The Epigenetic Factor Landscape of Developing Neocortex Is Regulated by Transcription Factors Pax6→ Tbr2→ Tbr1

Elsen, Gina E.; Bedogni, Francesco; Hodge, Rebecca D.; Bammler, Theo K.; MacDonald, James W.; Lindtner, Susan; Rubenstein, John L.R.; Hevner, Robert F.

doi:10.3389/fnins.2018.00571

Cited by 47 publications

(51 citation statements)

References 145 publications

(259 reference statements)

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“…Increased expression of Kat6b in Tbr2 cKO cortex may bias PNs towards a layer 5 fate (Elsen et al. ).…”

Section: Tbr2 Regulates the Differentiation Of Cortical Layersmentioning

confidence: 99%

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Intermediate progenitors and Tbr2 in cortical development

Hevner

2019

Journal of Anatomy

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In developing cerebral cortex, intermediate progenitors (IPs) are transit amplifying cells that specifically express Tbr2 (gene: Eomes), a T-box transcription factor. IPs are derived from radial glia (RG) progenitors, the neural stem cells of developing cortex. In turn, IPs generate glutamatergic projection neurons (PNs) exclusively. IPs are found in ventricular and subventricular zones, where they differentiate as distinct ventricular IP (vIP) and outer IP (oIP) subtypes. Morphologically, IPs have short processes, resembling filopodia or neurites, that transiently contact other cells, most importantly dividing RG cells to mediate Delta-Notch signaling. Also, IPs secrete a chemokine, Cxcl12, which guides interneuron and microglia migrations and promotes thalamocortical axon growth. In mice, IPs produce clones of 1-12 PNs, sometimes spanning multiple layers. After mitosis, IP daughter cells undergo asymmetric cell death in the majority of instances. In mice, Tbr2 is necessary for PN differentiation and subtype specification, and to repress IP-genic transcription factors. Tbr2 directly represses Insm1, an IP-genic transcription factor gene, as well as Pax6, a key activator of Tbr2 transcription. Without Tbr2, abnormal IPs transiently accumulate in elevated numbers. More broadly, Tbr2 regulates the transcriptome by activating or repressing hundreds of direct target genes. Notably, Tbr2 'unlocks' and activates PN-specific genes, such as Tbr1, by recruiting Jmjd3, a histone H3K27me3 demethylase that removes repressive epigenetic marks placed by polycomb repressive complex 2. IPs have played an important role in the evolution and gyrification of mammalian cerebral cortex, and TBR2 is essential for human brain development.

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“…Increased expression of Kat6b in Tbr2 cKO cortex may bias PNs towards a layer 5 fate (Elsen et al. ).…”

Section: Tbr2 Regulates the Differentiation Of Cortical Layersmentioning

confidence: 99%

“…) and Nes11 ‐Cre drivers (Elsen et al. , ). Because of problems with Foxg1 ‐Cre (Siegenthaler et al.…”

Section: Tbr2 Directly Regulates Hundreds Of Genes Including Epigenementioning

confidence: 99%

Intermediate progenitors and Tbr2 in cortical development

Hevner

2019

Journal of Anatomy

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“…Some vertebrate PCGF genes display spatial expression patterns, with higher levels in specific tissues or cells (72)(73)(74). We performed RNA in-situ hybridization at different developmental stages to determine whether such spatial regulation also occurs for Nematostella PCGF genes.…”

Section: Resultsmentioning

confidence: 99%

The genetic basis for PRC1 complex diversity emerged early in animal evolution

Gahan

Rentzsch

Schnitzler

2020

Preprint

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Polycomb group proteins are essential regulators of developmental processes across animals. Despite their importance, studies on Polycomb are often restricted to classical model systems and, as such, little is known about the evolution of these important chromatin regulators. Here we focus on Polycomb Repressive Complex 1 (PRC1) and trace the evolution of core components of canonical and non-canonical PRC1 complexes in animals. Previous work suggested that a major expansion in the number of PRC1 complexes occurred in the vertebrate lineage. Here we show that the expansion of the PCGF protein family, an essential step for the establishment of the large diversity of PRC1 complexes found in vertebrates, predates the bilateriancnidarian ancestor. This means that the genetic repertoire necessary to form all major vertebrate PRC1 complexes emerged early in animal evolution, over 550 million years ago. We further show that PCGF5, a gene conserved in cnidarians and vertebrates but lost in all other studied groups, is expressed in the nervous system in the sea anemone Nematostella vectensis, similar to its mammalian counterpart. Together this work provides an evolutionary framework to understand PRC1 complex diversity and evolution and establishes Nematostella as a promising model system in which this can be further explored.

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“…Also, feedback interactions between cell populations is only one of the source of time-dependency. The sequence of proliferation and differentiation of neural progenitors in the cortex is subject to numerous intrinsic and extrinsic dynamical processes [42], among which (i) cell-autonomous programming along successive cell generations (sequential genetic expression of molecular markers associated with an increasing differentiation status) (reviewed in [63]), (ii) spatio-temporal gradients of morphogens originating from organizing centers in the brain (reviewed in [64]) and (iii) transient cell-cell interactions between the different cell types, including possible feedback from post-mitotic cells onto progenitor cells (reviewed in [26]).…”

Section: Discussionmentioning

confidence: 99%

A multiscale mathematical model of cell dynamics during neurogenesis in the mouse cerebral cortex

et al. 2019

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Background Neurogenesis in the murine cerebral cortex involves the coordinated divisions of two main types of progenitor cells, whose numbers, division modes and cell cycle durations set up the final neuronal output. To understand the respective roles of these factors in the neurogenesis process, we combine experimental in vivo studies with mathematical modeling and numerical simulations of the dynamics of neural progenitor cells. A special focus is put on the population of intermediate progenitors (IPs), a transit amplifying progenitor type critically involved in the size of the final neuron pool. Results A multiscale formalism describing IP dynamics allows one to track the progression of cells along the subsequent phases of the cell cycle, as well as the temporal evolution of the different cell numbers. Our model takes into account the dividing apical progenitors (AP) engaged into neurogenesis, both neurogenic and proliferative IPs, and the newborn neurons. The transfer rates from one population to another are subject to the mode of division (proliferative, or neurogenic) and may be time-varying. The model outputs are successfully fitted to experimental cell numbers from mouse embryos at different stages of cortical development, taking into account IPs and neurons, in order to adjust the numerical parameters. We provide additional information on cell kinetics, such as the mitotic and S phase indexes, and neurogenic fraction. Conclusions Applying the model to a mouse mutant for Ftm/Rpgrip1l, a gene involved in human ciliopathies with severe brain abnormalities, reveals a shortening of the neurogenic period associated with an increased influx of newborn IPs from apical progenitors at mid-neurogenesis. Our model can be used to study other mouse mutants with cortical neurogenesis defects and can be adapted to study the importance of progenitor dynamics in cortical evolution and human diseases.

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The Epigenetic Factor Landscape of Developing Neocortex Is Regulated by Transcription Factors Pax6→ Tbr2→ Tbr1

Cited by 47 publications

References 145 publications

Intermediate progenitors and Tbr2 in cortical development

Intermediate progenitors and Tbr2 in cortical development

The genetic basis for PRC1 complex diversity emerged early in animal evolution

A multiscale mathematical model of cell dynamics during neurogenesis in the mouse cerebral cortex

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