embryonic brain development
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2022 ◽  
Vol 15 (1) ◽  
Author(s):  
Zhikun Zhang ◽  
Yongxiang Zhao

AbstractMyocyte Enhancer Factor 2 C (MEF2C), one of the transcription factors of the MADS-BOX family, is involved in embryonic brain development, neuronal formation and differentiation, as well as in the growth and pruning of axons and dendrites. MEF2C is also involved in the development of various neuropsychiatric disorders, such as autism spectrum disorders (ASD), epilepsy, schizophrenia and Alzheimer’s disease (AD). Here, we review the relationship between MEF2C and neuropsychiatric disorders, and provide further insights into the mechanism of these diseases.


Cancers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 6100
Author(s):  
Tiziana Servidei ◽  
Donatella Lucchetti ◽  
Pierluigi Navarra ◽  
Alessandro Sgambato ◽  
Riccardo Riccardi ◽  
...  

Intra-tumoral heterogeneity (ITH) is a complex multifaceted phenomenon that posits major challenges for the clinical management of cancer patients. Genetic, epigenetic, and microenvironmental factors are concurrent drivers of diversity among the distinct populations of cancer cells. ITH may also be installed by cancer stem cells (CSCs), that foster unidirectional hierarchy of cellular phenotypes or, alternatively, shift dynamically between distinct cellular states. Ependymoma (EPN), a molecularly heterogeneous group of tumors, shows a specific spatiotemporal distribution that suggests a link between ependymomagenesis and alterations of the biological processes involved in embryonic brain development. In children, EPN most often arises intra-cranially and is associated with an adverse outcome. Emerging evidence shows that EPN displays large intra-patient heterogeneity. In this review, after touching on EPN inter-tumoral heterogeneity, we focus on the sources of ITH in pediatric intra-cranial EPN in the framework of the CSC paradigm. We also examine how single-cell technology has shed new light on the complexity and developmental origins of EPN and the potential impact that this understanding may have on the therapeutic strategies against this deadly pediatric malignancy.


Author(s):  
Jiao Chen ◽  
Zhonghui Guan

AbstractHuman MYCN is an oncogene amplified in neuroblastoma and many other tumors. Both human MYCN and mouse Mycn genes are important in embryonic brain development, but their functions in adult healthy nerve system are completely unknown. Here, with Mycn-eGFP mice and quantitative RT-PCR, we found that Mycn was expressed in specific brain regions of young adult mice, including subventricular zone (SVZ), subgranular zone (SGZ), olfactory bulb (OB), subcallosal zone (SCZ), and corpus callosum (CC). With immunohistochemistry (IHC), we found that many Mycn-expressing cells expressed neuroblast marker doublecortin (DCX) and proliferation marker Ki67. With Dcx-creER and Mki67-creER mouse lines, we fate mapped Dcx-expressing neuroblasts and Mki67-expressing proliferation cells, along with deleting Mycn from these cells in adult mice. We found that knocking out Mycn from adult neuroblasts or proliferating cells significantly reduced cells in proliferation in SVZ, SGZ, OB, SCZ, and CC. We also demonstrated that the Mycn-deficient neuroblasts in SGZ matured quicker than wild-type neuroblasts, and that Mycn-deficient proliferating cells were more likely to survive in SVZ, SGZ, OB, SCZ, and CC compared to wild type. Thus, our results demonstrate that, in addition to causing tumors in the nervous system, oncogene Mycn has a crucial function in neurogenesis and oligodendrogenesis in adult healthy brain.


Genes ◽  
2021 ◽  
Vol 12 (5) ◽  
pp. 738
Author(s):  
Jair Tenorio-Castaño ◽  
Beatriz Morte ◽  
Julián Nevado ◽  
Víctor Martinez-Glez ◽  
Fernando Santos-Simarro ◽  
...  

Schuurs–Hoeijmakers syndrome (SHMS) or PACS1 Neurodevelopmental disorder is a rare disorder characterized by intellectual disability, abnormal craniofacial features and congenital malformations. SHMS is an autosomal dominant hereditary disease caused by pathogenic variants in the PACS1 gene. PACS1 is a trans-Golgi-membrane traffic regulator that directs protein cargo and several viral envelope proteins. It is upregulated during human embryonic brain development and has low expression after birth. So far, only 54 patients with SHMS have been reported. In this work, we report on seven new identified SHMS individuals with the classical c.607C > T: p.Arg206Trp PACS1 pathogenic variant and review clinical and molecular aspects of all the patients reported in the literature, providing a summary of clinical findings grouped as very frequent (≥75% of patients), frequent (50–74%), infrequent (26–49%) and rare (less than ≤25%).


Author(s):  
Samuel E. Ross ◽  
Daniel Hesselson ◽  
Ozren Bogdanovic

DNA methylation predominantly occurs at CG dinucleotides in vertebrate genomes; however, non-CG methylation (mCH) is also detectable in vertebrate tissues, most notably in the nervous system. In mammals it is well established that mCH is targeted to CAC trinucleotides by DNMT3A during nervous system development where it is enriched in gene bodies and associated with transcriptional repression. Nevertheless, the conservation of developmental mCH accumulation and its deposition by DNMT3A is largely unexplored and has yet to be functionally demonstrated in other vertebrates. In this study, by analyzing DNA methylomes and transcriptomes of zebrafish brains, we identified enrichment of mCH at CAC trinucleotides (mCAC) at defined transposon motifs as well as in developmentally downregulated genes associated with developmental and neural functions. We further generated and analyzed DNA methylomes and transcriptomes of developing zebrafish larvae and demonstrated that, like in mammals, mCH accumulates during post-embryonic brain development. Finally, by employing CRISPR/Cas9 technology, we unraveled a conserved role for Dnmt3a enzymes in developmental mCAC deposition. Overall, this work demonstrates the evolutionary conservation of developmental mCH dynamics and highlights the potential of zebrafish as a model to study mCH regulation and function during normal and perturbed development.


2021 ◽  
Vol 22 (4) ◽  
pp. 1745
Author(s):  
Paula Dlugosz ◽  
Magdalena Teufl ◽  
Maximilian Schwab ◽  
Katharina Eva Kohl ◽  
Johannes Nimpf

Disabled 1 (Dab1) is an adapter protein for very low density lipoprotein receptor (VLDLR) and apolipoprotein E receptor 2 (ApoER2) and an integral component of the Reelin pathway which orchestrates neuronal layering during embryonic brain development. Activation of Dab1 is induced by binding of Reelin to ApoER2 and VLDLR and phosphorylation of Dab1 mediated by Src family kinases. Here we show that Dab1 also acts as an adaptor for epidermal growth factor receptor (EGFR) and can be phosphorylated by epidermal growth factor (EGF) binding to EGFR. Phosphorylation of Dab1 depends on the kinase activity of EGFR constituting a signal pathway independent of Reelin and its receptors.


2021 ◽  
Author(s):  
Richard Kanyo ◽  
Md Ruhul Amin ◽  
Laszlo F. Locskai ◽  
Danika D. Bouvier ◽  
Alexandria M. Olthuis ◽  
...  

AbstractConsidering the wide spread use of cannabis as a recreational and medicinal drug, a knowledge gap exists regarding biological mechanisms and health implication. In the light of legislative changes, delayed effects of cannabis upon brief exposure during embryonic development are of high interest as early pregnancies often go undetected. We hypothesized that brief early cannabinoid exposure impacts neural activity by affecting embryonic brain development through cannabinoid-1 (CB1R) and -2 (CB2R). Zebrafish larvae were exposed to cannabidiol (CBD) and Δ□-tetrahydrocannabinol (THC) until the end of gastrulation (1-10 hours post-fertilization) and analyzed later in development (4-5 days post-fertilization). In order to measure neural activity, we implemented the fluorescence based calcium detector CaMPARI (Calcium-Modulated Photoactivatable Ratiometric Integrator) and optimized the protocol such that a high number of samples can be economically used in a 96-well format complemented by locomotor analysis. Our results revealed that neural activity was decreased by CBD more than THC. At higher doses both cannabinoids could reduce neural activity close to a level comparable to anesthetized samples and locomotor activity was abolished. Interestingly, the decrease was more pronounced when CBD and THC were combined. At the receptor level, CBD-mediated reduction of locomotor activity was partially prevented using CB1R or CB2R inhibitors. Overall, we provided a mechanistic link to perturbed brain development in vivo, which seems to involve CBD and receptors, CB1R and CB2R. Future studies are warranted to reveal other cannabinoids and receptors involved in this pathway to understand the full health implications of cannabis consumption on fetal development.


Author(s):  
Masamichi Nagae ◽  
Kei Suzuki ◽  
Norihisa Yasui ◽  
Terukazu Nogi ◽  
Takao Kohno ◽  
...  

Abstract The large, secreted glycoprotein reelin regulates embryonic brain development as well as adult brain functions. Although reelin binds to its receptors via its central part, the N-terminal region directs multimer formation and is critical for efficient signal transduction. In fact, the inhibitory antibody CR-50 interacts with the N-terminal region and prevents higher-order multimerization and signaling. Reelin is a multidomain protein in which the central part is composed of eight characteristic repeats, named reelin repeats, each of which is further divided by insertion of an EGF module into two subrepeats. In contrast, the N-terminal region shows unique “irregular” domain architecture since it comprises three consecutive subrepeats without the intervening EGF module. Here we determined the crystal structure of the murine reelin fragment named RX-R1 including the irregular region and the first reelin repeat at 2.0 Å resolution. The overall structure of RX-R1 has a branched Y-shaped form. Interestingly, two incomplete subrepeats cooperatively form one entire subrepeat structure, though an additional subrepeat is inserted between them. We further reveal that Arg335 of RX-R1 is crucial for binding CR-50. A possible self-association mechanism via the N-terminal region is proposed based on our results.


2020 ◽  
Author(s):  
Samuel E Ross ◽  
Daniel Hesselson ◽  
Ozren Bogdanovic

DNA methylation predominantly occurs at CG dinucleotides in vertebrate genomes; however, non-CG methylation (mCH) is also detectable in vertebrate tissues, most notably in the nervous system. In mammals it is well established that mCH is targeted to CAC trinucleotides by DNMT3A during nervous system development where it is enriched in gene bodies and associated with transcriptional repression. However, the conservation of developmental mCH accumulation and its deposition by DNMT3A is largely unexplored and has yet to be functionally demonstrated in other vertebrates. In this study, by analyzing DNA methylomes and transcriptomes of zebrafish brains, we identified enrichment of mCH at CAC trinucleotides (mCAC) at defined transposon motifs as well as in developmentally downregulated genes associated with developmental and neural functions. We further generated and analyzed DNA methylomes and transcriptomes of developing zebrafish larvae and demonstrated that, like in mammals, mCH accumulates during post-embryonic brain development. Finally, by employing CRISPR/Cas9 technology, we unraveled a conserved role for Dnmt3a enzymes in developmental mCAC deposition. Overall, this work demonstrates the evolutionary conservation of developmental mCH dynamics and highlights the potential of zebrafish as a model to study mCH regulation and function during normal and perturbed development.


2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Myron K. Evans ◽  
Yurika Matsui ◽  
Beisi Xu ◽  
Catherine Willis ◽  
Jennifer Loome ◽  
...  

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