentiation does not compensate for its antiproliferative effect. We conclude that IFNγ signaling via STAT1 in the SVZ acts dually as an antiproliferative and proneurogenic factor, and thereby regulates neurogenesis in normal adult brains.

No MeSH data available.


Related in: MedlinePlus

IFNγ modulates proliferation and neuronal differentiation in adult SVZ and causes a final neurogenesis impairment in the olfactory bulb(OB) in vivo. (A) Phosphorylation of STAT1 in the ipsilateral (Ip) and contralateral (ctr) SVZ niche of adult mice 30 min after they received an intracerebroventricular (ICV) injection of IFNγ (1 μl of 50 ng/ml) (n = 3). (B) Pictures illustrating the decrease of Ki67 in dorsal SVZ after in vivo gain of function of IFNγ (n = 4). (C) Histogram representing the total number of positive cells in the dorsal SVZ. BrdU+ cells and Ki67+ cells decreased in IFNγ-gain animals. (D) Pictures of dorsal SVZ showing substantial decrease in Nestin+ cells and mild differences in DCX+ cells of IFNγ-gain animals. (E) Quantification summarizes the robust decrease in Nestin+ progenitor cells and the mild reduction in neuroblast populations (DCX+ or PSA-NCAM+) in the SVZ niche of IFNγ-treated animals (n = 6). (F) Histograms summarizing cellular fate determination (expressed as percentage) in animals injected with BrdU at time 0 and with a pump implanted for 4d. Neuronal fate determination (BrdU+/DCX+) was significantly increased and glial production (BrdU+/Olig2+) was unaltered by IFNγ (n = 5). (G) Pictures of the OB showing the presence of BrdU+, NeuN+ and BrdU+/NeuN+ labeled cells in IFNγ-gain mice. The number of newborn cells (BrdU) and neurons (BrdU/NeuN) were reduced in the animals in which IFNγ activity was induced. (H) Histograms summarizing the quantification of total number of newborn cells and neurons per section in the OB of controls and IFNγ-gain animals (n = 5). The number of newborn cells (BrdU+) and neurons (BrdU+/NeuN+) was reduced in the presence of IFNγ. Scale bar: (B, D) and (G) 100 μm. Data are represented as mean ± SEM. *p ≤ 0.05; **p ≤ 0.01; ***p ≤ 0.01.
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Figure 5: IFNγ modulates proliferation and neuronal differentiation in adult SVZ and causes a final neurogenesis impairment in the olfactory bulb(OB) in vivo. (A) Phosphorylation of STAT1 in the ipsilateral (Ip) and contralateral (ctr) SVZ niche of adult mice 30 min after they received an intracerebroventricular (ICV) injection of IFNγ (1 μl of 50 ng/ml) (n = 3). (B) Pictures illustrating the decrease of Ki67 in dorsal SVZ after in vivo gain of function of IFNγ (n = 4). (C) Histogram representing the total number of positive cells in the dorsal SVZ. BrdU+ cells and Ki67+ cells decreased in IFNγ-gain animals. (D) Pictures of dorsal SVZ showing substantial decrease in Nestin+ cells and mild differences in DCX+ cells of IFNγ-gain animals. (E) Quantification summarizes the robust decrease in Nestin+ progenitor cells and the mild reduction in neuroblast populations (DCX+ or PSA-NCAM+) in the SVZ niche of IFNγ-treated animals (n = 6). (F) Histograms summarizing cellular fate determination (expressed as percentage) in animals injected with BrdU at time 0 and with a pump implanted for 4d. Neuronal fate determination (BrdU+/DCX+) was significantly increased and glial production (BrdU+/Olig2+) was unaltered by IFNγ (n = 5). (G) Pictures of the OB showing the presence of BrdU+, NeuN+ and BrdU+/NeuN+ labeled cells in IFNγ-gain mice. The number of newborn cells (BrdU) and neurons (BrdU/NeuN) were reduced in the animals in which IFNγ activity was induced. (H) Histograms summarizing the quantification of total number of newborn cells and neurons per section in the OB of controls and IFNγ-gain animals (n = 5). The number of newborn cells (BrdU+) and neurons (BrdU+/NeuN+) was reduced in the presence of IFNγ. Scale bar: (B, D) and (G) 100 μm. Data are represented as mean ± SEM. *p ≤ 0.05; **p ≤ 0.01; ***p ≤ 0.01.

Mentions: A single intracerebroventricular (ICV) administration of IFNγ into the LV of the mice induced STAT1Tyr705 phosphorylation in the SVZ niche of both hemispheres, contralateral and ipsilateral to the injection site (Figure 5A). This indicates that, as in the in vitro case, IFNγ activates STAT1 in vivo.


IFN gamma regulates proliferation and neuronal differentiation by STAT1 in adult SVZ niche.

Pereira L, Medina R, Baena M, Planas AM, Pozas E - Front Cell Neurosci (2015)

IFNγ modulates proliferation and neuronal differentiation in adult SVZ and causes a final neurogenesis impairment in the olfactory bulb(OB) in vivo. (A) Phosphorylation of STAT1 in the ipsilateral (Ip) and contralateral (ctr) SVZ niche of adult mice 30 min after they received an intracerebroventricular (ICV) injection of IFNγ (1 μl of 50 ng/ml) (n = 3). (B) Pictures illustrating the decrease of Ki67 in dorsal SVZ after in vivo gain of function of IFNγ (n = 4). (C) Histogram representing the total number of positive cells in the dorsal SVZ. BrdU+ cells and Ki67+ cells decreased in IFNγ-gain animals. (D) Pictures of dorsal SVZ showing substantial decrease in Nestin+ cells and mild differences in DCX+ cells of IFNγ-gain animals. (E) Quantification summarizes the robust decrease in Nestin+ progenitor cells and the mild reduction in neuroblast populations (DCX+ or PSA-NCAM+) in the SVZ niche of IFNγ-treated animals (n = 6). (F) Histograms summarizing cellular fate determination (expressed as percentage) in animals injected with BrdU at time 0 and with a pump implanted for 4d. Neuronal fate determination (BrdU+/DCX+) was significantly increased and glial production (BrdU+/Olig2+) was unaltered by IFNγ (n = 5). (G) Pictures of the OB showing the presence of BrdU+, NeuN+ and BrdU+/NeuN+ labeled cells in IFNγ-gain mice. The number of newborn cells (BrdU) and neurons (BrdU/NeuN) were reduced in the animals in which IFNγ activity was induced. (H) Histograms summarizing the quantification of total number of newborn cells and neurons per section in the OB of controls and IFNγ-gain animals (n = 5). The number of newborn cells (BrdU+) and neurons (BrdU+/NeuN+) was reduced in the presence of IFNγ. Scale bar: (B, D) and (G) 100 μm. Data are represented as mean ± SEM. *p ≤ 0.05; **p ≤ 0.01; ***p ≤ 0.01.
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Figure 5: IFNγ modulates proliferation and neuronal differentiation in adult SVZ and causes a final neurogenesis impairment in the olfactory bulb(OB) in vivo. (A) Phosphorylation of STAT1 in the ipsilateral (Ip) and contralateral (ctr) SVZ niche of adult mice 30 min after they received an intracerebroventricular (ICV) injection of IFNγ (1 μl of 50 ng/ml) (n = 3). (B) Pictures illustrating the decrease of Ki67 in dorsal SVZ after in vivo gain of function of IFNγ (n = 4). (C) Histogram representing the total number of positive cells in the dorsal SVZ. BrdU+ cells and Ki67+ cells decreased in IFNγ-gain animals. (D) Pictures of dorsal SVZ showing substantial decrease in Nestin+ cells and mild differences in DCX+ cells of IFNγ-gain animals. (E) Quantification summarizes the robust decrease in Nestin+ progenitor cells and the mild reduction in neuroblast populations (DCX+ or PSA-NCAM+) in the SVZ niche of IFNγ-treated animals (n = 6). (F) Histograms summarizing cellular fate determination (expressed as percentage) in animals injected with BrdU at time 0 and with a pump implanted for 4d. Neuronal fate determination (BrdU+/DCX+) was significantly increased and glial production (BrdU+/Olig2+) was unaltered by IFNγ (n = 5). (G) Pictures of the OB showing the presence of BrdU+, NeuN+ and BrdU+/NeuN+ labeled cells in IFNγ-gain mice. The number of newborn cells (BrdU) and neurons (BrdU/NeuN) were reduced in the animals in which IFNγ activity was induced. (H) Histograms summarizing the quantification of total number of newborn cells and neurons per section in the OB of controls and IFNγ-gain animals (n = 5). The number of newborn cells (BrdU+) and neurons (BrdU+/NeuN+) was reduced in the presence of IFNγ. Scale bar: (B, D) and (G) 100 μm. Data are represented as mean ± SEM. *p ≤ 0.05; **p ≤ 0.01; ***p ≤ 0.01.
Mentions: A single intracerebroventricular (ICV) administration of IFNγ into the LV of the mice induced STAT1Tyr705 phosphorylation in the SVZ niche of both hemispheres, contralateral and ipsilateral to the injection site (Figure 5A). This indicates that, as in the in vitro case, IFNγ activates STAT1 in vivo.

Bottom Line: Interferon gamma (IFNγ) has somewhat controversially been associated with SVZ progenitor proliferation and neurogenesis.The final result is deficient recruitment of newborn neurons to the olfactory bulb (OB), indicating that IFNγ-induced stimulation of neuronal differentiation does not compensate for its antiproliferative effect.We conclude that IFNγ signaling via STAT1 in the SVZ acts dually as an antiproliferative and proneurogenic factor, and thereby regulates neurogenesis in normal adult brains.

View Article: PubMed Central - PubMed

Affiliation: Unit of Brain Ischemia, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) Barcelona, Spain ; Department of Brain Ischemia and Neurodegeneration, Institute of Biomedical Research of Barcelona, Consejo Superior de Investigaciones Científicas (CSIC) Barcelona, Spain.

ABSTRACT
The adult subventricular zone (SVZ) is the main neurogenic niche in normal adult brains of mice and rats. Interferon gamma (IFNγ) has somewhat controversially been associated with SVZ progenitor proliferation and neurogenesis. The in vivo involvement of IFNγ in the physiology of the adult SVZ niche is not fully understood and its intracellular mediators are unknown. Here we show that IFNγ, through activation of its canonical signal transducer and activator of transcription 1 (STAT1) pathway, acts specifically on Nestin+ progenitors by decreasing both progenitor proliferation and the number of cycling cells. In addition, IFNγ increases the number of neuroblasts generated without shifting glial fate determination. The final result is deficient recruitment of newborn neurons to the olfactory bulb (OB), indicating that IFNγ-induced stimulation of neuronal differentiation does not compensate for its antiproliferative effect. We conclude that IFNγ signaling via STAT1 in the SVZ acts dually as an antiproliferative and proneurogenic factor, and thereby regulates neurogenesis in normal adult brains.

No MeSH data available.


Related in: MedlinePlus