Sequential transcriptional waves direct the differentiation of newborn neurons in the mouse neocortex

Telley, Ludovic; Govindan, Subashika; Prados, Julien; Stévant, Isabelle; Nef, Serge; Dermitzakis, Emmanouil T.; Dayer, Alexandre; Jabaudon, Denis

doi:10.1126/science.aad8361

Cited by 288 publications

(339 citation statements)

References 26 publications

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“…Only a few neuron-specific transcriptomes have been reported so far (Akimoto et al, 2006; Macosko et al, 2015; Siegert et al, 2012; Telley et al, 2016; Zhang et al, 2014). Here, we used the mouse rod photoreceptor as a model sensory neuron to establish temporal transcriptome dynamics driven by the rod cell fate determination factor NRL, using two distinct platforms – RNA-seq and exon arrays – for cross-validation and deeper coverage of differentially expressed genes.…”

Section: Discussionmentioning

confidence: 99%

NRL-Regulated Transcriptome Dynamics of Developing Rod Photoreceptors

et al. 2016

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SUMMARY Gene regulatory networks (GRNs) guiding differentiation of cell types and cell assemblies in the nervous system are poorly understood because of inherent complexities and interdependence of signaling pathways. Here, we report transcriptome dynamics of differentiating rod photoreceptors in the mammalian retina. As the transcription factor NRL determines rod cell fate, we performed expression profiling of developing NRL-positive (rods) and NRL-negative (S-cone like) mouse photoreceptors. We identified a large-scale, sharp transition in the transcriptome landscape between postnatal day 6 and 10 concordant with rod morphogenesis. Rod-specific temporal DNA methylation corroborated gene expression patterns. De novo assembly and alternative splicing analyses revealed previously un-annotated rod-enriched transcripts and the role of NRL in transcript maturation. Furthermore, we defined the relationship of NRL with other transcriptional regulators and downstream cognate effectors. Our studies provide the framework for comprehensive system-level analysis of the GRN underlying the development of a single sensory neuron, the rod photoreceptor.

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Section: Discussionmentioning

confidence: 99%

NRL-Regulated Transcriptome Dynamics of Developing Rod Photoreceptors

et al. 2016

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“…Cortical progenitors in the developing neocortex are highly heterogeneous and are distinguished according to unique transcriptional programs that remain dynamic during corticogenesis [57–60]. As a morphogen, Shh can trigger differential gene expression changes temporally and spatially that may influence progenitor heterogeneity and their ability to produce specific progenies throughout corticogenesis.…”

Section: Roles Of Shh Signaling In the Specification Of Cortical Progmentioning

confidence: 99%

Sonic Hedgehog Signaling Rises to the Surface: Emerging Roles in Neocortical Development

Yabut

Pleasure

2018

BPL

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The mammalian neocortex is composed of a diverse population of neuronal and glial cells that are crucial for cognition and consciousness. Orchestration of molecular events that lead to the production of distinct cell lineages is now a major research focus. Recent studies in mammalian animal models reveal that Sonic Hedgehog (Shh) signaling plays crucial roles in this process. In this review, we will evaluate these studies and provide insights on how Shh signaling specifically influence cortical development, beyond its established roles in telencephalic patterning, by specifically focusing on its impact on cells derived from the cortical radial glial (RG) cells. We will also assess how these findings further advance our knowledge of neurological diseases and discuss potential roles of targeting Shh signaling in therapies.

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“…The proposed functions of Akirin2 make it particularly interesting as a candidate regulator of cortical development, where progenitor populations divide rapidly in a highly regulated manner and where overlapping patterns of gene expression govern differentiation [20]. It has recently become clear that the mammalian BAF chromatin remodeling complex is a critical regulator of neuronal development.…”

Section: Introductionmentioning

confidence: 99%

Akirin2 is essential for the formation of the cerebral cortex

et al. 2016

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BackgroundThe proper spatial and temporal regulation of dorsal telencephalic progenitor behavior is a prerequisite for the formation of the highly-organized, six-layered cerebral cortex. Premature differentiation of cells, disruption of cell cycle timing, excessive apoptosis, and/or incorrect neuronal migration signals can have devastating effects, resulting in a number of neurodevelopmental disorders involving microcephaly and/or lissencephaly. Though genes encoding many key players in cortical development have been identified, our understanding remains incomplete. We show that the gene encoding Akirin2, a small nuclear protein, is expressed in the embryonic telencephalon. Converging evidence indicates that Akirin2 acts as a bridge between transcription factors (including Twist and NF-κB proteins) and the BAF (SWI/SNF) chromatin remodeling machinery to regulate patterns of gene expression. Constitutive knockout of Akirin2 is early embryonic lethal in mice, while restricted loss in B cells led to disrupted proliferation and cell survival.MethodsWe generated cortex-restricted Akirin2 knockouts by crossing mice harboring a floxed Akirin2 allele with the Emx1-Cre transgenic line and assessed the resulting embryos using in situ hybridization, EdU labeling, and immunohistochemistry.ResultsThe vast majority of Akirin2 mutants do not survive past birth, and exhibit extreme microcephaly, with little dorsal telencephalic tissue and no recognizable cortex. This is primarily due to massive cell death of early cortical progenitors, which begins at embryonic day (E)10, shortly after Emx1-Cre is active. Immunostaining and cell cycle analysis using EdU labeling indicate that Akirin2-null progenitors fail to proliferate normally, produce fewer neurons, and undergo extensive apoptosis. All of the neurons that are generated in Akirin2 mutants also undergo apoptosis by E12. In situ hybridization for Wnt3a and Wnt-responsive genes suggest defective formation and/or function of the cortical hem in Akirin2 null mice. Furthermore, the apical ventricular surface becomes disrupted, and Sox2-positive progenitors are found to “spill” into the lateral ventricle.ConclusionsOur data demonstrate a previously-unsuspected role for Akirin2 in early cortical development and, given its known nuclear roles, suggest that it may act to regulate gene expression patterns critical for early progenitor cell behavior and cortical neuron production.Electronic supplementary materialThe online version of this article (doi:10.1186/s13064-016-0076-8) contains supplementary material, which is available to authorized users.

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Sequential transcriptional waves direct the differentiation of newborn neurons in the mouse neocortex

Cited by 288 publications

References 26 publications

NRL-Regulated Transcriptome Dynamics of Developing Rod Photoreceptors

NRL-Regulated Transcriptome Dynamics of Developing Rod Photoreceptors

Sonic Hedgehog Signaling Rises to the Surface: Emerging Roles in Neocortical Development

Akirin2 is essential for the formation of the cerebral cortex

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