Dataset Information


Sip1 regulates sequential fate decisions through feedback signalling from postmitotic neurons to progenitor cells.

ABSTRACT: In the developing cerebral cortex different types of neurons and glial cells are born through a precisely controlled sequence of events. The fate of cortical progenitors, in turn, is determined by an elusive conundrum of temporally and spatially regulated signalling mechanisms. We found the DNA-binding transcription factor Sip1 (also known as Zfhx1b) to be produced at high levels in postmitotic neurons of the cerebral cortex. Conditional deletion of Sip1 in young neocortical neurons was found to induce premature and increased production of upper layer neurons at the expense of deep layer neurons. Furthermore, it caused precocious and increased generation of glial precursors during late corticogenesis, leading subsequently to enhanced astrocytogenesis at early postnatal stages. Expression profiling analysis indicated that the temporal shift in upper layer production coincides with overexpression of the neurotrophin-3 (NT3) gene and altered growth factor signalling in progenitors, while the premature gliogenesis is preceded by upregulation of fibroblast growth factor-9 (Fgf9) gene expression. Chromatin immunoprecipitation and in situ hybridization validates NT3 as a direct target of Sip1 in the cortex and confines the transcriptional repression by Sip1 to postmitotic neurons. Moreover, we show that exogenous application of Fgf9 in solution or via coated beads to wild-type cortical slices induces premature and excessive generation of glial precursors in the germinal zone. In conclusion, our data suggest that throughout corticogenesis Sip1 acts to restrain the level of production of secreted signalling factors in postmitotic neurons. These factors feed back to progenitor cells in order to regulate the timing of cell fate switch and the numbers of neurons and glial cells produced in the developing cerebral cortex. Overall design: In a first series of arrays, we examined differential gene expression in neocortex and hippocampal tissue from 2 control (WT|Nestin) and 2 mutant (Sip1|Nestin) E18.5 littermate mice, each taken from 2 different litters (x|Nestin1 and x|Nestin2). In a separate experiment, we tested differential gene expression in E14.5 neocortex and hippocampal tissue from 2 control (WT|NEX) and 2 mutant (Sip1|NEX) littermate mice. RNA from mouse neocortex and hippocampus tissues was isolated using RNeasy kit according to the manufacturer’s protocol (QIAGEN). Total RNA was controlled for integrity and purity using an Agilent Bioanalyzer and a NanoDrop spectrophotometer, respectively. All samples were of similar RNA quality. Starting with 1ug of total RNA, the RNA amplification was performed by in vitro transcription (IVT) with a biotin labeling reaction during the IVT, according to the recommendations of the manufacturer (Amersham Biosciences). The probes were purified and analyzed again for yield (> 20 ug) and purity (260:280 nm and 260:230 nm >1.8). Ten micrograms of the resulting antisense RNA was fragmented according to the recommendations of the manufacturer (Amersham Biosciences) and resuspended in 260 ml of hybridization buffer. Codelink Mouse Whole Genome array is a single array representing 35,000 transcripts. The gene array chips were hybridized in a shaker-incubator at 37°C at 300 rpm for 18 hours and washed and stained with Cy5-Streptavidin according to the recommendations of the manufacturer (Amersham Biosciences). The DNA Microarray scanner of Agilent was used for scanning and image analysis was performed with the Codelink Expression Analysis 4.1 software

INSTRUMENT(S): GE Healthcare/Amersham Biosciences CodeLink™ Mouse Whole Genome Bioarray

SUBMITTER: Wouter Van Delm   

PROVIDER: GSE16699 | GEO | 2009-10-30



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Sip1 regulates sequential fate decisions by feedback signaling from postmitotic neurons to progenitors.

Seuntjens Eve E   Nityanandam Anjana A   Miquelajauregui Amaya A   Debruyn Joke J   Stryjewska Agata A   Goebbels Sandra S   Nave Klaus-Armin KA   Huylebroeck Danny D   Tarabykin Victor V  

Nature neuroscience 20091018 11

The fate of cortical progenitors, which progressively generate neurons and glial cells during development, is determined by temporally and spatially regulated signaling mechanisms. We found that the transcription factor Sip1 (Zfhx1b), which is produced at high levels in postmitotic neocortical neurons, regulates progenitor fate non-cell autonomously. Conditional deletion of Sip1 in young neurons induced premature production of upper-layer neurons at the expense of deep layers, precocious and inc  ...[more]

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