scholarly journals Loss of Suppressor of Fused in Mid-Corticogenesis Leads to the Expansion of Intermediate Progenitors

2016 ◽  
Vol 4 (4) ◽  
pp. 29 ◽  
Author(s):  
Odessa Yabut ◽  
Hui Ng ◽  
Gloria Fernandez ◽  
Keejung Yoon ◽  
Jeremy Kuhn ◽  
...  
Keyword(s):  
Suppressor Of Fused ◽  
Intermediate Progenitors

Differential Notch signalling distinguishes neural stem cells from intermediate progenitors

Nature ◽  
2007 ◽  
Vol 449 (7160) ◽  
pp. 351-355 ◽  
Author(s):  
Ken-ichi Mizutani ◽  
Keejung Yoon ◽  
Louis Dang ◽  
Akinori Tokunaga ◽  
Nicholas Gaiano
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Notch Signalling ◽  
Intermediate Progenitors

scholarly journals Distinct, dosage-sensitive requirements for the autism-associated factor CHD8 during cortical development

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Shaun Hurley ◽  
Conor Mohan ◽  
Philipp Suetterlin ◽  
Robert Ellingford ◽  
Kimberley L. H. Riegman ◽  
...  
Keyword(s):  
Gene Expression ◽  
Brain Development ◽  
Brain Size ◽  
Cortical Development ◽  
Neural Progenitor ◽  
Conditional Knockout ◽  
P53 Pathway ◽  
Associated Factor ◽  
Transcriptional Dysregulation ◽  
Intermediate Progenitors

Abstract Background CHD8 haploinsufficiency causes autism and macrocephaly with high penetrance in the human population. Chd8 heterozygous mice exhibit relatively subtle brain overgrowth and little gene expression changes in the embryonic neocortex. The purpose of this study was to generate new, sub-haploinsufficient Chd8 mouse models to allow us to identify and study the functions of CHD8 during embryonic cortical development. Methods To examine the possibility that certain phenotypes may only appear at sub-heterozygous Chd8 levels in the mouse, we created an allelic series of Chd8-deficient mice to reduce CHD8 protein levels to approximately 35% (mild hypomorph), 10% (severe hypomorph) and 0% (neural-specific conditional knockout) of wildtype levels. We used RNA sequencing to compare transcriptional dysregulation, structural MRI and brain weight to investigate effects on brain size, and cell proliferation, differentiation and apoptosis markers in immunostaining assays to quantify changes in neural progenitor fate. Results Mild Chd8 hypomorphs displayed significant postnatal lethality, with surviving animals exhibiting more pronounced brain hyperplasia than heterozygotes. Over 2000 genes were dysregulated in mild hypomorphs, including autism-associated neurodevelopmental and cell cycle genes. We identify increased proliferation of non-ventricular zone TBR2+ intermediate progenitors as one potential cause of brain hyperplasia in these mutants. Severe Chd8 hypomorphs displayed even greater transcriptional dysregulation, including evidence for p53 pathway upregulation. In contrast to mild hypomorphs, these mice displayed reduced brain size and increased apoptosis in the embryonic neocortex. Homozygous, conditional deletion of Chd8 in early neuronal progenitors resulted in pronounced brain hypoplasia, partly caused by p53 target gene derepression and apoptosis in the embryonic neocortex. Limitations Our findings identify an important role for the autism-associated factor CHD8 in controlling the proliferation of intermediate progenitors in the mouse neocortex. We propose that CHD8 has a similar function in human brain development, but studies on human cells are required to confirm this. Because many of our mouse mutants with reduced CHD8 function die shortly after birth, it is not possible to fully determine to what extent reduced CHD8 function results in autism-associated behaviours in mice. Conclusions Together, these findings identify important, dosage-sensitive functions for CHD8 in p53 pathway repression, neurodevelopmental gene expression and neural progenitor fate in the embryonic neocortex. We conclude that brain development is acutely sensitive to reduced CHD8 expression and that the varying sensitivities of different progenitor populations and cellular processes to CHD8 dosage result in non-linear effects on gene transcription and brain growth. Shaun Hurley, Conor Mohan and Philipp Suetterlin have contributed equally to this work.

scholarly journals The Making of Hematopoiesis: Developmental Ancestry and Environmental Nurture

2018 ◽  
Vol 19 (7) ◽  
pp. 2122 ◽  
Author(s):  
Geoffrey Brown ◽  
Rhodri Ceredig ◽  
Panagiotis Tsapogas
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Progenitor Cells ◽  
Cell Fate ◽  
Hematopoietic Stem ◽  
Fate Determination ◽  
Intermediate Progenitors ◽  
Lineage Tree ◽  
Stem And Progenitor Cells ◽  
The Many

Evidence from studies of the behaviour of stem and progenitor cells and of the influence of cytokines on their fate determination, has recently led to a revised view of the process by which hematopoietic stem cells and their progeny give rise to the many different types of blood and immune cells. The new scenario abandons the classical view of a rigidly demarcated lineage tree and replaces it with a much more continuum-like view of the spectrum of fate options open to hematopoietic stem cells and their progeny. This is in contrast to previous lineage diagrams, which envisaged stem cells progressing stepwise through a series of fairly-precisely described intermediate progenitors in order to close down alternative developmental options. Instead, stem and progenitor cells retain some capacity to step sideways and adopt alternative, closely related, fates, even after they have “made a lineage choice.” The stem and progenitor cells are more inherently versatile than previously thought and perhaps sensitive to lineage guidance by environmental cues. Here we examine the evidence that supports these views and reconsider the meaning of cell lineages in the context of a continuum model of stem cell fate determination and environmental modulation.

Abstract B29: Inactivation of suppressor of fused alone is not sufficient to cause medulloblastoma

2009 ◽  
Author(s):  
Thevagi Satkunendran ◽  
Ryan J. Ward ◽  
Peter B. Dirks ◽  
Chi-chung Hui
Keyword(s):  
Suppressor Of Fused

scholarly journals Tuba8 Drives Differentiation of Cortical Radial Glia into Apical Intermediate Progenitors by Tuning Modifications of Tubulin C Termini

2020 ◽  
Vol 52 (4) ◽  
pp. 477-491.e8 ◽  
Author(s):  
Susana I. Ramos ◽  
Eugene V. Makeyev ◽  
Marcelo Salierno ◽  
Takashi Kodama ◽  
Yasuhiko Kawakami ◽  
...  
Keyword(s):  
Radial Glia ◽  
Intermediate Progenitors

scholarly journals Neddylation is critical to cortical development by regulating Wnt/β-catenin signaling

2020 ◽  
Vol 117 (42) ◽  
pp. 26448-26459 ◽  
Author(s):  
Lei Zhang ◽  
Hongyang Jing ◽  
Haiwen Li ◽  
Wenbing Chen ◽  
Bin Luo ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Protein Modification ◽  
Radial Glia ◽  
Critical Role ◽  
Cortical Development ◽  
Nuclear Accumulation ◽  
Progressive Reduction ◽  
Intermediate Progenitors

Wnt signaling plays a critical role in production and differentiation of neurons and undergoes a progressive reduction during cortical development. However, how Wnt signaling is regulated is not well understood. Here we provide evidence for an indispensable role of neddylation, a ubiquitylation-like protein modification, in inhibiting Wnt/β-catenin signaling. We show that β-catenin is neddylated; and inhibiting β-catenin neddylation increases its nuclear accumulation and Wnt/β-catenin signaling. To test this hypothesis in vivo, we mutated Nae1, an obligative subunit of the E1 for neddylation in cortical progenitors. The mutation leads to eventual reduction in radial glia progenitors (RGPs). Consequently, the production of intermediate progenitors (IPs) and neurons is reduced, and neuron migration is impaired, resulting in disorganization of the cerebral cortex. These phenotypes are similar to those of β-catenin gain-of-function mice. Finally, suppressing β-catenin expression is able to rescue deficits of Nae1 mutant mice. Together, these observations identified a mechanism to regulate Wnt/β-catenin signaling in cortical development.

scholarly journals Protein phosphatase 4 promotes Hedgehog signaling through dephosphorylation of Suppressor of fused

2020 ◽  
Vol 11 (8) ◽  
Author(s):  
Hengqing Liao ◽  
Jing Cai ◽  
Chen Liu ◽  
Longyan Shen ◽  
Xiaohong Pu ◽  
...  
Keyword(s):  
Protein Phosphatase ◽  
Hedgehog Signaling ◽  
Suppressor Of Fused
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