Abstract
Although neurogenic pathways have been described in the developing neocortex, less is known about mechanisms ensuring correct neuronal differentiation thus also preventing tumor growth. We have shown that RP58 (aka zfp238 or znf238) is highly expressed in differentiating neurons, that its expression is lost or diminished in brain tumors, and that its reintroduction blocks their proliferation. Mice with loss of RP58 die at birth with neocortical defects. Using a novel conditional RP58 allele here we show that its CNS-specific loss yields a novel postnatal phenotype: microencephaly, agenesis of the corpus callosum and cerebellar hypoplasia that resembles the chr1qter deletion microcephaly syndrome in human. RP58 mutant brains maintain precursor pools but have reduced neuronal and increased glial differentiation. Well-timed downregulation of pax6, ngn2 and neuroD1 depends on RP58 mediated transcriptional repression, ngn2 and neuroD1 being direct targets. Thus, RP58 may act to favor neuronal differentiation and brain growth by coherently repressing multiple proneurogenic genes in a timely manner.
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Abbreviations
- RGC:
-
radial glial stem/progenitor cell
- INP:
-
intermediate neurogenic progenitor
- VZ:
-
ventricular zone
- SVZ:
-
subventricular zone
- KO:
-
knockout
- cKO:
-
conditional knockout
- ChIP:
-
chromatin immunoprecipitation
- PFA:
-
paraformaldehyde
- PBST:
-
PBS–Triton 0.1%
- FACS:
-
fluorescence-activated cell sorting
References
Ever L, Gaiano N . Radial ‘glial’ progenitors: neurogenesis and signaling. Curr Opin Neurobiol 2005; 15: 29–33.
Kriegstein A, Noctor S, Martinez-Cerdeno V . Patterns of neural stem and progenitor cell division may underlie evolutionary cortical expansion. Nat Rev 2006; 7: 883–890.
Pontious A, Kowalczyk T, Englund C, Hevner RF . Role of intermediate progenitor cells in cerebral cortex development. Dev Neurosci 2008; 30: 24–32.
Kowalczyk T, Pontious A, Englund C, Daza RA, Bedogni F, Hodge R et al. Intermediate neuronal progenitors (basal progenitors) produce pyramidal-projection neurons for all layers of cerebral cortex. Cereb Cortex 2009; 19: 2439–2450.
Sessa A, Mao CA, Hadjantonakis AK, Klein WH, Broccoli V . Tbr2 directs conversion of radial glia into basal precursors and guides neuronal amplification by indirect neurogenesis in the developing neocortex. Neuron 2008; 60: 56–69.
Arnold SJ, Huang GJ, Cheung AF, Era T, Nishikawa S, Bikoff EK et al. The T-box transcription factor Eomes/Tbr2 regulates neurogenesis in the cortical subventricular zone. Genes Dev 2008; 22: 2479–2484.
Hevner RF . From radial glia to pyramidal-projection neuron: transcription factor cascades in cerebral cortex development. Mol Neurobiol 2006; 33: 33–50.
Hevner RF, Hodge RD, Daza RA, Englund C . Transcription factors in glutamatergic neurogenesis: conserved programs in neocortex, cerebellum, and adult hippocampus. Neurosci Res 2006; 55: 223–233.
Boland E, Clayton-Smith J, Woo VG, McKee S, Manson FD, Medne L et al. Mapping of deletion and translocation breakpoints in 1q44 implicates the serine/threonine kinase AKT3 in postnatal microcephaly and agenesis of the corpus callosum. Am J Hum Genet 2007; 81: 292–303.
Hill AD, Chang BS, Hill RS, Garraway LA, Bodell A, Sellers WR et al. A 2-Mb critical region implicated in the microcephaly associated with terminal 1q deletion syndrome. Am J Med Genet 2007; 143A: 1692–1698.
van Bon BW, Koolen DA, Borgatti R, Magee A, Garcia-Minaur S, Rooms L et al. Clinical and molecular characteristics of 1qter microdeletion syndrome: delineating a critical region for corpus callosum agenesis/hypogenesis. J Med Genet 2008; 45: 346–354.
Orellana C, Rosello M, Monfort S, Oltra S, Quiroga R, Ferrer I et al. Corpus callosum abnormalities and the controversy about the candidate genes located in 1q44. Cytogenet Genome Res 2009; 127: 5–8.
Tatard VM, Xiang C, Biegel JA, Dahmane N . ZNF238 is expressed in postmitotic brain cells and inhibits brain tumor growth. Cancer Res 2010; 70: 1236–1246.
Aoki K, Meng G, Suzuki K, Takashi T, Kameoka Y, Nakahara K et al. RP58 associates with condensed chromatin and mediates a sequence-specific transcriptional repression. J Biol Chem 1998; 273: 26698–26704.
Ohtaka-Maruyama C, Miwa A, Kawano H, Kasai M, Okado H . Spatial and temporal expression of RP58, a novel zinc finger transcriptional repressor, in mouse brain. J Comp Neurol 2007; 502: 1098–1108.
Okado H, Ohtaka-Maruyama C, Sugitani Y, Fukuda Y, Ishida R, Hirai S et al. The transcriptional repressor RP58 is crucial for cell-division patterning and neuronal survival in the developing cortex. Dev Biol 2009; 331: 140–151.
Tronche F, Kellendonk C, Kretz O, Gass P, Anlag K, Orban PC et al. Disruption of the glucocorticoid receptor gene in the nervous system results in reduced anxiety. Nat Genet 1999; 23: 99–103.
Molyneaux BJ, Arlotta P, Menezes JR, Macklis JD . Neuronal subtype specification in the cerebral cortex. Nat Rev Neurosci 2007; 8: 427–437.
Bayer SA, Altman J . Neocortical Development. Raven Press: New York, 1991.
Hevner RF, Shi L, Justice N, Hsueh Y, Sheng M, Smiga S et al. Tbr1 regulates differentiation of the preplate and layer 6. Neuron 2001; 29: 353–366.
Hartfuss E, Galli R, Heins N, Gotz M . Characterization of CNS precursor subtypes and radial glia. Dev Biol 2001; 229: 15–30.
Kawaguchi A, Ikawa T, Kasukawa T, Ueda HR, Kurimoto K, Saitou M et al. Single-cell gene profiling defines differential progenitor subclasses in mammalian neurogenesis. Development 2008; 135: 3113–3124.
Englund C, Fink A, Lau C, Pham D, Daza RA, Bulfone A et al. Pax6, Tbr2, and Tbr1 are expressed sequentially by radial glia, intermediate progenitor cells, and postmitotic neurons in developing neocortex. J Neurosci 2005; 25: 247–251.
Gong S, Zheng C, Doughty ML, Losos K, Didkovsky N, Schambra UB et al. A gene expression atlas of the central nervous system based on bacterial artificial chromosomes. Nature 2003; 425: 917–925.
Kwon GS, Hadjantonakis AK . Eomes::GFP-a tool for live imaging cells of the trophoblast, primitive streak, and telencephalon in the mouse embryo. Genesis 2007; 45: 208–217.
Mizutani K, Yoon K, Dang L, Tokunaga A, Gaiano N . Differential Notch signalling distinguishes neural stem cells from intermediate progenitors. Nature 2007; 449: 351–355.
Miyata T, Kawaguchi A, Saito K, Kawano M, Muto T, Ogawa M . Asymmetric production of surface-dividing and non-surface-dividing cortical progenitor cells. Development (Cambridge, England) 2004; 131: 3133–3145.
Mankinen CB, Hold JG, Sears JW . Partial trisomy 15 in a young girl. Clin Genet 1976; 10: 27–32.
Tiveron MC, Hirsch MR, Brunet JF . The expression pattern of the transcription factor Phox2 delineates synaptic pathways of the autonomic nervous system. J Neurosci 1996; 16: 7649–7660.
Arlotta P, Molyneaux BJ, Chen J, Inoue J, Kominami R, Macklis JD . Neuronal subtype-specific genes that control corticospinal motor neuron development in vivo. Neuron 2005; 45: 207–221.
Gradwohl G, Fode C, Guillemot F . Restricted expression of a novel murine atonal-related bHLH protein in undifferentiated neural precursors. Dev Biol 1996; 180: 227–241.
Kimura N, Nakashima K, Ueno M, Kiyama H, Taga T . A novel mammalian T-box-containing gene, Tbr2, expressed in mouse developing brain. Brain Res 1999; 115: 183–193.
Watakabe A, Ichinohe N, Ohsawa S, Hashikawa T, Komatsu Y, Rockland KS et al. Comparative analysis of layer-specific genes in mammalian neocortex. Cereb Cortex 2007; 17: 1918–1933.
Lee TI, Johnstone SE, Young RA . Chromatin immunoprecipitation and microarray-based analysis of protein location. Nat Protocols 2006; 1: 729–748.
Acknowledgements
We thank Frank Rauscher, Ariel Ruiz i Altaba, Louise Showe, Michael Showe and Russel Kaufman for comments on the manuscript, and Steve Potter, Tom Curran, Judy Grinspan, François Guillemot, Jeffrey Macklis, Tetsuya Taga and Akiya Watanabe for reagents. We also thank the Wistar Microscopy facility for the confocal microscopy images and pictures in Figures 1a–d, and the Wistar Flow Cytometry Facility for help with cortical cell sorting (NIH-NCI Core Grant CA010815). This work was supported by grants from the WW Smith Charitable Trust, the V Foundation, the American Cancer Society (RSG-08-045-01-DDC) and the National Brain Tumor Society to ND.
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Xiang, C., Baubet, V., Pal, S. et al. RP58/ZNF238 directly modulates proneurogenic gene levels and is required for neuronal differentiation and brain expansion. Cell Death Differ 19, 692–702 (2012). https://doi.org/10.1038/cdd.2011.144
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DOI: https://doi.org/10.1038/cdd.2011.144
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