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Genes Dev
2005 Jul 15;1914:1723-34. doi: 10.1101/gad.1319105.
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Geminin regulates neuronal differentiation by antagonizing Brg1 activity.
Seo S
,
Herr A
,
Lim JW
,
Richardson GA
,
Richardson H
,
Kroll KL
.
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Precise control of cell proliferation and differentiation is critical for organogenesis. Geminin (Gem) has been proposed to link cell cycle exit and differentiation as a prodifferentiation factor and plays a role in neural cell fate acquisition. Here, we identified the SWI/SNF chromatin-remodeling protein Brg1 as an interacting partner of Gem. Brg1 has been implicated in cell cycle withdrawal and cellular differentiation. Surprisingly, we discovered that Gem antagonizes Brg1 activity during neurogenesis to maintain the undifferentiated cell state. Down-regulation of Gem expression normally precedes neuronal differentiation, and gain- and loss-of-function experiments in Xenopus embryos and mouse P19 cells demonstrated that Gem was essential to prevent premature neurogenesis. Misexpression of Gem also suppressed ectopic neurogenesis driven by Ngn and NeuroD. Gem's activity to block differentiation depended upon its ability to bind Brg1 and could be mediated by Gem's inhibition of proneural basic helix-loop-helix (bHLH)-Brg1 interactions required for bHLH target gene activation. Our data demonstrate a novel mechanism of Gem activity, through regulation of SWI/SNF chromatin-remodeling proteins, and indicate that Gem is an essential regulator of neurogenesis that can control the timing of neural progenitor differentiation and maintain the undifferentiated cell state.
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16024661
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Figure 3. Brg1 and Gem have overlapping expression patterns but Gem diminishes prior to neuronal differentiation. In situ hybridization for X-Brg1 (A) and X-Gem (D) in Xenopus embryos. (A,D,G) Dorso-lateral views. (C,F) Dorsal views at tail- bud stages; anterior toward left. (B,E,H) Transverse sections at stages shown in A, D, and G, respectively. (I) Transverse section of N-tubulin-stained embryo. In H and I, a dashed line marks the neural plateomite boundary. (J) Expression profile of Gem and other markers during RA-induced neuronal differentiation of P19 cells.
Figure 4. Misexpression of Gem prevents neurogenesis. (A), Two-cell stage Xenopus embryos were injected in one cell as indicated (yellow) with beta-galactosidase mRNA coinjection for lineage tracing and analyzed for NCAM (A) or N-tubulin (DO) expression. (CT) C-terminal region. 3EA is an alanine sub- stitution mutant of acidic amino acids 18890 in Xenopus Gem (which correspond to mouse Gem amino acids 17476). Like GemE174Q (Fig. 2F,G), Xenopus Gem 3EA has severely reduced Brg1 binding (data not shown). Numbers indicate the number of affected embryos over the total number of embryos. In situ for markers is stained purple, and blue X-gal staining marks the injected side. Injected sides were oriented rightward. (P) Expression levels of Gem variants injected into Xenopus embryos. Embryos were injected as indicated at the two-cell stage and harvested at stage 12 to prepare lysates. Ten embryos were used for each sample, and one embryo-equivalent of lysate was loaded per lane for Western blotting with anti-Myc antibody.
igure 6. Loss of Gem activity results in premature neurogenesis. (A) Xenopus embryos were injected with 2.5 ng (A) or 1.5 ng (E,F) of GemMO or 20 ng of control MO (G,H) and probed as indicated (white). Red arrowheads in E and F mark the pos- terior end of N-tubulin expression in the medial stripe on each side of the embryo. (I) Reduction of Gem protein level in P19 cells by RNAi. (J) Reduction of Gem sensi- tized P19 cells to differentiate into neurons at a subthreshold level (50 ng) of NeuroD2. P19 cells were transfected as indicated and probed with TuJ1 antibody to detect neu- rons. GFP expression plasmid was cotrans- fected to trace transfected cells.
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