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Schultz KM
,
Banisadr G
,
Lastra RO
,
McGuire T
,
Kessler JA
,
Miller RJ
,
McGarry TJ
.
???displayArticle.abstract??? Neural stem cells (NSCs) are the progenitors of neurons and glial cells during both embryonic development and adult life. The unstable regulatory protein Geminin (Gmnn) is thought to maintain neural stem cells in an undifferentiated state while they proliferate. Geminin inhibits neuronal differentiation in cultured cells by antagonizing interactions between the chromatin remodeling protein Brg1 and the neural-specific transcription factors Neurogenin and NeuroD. Geminin is widely expressed in the CNS during throughout embryonic development, and Geminin expression is down-regulated when neuronal precursor cells undergo terminal differentiation. Over-expression of Geminin in gastrula-stage Xenopus embryos can expand the size of the neural plate. The role of Geminin in regulating vertebrate neurogenesis in vivo has not been rigorously examined. To address this question, we created a strain of Nestin-Cre/Gmnn(fl/fl) mice in which the Geminin gene was specifically deleted from NSCs. Interestingly, we found no major defects in the development or function of the central nervous system. Neural-specific Gmnn(Δ/Δ) mice are viable and fertile and display no obvious neurological or neuroanatomical abnormalities. They have normal numbers of BrdU(+) NSCs in the subgranular zone of the dentate gyrus, and Gmnn(Δ/Δ) NSCs give rise to normal numbers of mature neurons in pulse-chase experiments. Gmnn(Δ/Δ) neurosphere cells differentiate normally into both neurons and glial cells when grown in growth factor-deficient medium. Both the growth rate and the cell cycle distribution of cultured Gmnn(Δ/Δ) neurosphere cells are indistinguishable from controls. We conclude that Geminin is largely dispensable for most of embryonic and adult mammalian neurogenesis.
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???displayArticle.pmcLink???PMC3052383 ???displayArticle.link???PLoS One ???displayArticle.grants???[+]
Figure 1. Nes-Cre/Gmnnfl/fl Mice have Normal Neuroanatomy and Normal Survival.(A) Whole-mount brains of Gmnnfl/fl (left) and Nes-Cre/Gmnnfl/fl (right) mice. (B) Survival of Gmnnfl/fl (black) and Nes-Cre/Gmnnfl/fl (red) mice. Numbers above the X axis indicate the number of mice that were at risk at each timepoint (black, control animals; red, Nes-Cre/Gmnnfl/fl animals). Controls include both Gmnnfl/fl and Gmnnfl/+ animals. (C) Representative Nissl-stained sections of the cortex and the cerebellum of Gmnnfl/fl and Nes-Cre/Gmnnfl/fl mice. Scale bar, 2 mm.
Figure 2. Geminin is Deleted from the Brains of Nes-Cre/Gmnnfl/fl Mice.(A) Immunoblot showing the amount of Geminin protein in e14.5 mouse brain homogenates. (B) Xgal staining of coronal brain sections showing β-galactosidase activity in the brains of Nes-Cre/Gmnnfl/fl/R26R-LacZ and Gmnnfl/fl/R26R-LacZ mice. Scale bar, 0.25 mm. (C) Quantitative real-time PCR showing the amount of Geminin mRNA in the brains of e14.5 and e16.5 mice and in neurospheres cultured from newborn (P0) mice.
Figure 3. Normal Hippocampal Neurogenesis in Nes-Cre/Gmnnfl/fl Mice.(A) Adult mice were injected with BrdU 24 hours before sacrifice. Adjacent sections of the hippocampus were stained with either anti-BrdU antibodies or with DAPI. Scale bar, 50 µM. (B) Quantification of the number of BrdU(+) cells in the subgranular zone of the hippocampus in Nes-Cre/Gmnnfl/fl mice and control littermates. n = 4 for controls; n = 3 for Nes-Cre/Gmnnfl/fl mice. (C) 7 week-old mice were injected with BrdU for 12 days then sacrificed 9 weeks later. Sections of the hippocampus were stained with anti-BrdU antibodies and with anti-NeuN antibodies. The Z-stack image on the right shows BrdU+, NeuN+, and BrdU+NeuN+ cells. Scale bar, 50 µM. (D)Quantification of the number of BrdU(+)NeuN(+) cells in the hippocampus of Nes-Cre/Gmnnfl/fl mice and control littermates. n = 2 for both genotypes.
Figure 4. Normal Differentiation of Nes-Cre/Gmnnfl/fl Neurosphere Cells.(A)Representative images of TuJ1(+) neurons and GFAP(+) astrocytes derived from Nes-Cre/Gmnnfl/fl and control neurosphere cells. Scale bar, 50 µM. (B)Quantification of the number of TuJ1(+) neurons and GFAP(+) astrocytes derived from Nes-Cre/Gmnnfl/fl and control neurosphere cells. HPF, High Powered Field.
Figure 5. Nes-Cre/Gmnnfl/fl Neurosphere Cells Show Normal DNA Replication and Normal Cell Cycle Kinetics.(A)Doubling time, (B) cell cycle phase distribution, and (C) DNA content of neurosphere cells derived from Nes-Cre/Gmnnfl/fl mice and control littermates.
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