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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

STAT1 mediates IFNγ activities in vivo. (A) Quantification summarizes how, in the absence of STAT1, proliferation (BrdU) and the expression of neuronal markers such a DCX and olig2 were unaltered. (B) Histogram representing a similar proportion of newborn determined neurons (BrdU+/DCX+) and glial cells in the SVZ of STAT1-KO animals that received a single BrdU 4 days before sacrifice, (n = 6). (C) Pictures of the SVZ sections illustrating that STAT1 deficiency impeded IFNγ functions in the in vivo model. The numbers of proliferative cells (BrdU, green) and neuroblasts (red) were unchanged in KO samples in the IFNγ-treated animals. (D) Quantification summarizes how IFNγ effects on proliferation (BrdU incorporation) and neuroblast populations (DCX+ cells) were abolished in the absence of STAT1 mediator (n = 6). (E) Histogram representing the impossibility of IFNγ inducing neuronal differentiation (BrdU+/DCX+ cells) in STAT1-KO animals that received a single BrdU administration 4 days before sacrifice. (n = 6). Scale bar: 50 μm. Data are represented as mean ± SEM. *p < 0.05; **p ≤ 0.01.
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Figure 6: STAT1 mediates IFNγ activities in vivo. (A) Quantification summarizes how, in the absence of STAT1, proliferation (BrdU) and the expression of neuronal markers such a DCX and olig2 were unaltered. (B) Histogram representing a similar proportion of newborn determined neurons (BrdU+/DCX+) and glial cells in the SVZ of STAT1-KO animals that received a single BrdU 4 days before sacrifice, (n = 6). (C) Pictures of the SVZ sections illustrating that STAT1 deficiency impeded IFNγ functions in the in vivo model. The numbers of proliferative cells (BrdU, green) and neuroblasts (red) were unchanged in KO samples in the IFNγ-treated animals. (D) Quantification summarizes how IFNγ effects on proliferation (BrdU incorporation) and neuroblast populations (DCX+ cells) were abolished in the absence of STAT1 mediator (n = 6). (E) Histogram representing the impossibility of IFNγ inducing neuronal differentiation (BrdU+/DCX+ cells) in STAT1-KO animals that received a single BrdU administration 4 days before sacrifice. (n = 6). Scale bar: 50 μm. Data are represented as mean ± SEM. *p < 0.05; **p ≤ 0.01.

Mentions: Next, the effects of IFNγ on a STAT1 KO animal were explored. First, we evaluated regular proliferation and neurogenesis in the SVZ of STAT1 KO animals. No difference was observed in the presence of proliferating cells (BrdU+), neuroblasts (DCX+) or glial progenitors (Olig2+ cells) in the SVZ of STAT1 KO animals compared with the corresponding wild-type (WT) mice (Figure 6A). In addition, in vivo differentiation studies also showed that neuronal and oligodrendroglial differentiation was normal in the adult SVZ niche in the absence of STAT1 (Figure 6B).


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)

STAT1 mediates IFNγ activities in vivo. (A) Quantification summarizes how, in the absence of STAT1, proliferation (BrdU) and the expression of neuronal markers such a DCX and olig2 were unaltered. (B) Histogram representing a similar proportion of newborn determined neurons (BrdU+/DCX+) and glial cells in the SVZ of STAT1-KO animals that received a single BrdU 4 days before sacrifice, (n = 6). (C) Pictures of the SVZ sections illustrating that STAT1 deficiency impeded IFNγ functions in the in vivo model. The numbers of proliferative cells (BrdU, green) and neuroblasts (red) were unchanged in KO samples in the IFNγ-treated animals. (D) Quantification summarizes how IFNγ effects on proliferation (BrdU incorporation) and neuroblast populations (DCX+ cells) were abolished in the absence of STAT1 mediator (n = 6). (E) Histogram representing the impossibility of IFNγ inducing neuronal differentiation (BrdU+/DCX+ cells) in STAT1-KO animals that received a single BrdU administration 4 days before sacrifice. (n = 6). Scale bar: 50 μm. Data are represented as mean ± SEM. *p < 0.05; **p ≤ 0.01.
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Related In: Results  -  Collection

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Figure 6: STAT1 mediates IFNγ activities in vivo. (A) Quantification summarizes how, in the absence of STAT1, proliferation (BrdU) and the expression of neuronal markers such a DCX and olig2 were unaltered. (B) Histogram representing a similar proportion of newborn determined neurons (BrdU+/DCX+) and glial cells in the SVZ of STAT1-KO animals that received a single BrdU 4 days before sacrifice, (n = 6). (C) Pictures of the SVZ sections illustrating that STAT1 deficiency impeded IFNγ functions in the in vivo model. The numbers of proliferative cells (BrdU, green) and neuroblasts (red) were unchanged in KO samples in the IFNγ-treated animals. (D) Quantification summarizes how IFNγ effects on proliferation (BrdU incorporation) and neuroblast populations (DCX+ cells) were abolished in the absence of STAT1 mediator (n = 6). (E) Histogram representing the impossibility of IFNγ inducing neuronal differentiation (BrdU+/DCX+ cells) in STAT1-KO animals that received a single BrdU administration 4 days before sacrifice. (n = 6). Scale bar: 50 μm. Data are represented as mean ± SEM. *p < 0.05; **p ≤ 0.01.
Mentions: Next, the effects of IFNγ on a STAT1 KO animal were explored. First, we evaluated regular proliferation and neurogenesis in the SVZ of STAT1 KO animals. No difference was observed in the presence of proliferating cells (BrdU+), neuroblasts (DCX+) or glial progenitors (Olig2+ cells) in the SVZ of STAT1 KO animals compared with the corresponding wild-type (WT) mice (Figure 6A). In addition, in vivo differentiation studies also showed that neuronal and oligodrendroglial differentiation was normal in the adult SVZ niche in the absence of STAT1 (Figure 6B).

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