scholarly journals Critical role of the BAF chromatin remodeling complex during murine neural crest development

PLoS Genetics ◽  
2021 ◽  
Vol 17 (3) ◽  
pp. e1009446
Author(s):  
Kathleen Wung Bi-Lin ◽  
Pratap Veerabrahma Seshachalam ◽  
Tran Tuoc ◽  
Anastassia Stoykova ◽  
Sujoy Ghosh ◽  
...  
Keyword(s):  
Neural Crest ◽  
Target Genes ◽  
Critical Role ◽  
Enrichment Analysis ◽  
Developmental Defects ◽  
Baf Complex ◽  
Neural Crest Development ◽  
Wide Range ◽  
Proliferation And Differentiation

The BAF complex plays an important role in the development of a wide range of tissues by modulating gene expression programs at the chromatin level. However, its role in neural crest development has remained unclear. To determine the role of the BAF complex, we deleted BAF155/BAF170, the core subunits required for the assembly, stability, and functions of the BAF complex in neural crest cells (NCCs). Neural crest-specific deletion of BAF155/BAF170 leads to embryonic lethality due to a wide range of developmental defects including craniofacial, pharyngeal arch artery, and OFT defects. RNAseq and transcription factor enrichment analysis revealed that the BAF complex modulates the expression of multiple signaling pathway genes including Hippo and Notch, essential for the migration, proliferation, and differentiation of the NCCs. Furthermore, we demonstrated that the BAF complex is essential for the Brg1-Yap-Tead-dependent transcription of target genes in NCCs. Together, our results demonstrate an important role of the BAF complex in modulating the gene regulatory network essential for neural crest development.

scholarly journals Kdm6b confers Tfdp1 with the competence to activate p53 signalling in regulating palatogenesis

2021 ◽  
Author(s):  
Yang Chai ◽  
Tingwei Guo ◽  
Xia Han ◽  
Jinzhi He ◽  
Jifan Feng ◽  
...  
Keyword(s):  
Neural Crest ◽  
Epigenetic Regulation ◽  
Developmental Defects ◽  
P53 Expression ◽  
Cell Proliferation And Differentiation ◽  
Proliferation And Differentiation ◽  
Epigenetic Regulator ◽  
Cranial Neural Crest Cells ◽  
Risk Of Cancer

Epigenetic regulation plays extensive roles in diseases and development. Disruption of epigenetic regulation not only increases the risk of cancer, but can also cause various developmental defects. However, it is still unclear how epigenetic regulators coordinate with tissue-specific regulatory factors during morphogenesis of specific organs. Using palatogenesis as a model, we reveal the functional significance of Kdm6b, a H3K27me3 demethylase, in regulating embryonic development. Our study shows that Kdm6b plays an essential role in neural crest development, and loss of Kdm6b disturbs p53 pathway-mediated activity, leading to complete cleft palate along with cell proliferation and differentiation defects. Furthermore, activity of H3K27me3 on the promoter of p53 is precisely controlled by Kdm6b, and Ezh2 in regulating p53 expression in cranial neural crest cells. More importantly, Kdm6b renders chromatin accessible to the transcription factor Tfdp1, which binds to the promoter of p53 along with Kdm6b to specifically activate p53 expression during palatogenesis. Collectively our results highlight the important role of the epigenetic regulator Kdm6b and how it cooperates with Tfdp1 to achieve its functional specificity in regulating p53 expression, and further provide mechanistic insights into the epigenetic regulatory network during organogenesis.

scholarly journals Development of cancer metabolism as a therapeutic target: new pathways, patient studies, stratification and combination therapy

2019 ◽  
Vol 122 (1) ◽  
pp. 1-3 ◽  
Author(s):  
Adrian L. Harris
Keyword(s):  
Metabolic Pathways ◽  
Trial Design ◽  
Cancer Metabolism ◽  
Aerobic Glycolysis ◽  
Critical Role ◽  
Therapeutic Approaches ◽  
Preclinical Models ◽  
Wide Range ◽  
Patient Studies

AbstractCancer metabolism has undergone a resurgence in the last decade, 70 years after Warburg described aerobic glycolysis as a feature of cancer cells. A wide range of techniques have elucidated the complexity and heterogeneity in preclinical models and clinical studies. What emerges are the large differences between tissues, tumour types and intratumour heterogeneity. However, synergies with inhibition of metabolic pathways have been found for many drugs and therapeutic approaches, and a critical role of window studies and translational trial design is key to success.

scholarly journals Critical role of Brg1 member of the SWI/SNF chromatin remodeling complex during neurogenesis and neural crest induction in zebrafish

2006 ◽  
Vol 235 (10) ◽  
pp. 2722-2735 ◽  
Author(s):  
Binnur Eroglu ◽  
Guanghu Wang ◽  
Naxin Tu ◽  
Xutong Sun ◽  
Nahid F. Mivechi
Keyword(s):  
Neural Crest ◽  
Chromatin Remodeling ◽  
Critical Role ◽  
Chromatin Remodeling Complex

Wildlife management and the debate on the ethics of animal use. II. A challenge for the animal protection movement.

2012 ◽  
Vol 18 (2) ◽  
pp. 81 ◽  
Author(s):  
Daniel Lunney
Keyword(s):  
Wildlife Management ◽  
Critical Role ◽  
Animal Liberation ◽  
Ethical Imperative ◽  
Animal Protection ◽  
Wide Range ◽  
Animal Use

How people coexist and interact with animals has become an intensely debated issue in recent times, particularly with the rise of the animal protection movement following the publication of Peter Singer’s book Animal Liberation in 1975. This paper discusses some shortcomings of the philosophical positions taken in this complex debate. Singer has helped put animals on a new footing as a group that cannot morally be ignored, but his focus is mainly on individual, familiar animals that are used or abused by humans. The argument of this paper is that the ethics of managing wildlife hinges on a broader view of animals, and their contexts, than is apparent from Singer’s text. Wildlife managers aim to conserve populations of a wide range of species, and their habitats, but some mechanisms for achieving these aims, such as research and the control of invasive animals, are frequently opposed by elements of the animal protection movement. We need to adapt our attitude to animals, particularly wildlife, away from the traditional legacy of a few familiar species to embrace an ethic that is more ecological and relevant to Australian contexts. The case argued here has been to see the critical role of context — geographical, ecological, historical, relational — as a basis for a degree of reconciliation between conservation-oriented wildlife managers and the rising interest in the ethics of animal use. There is much to be gained for zoologists, wildlife managers and conservation biologists by framing key elements of their case in ethical arguments. Conversely, the challenge for those in the animal protection movement is to expand their philosophical ideas to include the ethical imperative of the conservation of populations of wildlife.

scholarly journals Calcium Signaling in Vertebrate Development and Its Role in Disease

2018 ◽  
Vol 19 (11) ◽  
pp. 3390 ◽  
Author(s):  
Sudip Paudel ◽  
Regan Sindelar ◽  
Margaret Saha
Keyword(s):  
Calcium Signaling ◽  
Critical Role ◽  
Molecular Techniques ◽  
Model Organisms ◽  
Vertebrate Development ◽  
Developmental Defects ◽  
Calcium Activity ◽  
Human Genes ◽  
Underlying Mechanisms

Accumulating evidence over the past three decades suggests that altered calcium signaling during development may be a major driving force for adult pathophysiological events. Well over a hundred human genes encode proteins that are specifically dedicated to calcium homeostasis and calcium signaling, and the majority of these are expressed during embryonic development. Recent advances in molecular techniques have identified impaired calcium signaling during development due to either mutations or dysregulation of these proteins. This impaired signaling has been implicated in various human diseases ranging from cardiac malformations to epilepsy. Although the molecular basis of these and other diseases have been well studied in adult systems, the potential developmental origins of such diseases are less well characterized. In this review, we will discuss the recent evidence that examines different patterns of calcium activity during early development, as well as potential medical conditions associated with its dysregulation. Studies performed using various model organisms, including zebrafish, Xenopus, and mouse, have underscored the critical role of calcium activity in infertility, abortive pregnancy, developmental defects, and a range of diseases which manifest later in life. Understanding the underlying mechanisms by which calcium regulates these diverse developmental processes remains a challenge; however, this knowledge will potentially enable calcium signaling to be used as a therapeutic target in regenerative and personalized medicine.

scholarly journals NUSAP1 Promotes Gastric Cancer Progression Through Regulation of Yap Stability

2020 ◽  
Author(s):  
Hui Guo ◽  
Jianping Zou ◽  
Ling Zhou ◽  
Yan He ◽  
Miao Feng ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Progression ◽  
Target Genes ◽  
Hippo Pathway ◽  
Critical Role ◽  
Xenograft Model ◽  
Migration And Invasion

Abstract Background:Nucleolar and spindle associated protein (NUSAP1) is involved in tumor initiation, progression and metastasis. However, there are limited studies regarding the role of NUSAP1 in gastric cancer (GC). Methods: The expression profile and clinical significance of NUSAP1 in GC were analysed in online database using GEPIA, Oncomine and KM plotter, which was further confirmed in clinical specimens.The functional role of NUSAP1 were detected utilizing in vitro and in vivo assays. Western blotting, qRT-PCR, the cycloheximide-chase, immunofluorescence staining and Co-immunoprecipitaion (Co-IP) assays were performed to explore the possible molecular mechanism by which NUSAP1 stabilizes YAP protein. Results:In this study, we found that the expression of NUSAP1 was upregulated in GC tissues and correlates closely with progression and prognosis. Additionally, abnormal NUSAP1 expression promoted malignant behaviors of GC cells in vitro and in a xenograft model. Mechanistically, we discovered that NUSAP1 physically interacts with YAP and furthermore stabilizes YAP protein expression, which induces the transcription of Hippo pathway downstream target genes. Furthermore, the effects of NUSAP1 on GC cell growth, migration and invasion were mainly mediated by YAP. Conclusions:Our data demonstrates that the novel NUSAP1-YAP axis exerts an critical role in GC tumorigenesis and progression, and therefore could provide a novel therapeutic target for GC treatment.

scholarly journals Critical role of WNK1 in MYC-dependent early mouse thymocyte development

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Robert Köchl ◽  
Lesley Vanes ◽  
Miriam Llorian Sopena ◽  
Probir Chakravarty ◽  
Harald Hartweger ◽  
...  
Keyword(s):  
Critical Role ◽  
Ion Homeostasis ◽  
Thymocyte Development ◽  
Double Positive ◽  
Mouse Thymocyte ◽  
Proliferation And Differentiation ◽  
Tcr Signals ◽  
And Migration ◽  
Early Mouse

WNK1, a kinase that controls kidney salt homeostasis, also regulates adhesion and migration in CD4+ T cells. Wnk1 is highly expressed in thymocytes, and since migration is important for thymocyte maturation, we investigated a role for WNK1 in mouse thymocyte development. We find that WNK1 is required for the transition of double negative (DN) thymocytes through the β-selection checkpoint and subsequent proliferation and differentiation into double positive (DP) thymocytes. Furthermore, we show that WNK1 negatively regulates LFA1-mediated adhesion and positively regulates CXCL12-induced migration in DN thymocytes. Despite this, migration defects of WNK1-deficient thymocytes do not account for the developmental arrest. Instead, we show that in DN thymocytes WNK1 transduces pre-TCR signals via OXSR1 and STK39 kinases, and the SLC12A2 ion co-transporter that are required for post-transcriptional upregulation of MYC and subsequent proliferation and differentiation into DP thymocytes. Thus, a pathway regulating ion homeostasis is a critical regulator of thymocyte development.

scholarly journals Lineage-specific requirements of β-catenin in neural crest development

2002 ◽  
Vol 159 (5) ◽  
pp. 867-880 ◽  
Author(s):  
Lisette Hari ◽  
Véronique Brault ◽  
Maurice Kléber ◽  
Hye-Youn Lee ◽  
Fabian Ille ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Neural Crest ◽  
Neural Crest Cells ◽  
Neural Crest Stem Cells ◽  
Downstream Signaling ◽  
Neural Crest Development ◽  
Sensory Neurogenesis

β-Catenin plays a pivotal role in cadherin-mediated cell adhesion. Moreover, it is a downstream signaling component of Wnt that controls multiple developmental processes such as cell proliferation, apoptosis, and fate decisions. To study the role of β-catenin in neural crest development, we used the Cre/loxP system to ablate β-catenin specifically in neural crest stem cells. Although several neural crest–derived structures develop normally, mutant animals lack melanocytes and dorsal root ganglia (DRG). In vivo and in vitro analyses revealed that mutant neural crest cells emigrate but fail to generate an early wave of sensory neurogenesis that is normally marked by the transcription factor neurogenin (ngn) 2. This indicates a role of β-catenin in premigratory or early migratory neural crest and points to heterogeneity of neural crest cells at the earliest stages of crest development. In addition, migratory neural crest cells lateral to the neural tube do not aggregate to form DRG and are unable to produce a later wave of sensory neurogenesis usually marked by the transcription factor ngn1. We propose that the requirement of β-catenin for the specification of melanocytes and sensory neuronal lineages reflects roles of β-catenin both in Wnt signaling and in mediating cell–cell interactions.

scholarly journals The role of Sip1 in cranial neural crest development

2011 ◽  
Vol 356 (1) ◽  
pp. 238-239 ◽  
Author(s):  
Crystal Rogers ◽  
Marianne Bronner-Fraser
Keyword(s):  
Neural Crest ◽  
Cranial Neural Crest ◽  
Neural Crest Development

Hedgehog signals regulate multiple aspects of gastrointestinal development

Development ◽  
2000 ◽  
Vol 127 (12) ◽  
pp. 2763-2772 ◽  
Author(s):  
M. Ramalho-Santos ◽  
D.A. Melton ◽  
A.P. McMahon
Keyword(s):  
Gastrointestinal Tract ◽  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
Target Genes ◽  
Critical Role ◽  
Indian Hedgehog ◽  
Cell Proliferation And Differentiation ◽  
Proliferation And Differentiation ◽  
Mesodermal Origin ◽  
Gut Endoderm

The gastrointestinal tract develops from the embryonic gut, which is composed of an endodermally derived epithelium surrounded by cells of mesodermal origin. Cell signaling between these two tissue layers appears to play a critical role in coordinating patterning and organogenesis of the gut and its derivatives. We have assessed the function of Sonic hedgehog and Indian hedgehog genes, which encode members of the Hedgehog family of cell signals. Both are expressed in gut endoderm, whereas target genes are expressed in discrete layers in the mesenchyme. It was unclear whether functional redundancy between the two genes would preclude a genetic analysis of the roles of Hedgehog signaling in the mouse gut. We show here that the mouse gut has both common and separate requirements for Sonic hedgehog and Indian hedgehog. Both Sonic hedgehog and Indian hedgehog mutant mice show reduced smooth muscle, gut malrotation and annular pancreas. Sonic hedgehog mutants display intestinal transformation of the stomach, duodenal stenosis (obstruction), abnormal innervation of the gut and imperforate anus. Indian hedgehog mutants show reduced epithelial stem cell proliferation and differentiation, together with features typical of Hirschsprung's disease (aganglionic colon). These results show that Hedgehog signals are essential for organogenesis of the mammalian gastrointestinal tract and suggest that mutations in members of this signaling pathway may be involved in human gastrointestinal malformations.

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