scholarly journals PDTM-09. Yap1 FUNCTION IN SEX-BIASED MEDULLOBLASTOMA FORMATION AND ANTI-TUMOR IMMUNITY

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi188-vi188
Author(s):  
Nourhan Abdelfattah ◽  
Sivaraman Natarajan ◽  
Yaohui Chen ◽  
Kin-Hoe Chow ◽  
Shu-hsia Chen ◽  
...  
Keyword(s):  
Cytotoxic T Cells ◽  
Therapeutic Benefit ◽  
Tumor Formation ◽  
Normal Brain ◽  
A Cell ◽  
Developing Mouse Brain ◽  
Pediatric Brain ◽  
Normal Brain Development ◽  
Extended Survival

Abstract Immunotherapies offer remarkable potential to provide robust therapeutic benefit. Patients suffering from medulloblastoma (MB), the most frequent pediatric brain malignancy, can especially benefit from this approach, minimizing the devastating side effects of aggressive radiation and chemotherapies that disrupt normal brain development. However, regulators of the immune landscape remain poorly understood and no effective immunotherapies exist yet for MB. Here, we describe a sex-dependent Yap1 function in fSmoM2;GFAPcre SHH-MB (SG) mouse model. We show that Yap1 is both a cell-autonomous regulator of MB stem-cells and a non-cell-autonomous regulator of immune infiltrates in SHH-MB. Yap1 deletion in SG mice results in increased neuronal differentiation, significantly extended survival, and enhanced infiltration of peripheral blood immune cells (including cytotoxic T-cells, neutrophils, and macrophages). Additionally, this rescue phenotype is observed in a sex-biased manner: 65% of Yap1f/f;fSmoM2;GFAPcre males are rescued in contrast to 35% of females. These observations implicate Yap1 as a mediator of sex-biased brain-tumor formation, either through direct modulation of MB cells and/or through indirectly mediating the MB immune landscape. We are currently testing the role of sex-specific differences in the developing mouse brain to elucidate context-dependent function of Yap1 in MB genesis and maintenance.

Extracellular vesicles, stem cells and the role of miRNAs in neurodegeneration

2021 ◽  
Vol 19 ◽  
Author(s):  
Ayaz M. Belkozhayev ◽  
Minnatallah Al-Yozbaki ◽  
Alex George ◽  
Raigul Ye Niyazova ◽  
Kamalidin O. Sharipov ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neurodegenerative Diseases ◽  
Extracellular Vesicles ◽  
Intercellular Communication ◽  
Direct Consequence ◽  
Therapeutic Benefit ◽  
The Body ◽  
A Cell ◽  
Crucial Information

There are different modalities of intercellular communication governed by cellular homeostasis. In this review, we will explore one of these forms of communication called extracellular vesicles (EVs). These vesicles are released by all cells in the body and are heterogeneous in nature. The primary function of EVs is to share information through their cargo consisting of proteins, lipids and nucleic acids (mRNA, miRNA, dsDNA etc.) with other cells, which have a direct consequence on their microenvironment. We will focus on the role of EVs of mesenchymal stem cells (MSCs) in the nervous system and how these participate in intercellular communication to maintain physiological function and provide neuroprotection. However, deregulation of this same communication system could play a role in several neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Amyotrophic lateral sclerosis, multiple sclerosis, prion disease and Huntington’s disease. The release of EVs from a cell provides crucial information to what is happening inside the cell and thus could be used in diagnostics and therapy. We will discuss and explore new avenues for the clinical applications of using engineered MSC-EVs and their potential therapeutic benefit in treating neurodegenerative diseases.

scholarly journals Dynamic N6-methyladenosine RNA methylation in brain and diseases

Epigenomics ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 371-380 ◽  
Author(s):  
Andrew M Shafik ◽  
Emily G Allen ◽  
Peng Jin
Keyword(s):  
Brain Development ◽  
Rna Modification ◽  
Normal Brain ◽  
Biological Processes ◽  
Future Directions ◽  
Body Of Knowledge ◽  
Neuropsychiatric Diseases ◽  
The Brain ◽  
Normal Brain Development

N6-methyladenosine (m6A) is a dynamic RNA modification that regulates various aspects of RNA metabolism and has been implicated in many biological processes and transitions. m6A is highly abundant in the brain; however, only recently has the role of m6A in brain development been a focus. The machinery that controls m6A is critically important for proper neurodevelopment, and the precise mechanisms by which m6A regulates these processes are starting to emerge. However, the role of m6A in neurodegenerative and neuropsychiatric diseases still requires much elucidation. This review discusses and summarizes the current body of knowledge surrounding the function of the m6A modification in regulating normal brain development, neurodegenerative diseases and outlines possible future directions.

scholarly journals Intracerebroventricular Infusion of Gangliosides Augments the Adult Neural Stem Cell Pool in Mouse Brain

ASN NEURO ◽  
2019 ◽  
Vol 11 ◽  
pp. 175909141988485
Author(s):  
Yutaka Itokazu ◽  
Dongpei Li ◽  
Robert K. Yu
Keyword(s):  
Mouse Brain ◽  
Expression Profiles ◽  
Normal Brain ◽  
Behavioral Deficits ◽  
Adult Neural Stem Cell ◽  
Intracerebroventricular Infusion ◽  
5Xfad Mouse ◽  
Developing Mouse Brain ◽  
Ganglioside Gd3

We previously reported that ganglioside GD3 is the predominant species in neural stem cells (NSCs) and reduced postnatal NSC pools are observed in both the subventricular zone and dentate gyrus (DG) of GD3-synthase knockout (GD3S-KO) mouse brains. Specifically, deficiency of GD3 in GD3S-KO animals revealed a dramatic reduction in cellularity in the DG of the hippocampus of the developing mouse brain, resulting in severe behavioral deficits in these animals. To further evaluate the functional role of GD3 in postnatal brain, we performed rescue experiments by intracerebroventricular infusion of ganglioside GD3 in adult GD3S-KO animals and found that it could restore the NSC pools and enhance the NSCs for self-renewal. Furthermore, 5xFAD mouse model was utilized, and GD3 restored NSC numbers and GM1 promoted neuronal differentiation. Our results thus demonstrate that exogenously administered gangliosides are capable to restore the function of postnatal NSCs. Since ganglioside expression profiles are associated not only with normal brain development but also with pathogenic mechanisms of diseases, such as Alzheimer’s disease, we anticipate that the administration of exogenous gangliosides, such as GD3 and GM1, may represent a novel and effective strategy for promoting adult neurogenesis in damaged brain for disease treatment.

p53 functions as a cell cycle control protein in osteosarcomas

1990 ◽  
Vol 10 (11) ◽  
pp. 5772-5781
Author(s):  
L Diller ◽  
J Kassel ◽  
C E Nelson ◽  
M A Gryka ◽  
G Litwak ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Control ◽  
P53 Gene ◽  
Tumor Formation ◽  
Wild Type ◽  
Gene Encoding ◽  
Wide Range ◽  
A Cell ◽  
Wild Type P53

Mutations in the p53 gene have been associated with a wide range of human tumors, including osteosarcomas. Although it has been shown that wild-type p53 can block the ability of E1a and ras to cotransform primary rodent cells, it is poorly understood why inactivation of the p53 gene is important for tumor formation. We show that overexpression of the gene encoding wild-type p53 blocks the growth of osteosarcoma cells. The growth arrest was determined to be due to an inability of the transfected cells to progress into S phase. This suggests that the role of the p53 gene as an antioncogene may be in controlling the cell cycle in a fashion analogous to the check-point control genes in Saccharomyces cerevisiae.

scholarly journals Altered GABA Signaling in Early Life Epilepsies

2011 ◽  
Vol 2011 ◽  
pp. 1-16 ◽  
Author(s):  
Stephen W. Briggs ◽  
Aristea S. Galanopoulou
Keyword(s):  
Brain Function ◽  
Therapeutic Potential ◽  
Physiological Role ◽  
Neuronal Morphology ◽  
Normal Brain ◽  
Pathological Conditions ◽  
Neurodevelopmental Deficits ◽  
The Brain ◽  
Normal Brain Development

The incidence of seizures is particularly high in the early ages of life. The immaturity of inhibitory systems, such as GABA, during normal brain development and its further dysregulation under pathological conditions that predispose to seizures have been speculated to play a major role in facilitating seizures. Seizures can further impair or disrupt GABAAsignaling by reshuffling the subunit composition of its receptors or causing aberrant reappearance of depolarizing or hyperpolarizing GABAAreceptor currents. Such effects may not result in epileptogenesis as frequently as they do in adults. Given the central role of GABAAsignaling in brain function and development, perturbation of its physiological role may interfere with neuronal morphology, differentiation, and connectivity, manifesting as cognitive or neurodevelopmental deficits. The current GABAergic antiepileptic drugs, while often effective for adults, are not always capable of stopping seizures and preventing their sequelae in neonates. Recent studies have explored the therapeutic potential of chloride cotransporter inhibitors, such as bumetanide, as adjunctive therapies of neonatal seizures. However, more needs to be known so as to develop therapies capable of stopping seizures while preserving the age- and sex-appropriate development of the brain.

Effects of Alcohol and Nicotine on the Developing Brain: An Authoritative Guide

2007 ◽  
Vol 13 (6) ◽  
pp. 1072-1073
Author(s):  
Doug Johnson-Greene
Keyword(s):  
New York ◽  
Brain Development ◽  
Developmental Disorders ◽  
Theoretical Models ◽  
Normal Brain ◽  
Oxford University ◽  
History Of ◽  
Early Developmental ◽  
Normal Brain Development

Brain Development: Normal Processes and the Effects of Alcohol and Nicotine. Michael W. Miller (Ed.). 2006. New York: Oxford University Press, 424 pp., $98.50 (HB)The process of brain development is an essential yet often overlooked area in the neuropsychological literature. The topic has a natural appeal to those who work with children where developmental disorders predominate. However, it is often more difficult for those who work with adults to appreciate the role of developmental aberrations and their contribution to pathological processes that may seem far removed from the early developmental history of our patients. The tendency for some to deemphasize early developmental influences may stem in part from a lack of clarity about how common toxin exposures, such as alcohol and nicotine, alter normal brain development and contribute to changes in cognitive function. Increasingly, evidence of early developmental influences has emerged in a host of epigenetically-based developmental disorders and neuropathological conditions, such as schizophrenia, and these influences are also implicated in theoretical models, such as cognitive reserve.

scholarly journals ETMR-03. THE ROLE OF FOXR2 IN PEDIATRIC BRAIN CANCER

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii323-iii323
Author(s):  
Felix Schmitt-Hoffner ◽  
Sjoerd van Rijn ◽  
Jens-Martin Hübner ◽  
Sander Lambo ◽  
Monika Mauermann ◽  
...  
Keyword(s):  
Pediatric Brain Tumors ◽  
Tumor Formation ◽  
Human Neural Stem Cells ◽  
Chip Sequencing ◽  
Nsg Mice ◽  
Forkhead Box ◽  
Neuroectodermal Tumors ◽  
The Central Nervous System ◽  
Pediatric Brain

Abstract Forkhead Box R2 (FOXR2) is a transcription factor of the Forkhead Box family that has been correlated with tumorigenesis, aberrant cell growth or tumor progression. Expression of FOXR2 in pediatric brain tumors is, besides in subsets of medullo-, pineo- and glioblastoma, primarily present in CNS neuroblastoma with FOXR2 activation (CNS NB-FOXR2), a novel entity that we in 2016 identified from the former class of primitive neuroectodermal tumors of the central nervous system (CNS-PNET). Analyzing CNS-NB-FOXR2 tumors we found that FOXR2 mRNA is expressed in an anti-correlative manner compared to the proto-oncogenes MYC and MYCN. With immunoprecipitation analyses we show that FOXR2 binds to MYC and MYCN and is thereby stabilizing these proteins. These observations on the interaction and the anti-correlative manner suggest that FOXR2 and MYC(N) may drive tumor formation in a molecularly similar fashion. To investigate this further we stably expressed FOXR2, MYCN and MYC and a combination of FOXR2 with MYC(N) in human neural stem cells (hNSC) and injected these in the striatum of NSG mice. We could show that hNSC itself do not from a tumor, whereas the expression of FOXR2 and/or MYC(N) in hNSC results in tumorigenesis. Tumors expressing both, FOXR2 and MYC(N) were growing faster than tumors with FOXR2 alone. In addition, tumors are currently being analyzed by ChIP-sequencing for FOXR2, MYC, and MYCN, to better understand the mechanisms how FOXR2 drives tumor formation compared to its interaction partners MYC and MYCN.

scholarly journals Site-Specific Distribution of CD68-Positive Microglial Cells in the Brains of Human Midterm Fetuses: A Topographical Relationship with Growing Axons

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Kwang Ho Cho ◽  
Jin Sung Cheong ◽  
Ji Hyun Kim ◽  
Hiroshi Abe ◽  
Gen Murakami ◽  
...  
Keyword(s):  
Microglial Cell ◽  
Optic Tract ◽  
Internal Capsule ◽  
Normal Brain ◽  
Cell Distribution ◽  
Specific Distribution ◽  
Supportive Role ◽  
Topographical Anatomy ◽  
Normal Brain Development

Using 5 fetuses of gestational age (GA) of 15-16 weeks and 4 of GA of 22–25 weeks, we examined site- and stage-dependent differences in CD68-positive microglial cell distribution in human fetal brains. CD68 positive cells were evident in the floor of the fourth ventricle and the pons and olive at 15-16 weeks, accumulating in and around the hippocampus at 22–25 weeks. At both stages, the accumulation of these cells was evident around the optic tract and the anterior limb of the internal capsule. When we compared CD68-positive cell distribution with the topographical anatomy of GAP43-positive developing axons, we found that positive axons were usually unaccompanied by CD68-positive cells, except in the transpontine corticofugal tract and the anterior limb of the internal capsule. Likewise, microglial cell distribution did not correspond with habenulointerpeduncular tract. Therefore, the distribution of CD68-positive cells during normal brain development may not reflect a supportive role of these microglia in axonogenesis of midterm human fetuses.

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