Differential expression of mammalian Numb, Numblike and Notch1 suggests distinct roles during mouse cortical neurogenesis

Development ◽  
1997 ◽  
Vol 124 (10) ◽  
pp. 1887-1897 ◽  
Author(s):  
W. Zhong ◽  
M.M. Jiang ◽  
G. Weinmaster ◽  
L.Y. Jan ◽  
Y.N. Jan
Keyword(s):  
Sequence Similarity ◽  
Ventricular Zone ◽  
Cell Interaction ◽  
Cortical Plate ◽  
Loss Of Function ◽  
Cortical Neurogenesis ◽  
Daughter Cells ◽  
Embryonic Nervous System ◽  
Progenitor Cell Proliferation ◽  
Developing Neocortex

During Drosophila neurogenesis, asymmetric cell divisions are achieved by differential segregation of Numb (d-Numb) into one of the daughter cells to cause a bias in the Notch mediated cell-cell interaction. We have isolated a second mammalian gene with significant sequence similarity to d-numb, mouse numblike. When expressed in dividing neural precursors in Drosophila, Numblike is symmetrically distributed in the cytoplasm, unlike endogenous d-Numb or expressed mouse Numb (m-Numb), both of which are asymmetrically localized to one half of the cell membrane. In d-numb loss-of-function mutant embryos, expression of Numblike allows both daughter cells of a neural precursor to adopt the fate of the cell that normally inherits d-Numb. In mice, numblike mRNA is preferentially expressed in adult and embryonic nervous system. In the developing neocortex, Numblike is expressed in postmitotic neurons in the cortical plate, but not in progenitors within the ventricular zone where m-Numb and Notch1 are expressed. We have also found that, in dividing cortical progenitors, Notch1 is distributed around the entire membrane, unlike m-Numb which is asymmetrically localized to the apical membrane. We propose that an interplay between cell-intrinsic mechanisms (executed by m-numb and numblike) and cell-extrinsic mechanisms (mediated by Notch1) may be involved in both progenitor cell proliferation and neuronal differentiation during mammalian cortical neurogenesis.

A Similarity Searching System for Biological Phenotype Images Using Deep Convolutional Encoder-decoder Architecture

2019 ◽  
Vol 14 (7) ◽  
pp. 628-639 ◽  
Author(s):  
Bizhi Wu ◽  
Hangxiao Zhang ◽  
Limei Lin ◽  
Huiyuan Wang ◽  
Yubang Gao ◽  
...  
Keyword(s):  
Neural Network ◽  
Retrieval System ◽  
Sequence Similarity ◽  
Local Alignment ◽  
Similarity Searching ◽  
Loss Of Function ◽  
Biological Images ◽  
The Neural Network ◽  
Convolutional Autoencoder ◽  
Biological Phenotype

Background: The BLAST (Basic Local Alignment Search Tool) algorithm has been widely used for sequence similarity searching. Analogously, the public phenotype images must be efficiently retrieved using biological images as queries and identify the phenotype with high similarity. Due to the accumulation of genotype-phenotype-mapping data, a system of searching for similar phenotypes is not available due to the bottleneck of image processing. Objective: In this study, we focus on the identification of similar query phenotypic images by searching the biological phenotype database, including information about loss-of-function and gain-of-function. Methods: We propose a deep convolutional autoencoder architecture to segment the biological phenotypic images and develop a phenotype retrieval system to enable a better understanding of genotype–phenotype correlation. Results: This study shows how deep convolutional autoencoder architecture can be trained on images from biological phenotypes to achieve state-of-the-art performance in a phenotypic images retrieval system. Conclusion: Taken together, the phenotype analysis system can provide further information on the correlation between genotype and phenotype. Additionally, it is obvious that the neural network model of image segmentation and the phenotype retrieval system is equally suitable for any species, which has enough phenotype images to train the neural network.

scholarly journals Loss-of-function of p53 isoform Δ113p53 accelerates brain aging in zebrafish

2021 ◽  
Vol 12 (2) ◽  
Author(s):  
Ting Zhao ◽  
Shengfan Ye ◽  
Zimu Tang ◽  
Liwei Guo ◽  
Zhipeng Ma ◽  
...  
Keyword(s):  
Replicative Senescence ◽  
Brain Aging ◽  
Ventricular Zone ◽  
Human Fibroblasts ◽  
Cell Lineage ◽  
Lineage Tracing ◽  
Dependent Manner ◽  
Loss Of Function ◽  
Antioxidant Genes ◽  
Age Related

AbstractReactive oxygen species (ROS) stress has been demonstrated as potentially critical for induction and maintenance of cellular senescence, and been considered as a contributing factor in aging and in various neurological disorders including Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS). In response to low-level ROS stress, the expression of Δ133p53, a human p53 isoform, is upregulated to promote cell survival and protect cells from senescence by enhancing the expression of antioxidant genes. In normal conditions, the basal expression of Δ133p53 prevents human fibroblasts, T lymphocytes, and astrocytes from replicative senescence. It has been also found that brain tissues from AD and ALS patients showed decreased Δ133p53 expression. However, it is uncharacterized if Δ133p53 plays a role in brain aging. Here, we report that zebrafish Δ113p53, an ortholog of human Δ133p53, mainly expressed in some of the radial glial cells along the telencephalon ventricular zone in a full-length p53-dependent manner. EDU-labeling and cell lineage tracing showed that Δ113p53-positive cells underwent cell proliferation to contribute to the neuron renewal process. Importantly, Δ113p53M/M mutant telencephalon possessed less proliferation cells and more senescent cells compared to wild-type (WT) zebrafish telencephalon since 9-months old, which was associated with decreased antioxidant genes expression and increased level of ROS in the mutant telencephalon. More interestingly, unlike the mutant fish at 5-months old with cognition ability, Δ113p53M/M zebrafish, but not WT zebrafish, lost their learning and memory ability at 19-months old. The results demonstrate that Δ113p53 protects the brain from aging by its antioxidant function. Our finding provides evidence at the organism level to show that depletion of Δ113p53/Δ133p53 may result in long-term ROS stress, and finally lead to age-related diseases, such as AD and ALS in humans.

scholarly journals Dab2IP Regulates Neuronal Positioning, Rap1 Activity and Integrin Signaling in the Developing Cortex

2015 ◽  
Vol 37 (2) ◽  
pp. 131-141 ◽  
Author(s):  
Shuhong Qiao ◽  
Ramin Homayouni
Keyword(s):  
Brain Development ◽  
Cortical Neurons ◽  
Ventricular Zone ◽  
Physiological Role ◽  
Immunohistochemical Analysis ◽  
Superficial Layer ◽  
Tumor Formation ◽  
Intermediate Zone ◽  
Cortical Plate ◽  
Integrin Signaling

Dab2IP (DOC-2/DAB2 interacting protein) is a GTPase-activating protein which is involved in various aspects of brain development in addition to its roles in tumor formation and apoptosis in other systems. In this study, we carefully examined the expression profile of Dab2IP and investigated its physiological role during brain development using a Dab2IP-knockdown (KD) mouse model created by retroviral insertion of a LacZ-encoding gene-trapping cassette. LacZ staining revealed that Dab2IP is expressed in the ventricular zone as well as the cortical plate and the intermediate zone. Immunohistochemical analysis showed that Dab2IP protein is localized in the leading process and proximal cytoplasmic regions of migrating neurons in the intermediate zone. Bromodeoxyuridine birth dating experiments in combination with immunohistochemical analysis using layer-specific markers showed that Dab2IP is important for proper positioning of a subset of layer II-IV neurons in the developing cortex. Notably, neuronal migration was not completely disrupted in the cerebral cortex of Dab2IP-KD mice and disruption of migration was not strictly layer specific. Previously, we found that Dab2IP regulates multipolar transition in cortical neurons. Others have shown that Rap1 regulates the transition from multipolar to bipolar morphology in migrating postmitotic neurons through N-cadherin signaling and somal translocation in the superficial layer of the cortical plate through integrin signaling. Therefore, we examined whether Rap1 and integrin signaling were affected in Dab2IP-KD brains. We found that Dab2IP-KD resulted in higher levels of activated Rap1 and integrin in the developing cortex. Taken together, our results suggest that Dab2IP plays an important role in the migration and positioning of a subpopulation of later-born (layers II-IV) neurons, likely through the regulation of Rap1 and integrin signaling.

DNA sequence, structure, and tyrosine kinase activity of the Drosophila melanogaster Abelson proto-oncogene homolog

1988 ◽  
Vol 8 (2) ◽  
pp. 843-853
Author(s):  
M J Henkemeyer ◽  
R L Bennett ◽  
F B Gertler ◽  
F M Hoffmann
Keyword(s):  
Drosophila Melanogaster ◽  
Tyrosine Kinase ◽  
Dna Sequence ◽  
Kinase Activity ◽  
Essential Gene ◽  
Sequence Similarity ◽  
Homologous Region ◽  
Loss Of Function ◽  
Tyrosine Kinase Activity ◽  
Stage Of Development

We report our molecular characterization of the Drosophila melanogaster Abelson gene (abl), a gene in which recessive loss-of-function mutations result in lethality at the pupal stage of development. This essential gene consists of 10 exons extending over 26 kilobase pairs of genomic DNA. The DNA sequence encodes a protein of 1,520 amino acids with strong sequence similarity to the human c-abl proto-oncogene beginning in the type lb 5' exon and extending through the region essential for tyrosine kinase activity. When the tyrosine kinase homologous region was expressed in Escherichia coli, phosphorylation of proteins on tyrosine residues was observed with an antiphosphotyrosine antibody. These results show that the abl gene is highly conserved through evolution and encodes a functional tyrosine protein kinase required for Drosophila development.

scholarly journals Caenorhabditis elegans SUR-5, a Novel but Conserved Protein, Negatively Regulates LET-60 Ras Activity during Vulval Induction

1998 ◽  
Vol 18 (8) ◽  
pp. 4556-4564 ◽  
Author(s):  
Trent Gu ◽  
Satoshi Orita ◽  
Min Han
Keyword(s):  
Caenorhabditis Elegans ◽  
Sequence Similarity ◽  
Signal Transduction Pathway ◽  
Specific Aspect ◽  
Dominant Negative ◽  
Loss Of Function ◽  
Negative Function ◽  
Ras Activation ◽  
Dominant Negative Mutations ◽  
Novel Protein

ABSTRACT The let-60 ras gene acts in a signal transduction pathway to control vulval differentiation in Caenorhabditis elegans. By screening suppressors of a dominant negativelet-60 ras allele, we isolated three loss-of-function mutations in the sur-5 gene which appear to act as negative regulators of let-60 ras during vulval induction.sur-5 mutations do not cause an obvious mutant phenotype of their own, and they appear to specifically suppress only one of the two groups of let-60 ras dominant negative mutations, suggesting that the gene may be involved in a specific aspect of Ras activation. Consistent with its negative function, overexpressing sur-5 from an extragenic array partially suppresses the Multivulva phenotype of an activatedlet-60 ras mutation and causes synergistic phenotypes with a lin-45 raf mutation. We have clonedsur-5 and shown that it encodes a novel protein. We have also identified a potential mammalian SUR-5 homolog that is about 35% identical to the worm protein. SUR-5 also has some sequence similarity to acetyl coenzyme A synthetases and is predicted to contain ATP/GTP and AMP binding sites. Our results suggest thatsur-5 gene function may be conserved through evolution.

scholarly journals Asp1 Bifunctional Activity Modulates Spindle Function via Controlling Cellular Inositol Pyrophosphate Levels inSchizosaccharomyces pombe

2018 ◽  
Vol 38 (9) ◽  
pp. e00047-18 ◽  
Author(s):  
Marina Pascual-Ortiz ◽  
Adolfo Saiardi ◽  
Eva Walla ◽  
Visnja Jakopec ◽  
Natascha A. Künzel ◽  
...  
Keyword(s):  
High Energy ◽  
Loss Of Function ◽  
Content Type ◽  
Inositol Pyrophosphate ◽  
Daughter Cells ◽  
Chromosome Transmission ◽  
Microtubule Stability ◽  
Mitochondrial Distribution ◽  
Spindle Function

ABSTRACTThe generation of two daughter cells with the same genetic information requires error-free chromosome segregation during mitosis. Chromosome transmission fidelity is dependent on spindle structure/function, which requires Asp1 in the fission yeastSchizosaccharomyces pombe. Asp1 belongs to the diphosphoinositol pentakisphosphate kinase (PPIP5K)/Vip1 family which generates high-energy inositol pyrophosphate (IPP) molecules. Here, we show that Asp1 is a bifunctional enzymein vivo: Asp1 kinase generates specific IPPs which are the substrates of the Asp1 pyrophosphatase. Intracellular levels of these IPPs directly correlate with microtubule stability: pyrophosphatase loss-of-function mutants raised Asp1-made IPP levels 2-fold, thus increasing microtubule stability, while overexpression of the pyrophosphatase decreased microtubule stability. Absence of Asp1-generated IPPs resulted in an aberrant, increased spindle association of theS. pombekinesin-5 family member Cut7, which led to spindle collapse. Thus, chromosome transmission is controlled via intracellular IPP levels. Intriguingly, identification of the mitochondrion-associated Met10 protein as the first pyrophosphatase inhibitor revealed that IPPs also regulate mitochondrial distribution.

scholarly journals Motifs of VDAC2 required for mitochondrial Bak import and tBid-induced apoptosis

2015 ◽  
Vol 112 (41) ◽  
pp. E5590-E5599 ◽  
Author(s):  
Shamim Naghdi ◽  
Péter Várnai ◽  
György Hajnóczky
Keyword(s):  
Sequence Similarity ◽  
Anion Channel ◽  
Loss Of Function ◽  
Voltage Dependent Anion Channel ◽  
Fundamental Function ◽  
Cytoplasmic Surface ◽  
Voltage Dependent ◽  
Critical Residues ◽  
Induced Apoptosis ◽  
Relevant Domain

Voltage-dependent anion channel (VDAC) proteins are major components of the outer mitochondrial membrane. VDAC has three isoforms with >70% sequence similarity and redundant roles in metabolite and ion transport. However, only Vdac2−/− (V2−/−) mice are embryonic lethal, indicating a unique and fundamental function of VDAC2 (V2). Recently, a specific V2 requirement was demonstrated for mitochondrial Bak import and truncated Bid (tBid)-induced apoptosis. To determine the relevant domain(s) of V2 involved, VDAC1 (V1) and V2 chimeric constructs were created and used to rescue V2−/− fibroblasts. Surprisingly, the commonly cited V2-specific N-terminal extension and cysteines were found to be dispensable for Bak import and high tBid sensitivity. In gain-of-function studies, V2 (123–179) was the minimal sequence sufficient to render V1 competent to support Bak insertion. Furthermore, in loss-of-function experiments, T168 and D170 were identified as critical residues. These motifs are conserved in zebrafish V2 (zfV2) that also rescued V2-deficient fibroblasts. Because high-resolution structures of zfV2 and mammalian V1 have become available, we could superimpose these structures and recognized that the critical V2-specific residues help to create a distinctive open “pocket” on the cytoplasmic surface that could facilitate Bak recruitment.

scholarly journals Olig3 regulates early cerebellar development

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Elijah D Lowenstein ◽  
Aleksandra Rusanova ◽  
Jonas Stelzer ◽  
Marc Hernaiz-Llorens ◽  
Adrian E Schroer ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Purkinje Cell ◽  
Ventricular Zone ◽  
Cerebellar Development ◽  
Brain Functions ◽  
Key Factor ◽  
Progenitor Cell Proliferation ◽  
Molecular Machinery ◽  
Neuronal Types ◽  
Rhombic Lip

The mature cerebellum controls motor skill precision and participates in other sophisticated brain functions that include learning, cognition, and speech. Different types of GABAergic and glutamatergic cerebellar neurons originate in temporal order from two progenitor niches, the ventricular zone and rhombic lip, which express the transcription factors Ptf1a and Atoh1, respectively. However, the molecular machinery required to specify the distinct neuronal types emanating from these progenitor zones is still unclear. Here, we uncover the transcription factor Olig3 as a major determinant in generating the earliest neuronal derivatives emanating from both progenitor zones in mice. In the rhombic lip, Olig3 regulates progenitor cell proliferation. In the ventricular zone, Olig3 safeguards Purkinje cell specification by curtailing the expression of Pax2, a transcription factor that suppresses the Purkinje cell differentiation program. Our work thus defines Olig3 as a key factor in early cerebellar development.

scholarly journals WNT/B-catenin dependant alteration of cortical neurogenesis in a human stem cell model of SETBP1 disorder

2021 ◽  
Author(s):  
Lucia F Cardo ◽  
Meng Li
Keyword(s):  
Neuronal Differentiation ◽  
Cell Model ◽  
Embryonic Stem ◽  
Autistic Traits ◽  
Transcriptome Profiling ◽  
Loss Of Function ◽  
Cortical Neurogenesis ◽  
Severe Intellectual Disability ◽  
Genome Wide

Disruptions of SETBP1 (SET binding protein 1) on 18q12.3 by heterozygous gene deletion or loss-of-function variants cause SETBP1 disorder. Clinical features are frequently associated with moderate to severe intellectual disability, autistic traits and speech and motor delays. Despite SETBP1 association with neurodevelopmental disorders, little is known about its role in brain development. Using CRISPR/CAS9 genome editing technology, we generated a SETBP1 deletion model in human embryonic stem cells (hESCs), and examined the effects of SETBP1-deficiency in in vitro derived neural progenitors (NPCs) and neurons using a battery of cellular assays, genome wide transcriptomic profiling and drug-based phenotypic rescue. SETBP1-deficient NPCs exhibit protracted proliferation and distorted layer-specific neuronal differentiation with overall decrease in neurogenesis. Genome wide transcriptome profiling and protein biochemical analysis showed that SETBP1 deletion led to enhanced activation of WNT/B-catenin signaling. Crucially, treatment of the SETBP1-deficient NPCs with a small molecule WNT inhibitor XAV939 restored hyper canonical B-catenin activity and rescued cortical neuronal differentiation. Our study establishes a novel regulatory link between SETBP1 and WNT/B-catenin signaling during human cortical neurogenesis and provides mechanistic insights into structural abnormalities and potential therapeutic avenues for SETBP1 disorder.

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