scholarly journals The novel lncRNA lnc-NR2F1 is pro-neurogenic and mutated in human neurodevelopmental disorders

2018 ◽  
Author(s):  
Cheen Euong Ang ◽  
Qing Ma ◽  
Orly L. Wapinski ◽  
Shenghua Fan ◽  
Ryan A. Flynn ◽  
...  
Keyword(s):  
Cell Fate ◽  
Human Genetics ◽  
Neuronal Cell ◽  
Chromosomal Translocation ◽  
Autism Spectrum ◽  
Cell Fate Decisions ◽  
Number Variation ◽  
Neuronal Genes ◽  
Neuronal Lineage ◽  
Candidate Loci

AbstractLong noncoding RNAs (lncRNAs) have been shown to act as important cell biological regulators including cell fate decisions but are often ignored in human genetics. Combining differential lncRNA expression during neuronal lineage induction with copy number variation morbidity maps of a cohort of children with autism spectrum disorder/intellectual disability versus healthy controls revealed focal genomic mutations affecting several lncRNA candidate loci. Here we find that a t(5:12) chromosomal translocation in a family manifesting neurodevelopmental symptoms disrupts specifically lnc-NR2F1. We further show that lnc-NR2F1 is an evolutionarily conserved lncRNA functionally enhances induced neuronal cell maturation and directly occupies and regulates transcription of neuronal genes including autism-associated genes. Thus, integrating human genetics and functional testing in neuronal lineage induction is a promising approach for discovering candidate lncRNAs involved in neurodevelopmental diseases.

scholarly journals The novel lncRNA lnc-NR2F1 is pro-neurogenic and mutated in human neurodevelopmental disorders

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Cheen Euong Ang ◽  
Qing Ma ◽  
Orly L Wapinski ◽  
ShengHua Fan ◽  
Ryan A Flynn ◽  
...  
Keyword(s):  
Cell Fate ◽  
Human Genetics ◽  
Neuronal Cell ◽  
Chromosomal Translocation ◽  
Autism Spectrum ◽  
Cell Fate Decisions ◽  
Number Variation ◽  
Neuronal Genes ◽  
Neuronal Lineage ◽  
Candidate Loci

Long noncoding RNAs (lncRNAs) have been shown to act as important cell biological regulators including cell fate decisions but are often ignored in human genetics. Combining differential lncRNA expression during neuronal lineage induction with copy number variation morbidity maps of a cohort of children with autism spectrum disorder/intellectual disability versus healthy controls revealed focal genomic mutations affecting several lncRNA candidate loci. Here we find that a t(5:12) chromosomal translocation in a family manifesting neurodevelopmental symptoms disrupts specifically lnc-NR2F1. We further show that lnc-NR2F1 is an evolutionarily conserved lncRNA functionally enhances induced neuronal cell maturation and directly occupies and regulates transcription of neuronal genes including autism-associated genes. Thus, integrating human genetics and functional testing in neuronal lineage induction is a promising approach for discovering candidate lncRNAs involved in neurodevelopmental diseases.

scholarly journals Stochasticity and determinism in cell fate decisions

Development ◽  
2020 ◽  
Vol 147 (14) ◽  
pp. dev181495 ◽  
Author(s):  
Christoph Zechner ◽  
Elisa Nerli ◽  
Caren Norden
Keyword(s):  
Cell Fate ◽  
Neuronal Cell ◽  
Cell Fate Decisions ◽  
Over Time

ABSTRACTDuring development, cells need to make decisions about their fate in order to ensure that the correct numbers and types of cells are established at the correct time and place in the embryo. Such cell fate decisions are often classified as deterministic or stochastic. However, although these terms are clearly defined in a mathematical sense, they are sometimes used ambiguously in biological contexts. Here, we provide some suggestions on how to clarify the definitions and usage of the terms stochastic and deterministic in biological experiments. We discuss the frameworks within which such clear definitions make sense and highlight when certain ambiguity prevails. As an example, we examine how these terms are used in studies of neuronal cell fate decisions and point out areas in which definitions and interpretations have changed and matured over time. We hope that this Review will provide some clarification and inspire discussion on the use of terminology in relation to fate decisions.

Expression pattern of Motch, a mouse homolog of Drosophila Notch, suggests an important role in early postimplantation mouse development

Development ◽  
1992 ◽  
Vol 115 (3) ◽  
pp. 737-744 ◽  
Author(s):  
F.F. Del Amo ◽  
D.E. Smith ◽  
P.J. Swiatek ◽  
M. Gendron-Maguire ◽  
R.J. Greenspan ◽  
...  
Keyword(s):  
Cell Fate ◽  
Mouse Embryo ◽  
Transmembrane Protein ◽  
Neuronal Cell ◽  
Cell Types ◽  
Drosophila Embryo ◽  
Mouse Development ◽  
Cell Fate Decisions ◽  
Early Mouse ◽  
Partial Cdna Clone

The Notch gene of Drosophila encodes a large transmembrane protein involved in cell-cell interactions and cell fate decisions in the Drosophila embryo. To determine if a gene homologous to Drosophila Notch plays a role in early mouse development, we screened a mouse embryo cDNA library with probes from the Xenopus Notch homolog, Xotch. A partial cDNA clone encoding the mouse Notch homolog, which we have termed Motch, was used to analyze expression of the Motch gene. Motch transcripts were detected in a wide variety of adult tissues, which included derivatives of all three germ layers. Differentiation of P19 embryonal carcinoma cells into neuronal cell types resulted in increased expression of Motch RNA. In the postimplantation mouse embryo Motch transcripts were first detected in mesoderm at 7.5 days post coitum (dpc). By 8.5 dpc, transcript levels were highest in presomitic mesoderm, mesenchyme and endothelial cells, while much lower levels were detected in neuroepithelium. In contrast, at 9.5 dpc, neuroepithelium was a major site of Motch expression. Transcripts were also abundant in cell types derived from neural crest. These data suggest that the Motch gene plays multiple roles in patterning and differentiation of the early postimplantation mouse embryo.

scholarly journals Exclusive development of T cell neoplasms in mice transplanted with bone marrow expressing activated Notch alleles.

1996 ◽  
Vol 183 (5) ◽  
pp. 2283-2291 ◽  
Author(s):  
W S Pear ◽  
J C Aster ◽  
M L Scott ◽  
R P Hasserjian ◽  
B Soffer ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Cell Fate ◽  
Transmembrane Protein ◽  
Leukemia Virus ◽  
Chromosomal Translocation ◽  
Cell Types ◽  
Marrow Transplant ◽  
Cell Fate Decisions ◽  
T Cell Phenotypes

Notch is a highly conserved transmembrane protein that is involved in cell fate decisions and is found in organisms ranging from Drosophila to humans. A human homologue of Notch, TAN1, was initially identified at the chromosomal breakpoint of a subset of T-cell lymphoblastic leukemias/lymphomas containing a t(7;9) chromosomal translocation; however, its role in oncogenesis has been unclear. Using a bone marrow reconstitution assay with cells containing retrovirally transduced TAN1 alleles, we analyzed the oncogenic potential of both nuclear and extranuclear forms of truncated TAN1 in hematopoietic cells. Although the Moloney leukemia virus long terminal repeat drives expression in most hematopoietic cell types, retroviruses encoding either form of the TAN1 protein induced clonal leukemias of exclusively immature T cell phenotypes in approximately 50% of transplanted animals. All tumors overexpressed truncated TAN1 of the size and subcellular localization predicted from the structure of the gene. These results show that TAN1 is an oncoprotein and suggest that truncation and overexpression are important determinants of transforming activity. Moreover, the murine tumors caused by TAN1 in the bone marrow transplant model are very similar to the TAN1-associated human tumors and suggest that TAN1 may be specifically oncotropic for T cells.

scholarly journals A Myt1 family transcription factor defines neuronal fate by repressing non-neuronal genes

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Joo Lee ◽  
Caitlin A Taylor ◽  
Kristopher M Barnes ◽  
Ao Shen ◽  
Emerson V Stewart ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Cell Fate ◽  
Zinc Finger ◽  
Target Cell ◽  
Ectopic Expression ◽  
Neuronal Cell ◽  
Corepressor Complex ◽  
Neuronal Precursors ◽  
Neuronal Genes

Cellular differentiation requires both activation of target cell transcriptional programs and repression of non-target cell programs. The Myt1 family of zinc finger transcription factors contributes to fibroblast to neuron reprogramming in vitro. Here, we show that ztf-11 (Zinc-finger Transcription Factor-11), the sole Caenorhabditis elegans Myt1 homolog, is required for neurogenesis in multiple neuronal lineages from previously differentiated epithelial cells, including a neuron generated by a developmental epithelial-to-neuronal transdifferentiation event. ztf-11 is exclusively expressed in all neuronal precursors with remarkable specificity at single-cell resolution. Loss of ztf-11 leads to upregulation of non-neuronal genes and reduced neurogenesis. Ectopic expression of ztf-11 in epidermal lineages is sufficient to produce additional neurons. ZTF-11 functions together with the MuvB corepressor complex to suppress the activation of non-neuronal genes in neurons. These results dovetail with the ability of Myt1l (Myt1-like) to drive neuronal transdifferentiation in vitro in vertebrate systems. Together, we identified an evolutionarily conserved mechanism to specify neuronal cell fate by repressing non-neuronal genes.

scholarly journals Wnt/β-Catenin-Dependent Transcription in Autism Spectrum Disorders

2021 ◽  
Vol 14 ◽  
Author(s):  
Mario O. Caracci ◽  
Miguel E. Avila ◽  
Francisca A. Espinoza-Cavieres ◽  
Héctor R. López ◽  
Giorgia D. Ugarte ◽  
...  
Keyword(s):  
Autism Spectrum Disorders ◽  
Cell Fate ◽  
Pyramidal Neurons ◽  
Cell Types ◽  
Autism Spectrum ◽  
Loss Of Function ◽  
High Confidence ◽  
Developmental Abnormalities ◽  
Cell Fate Decisions ◽  
Spectrum Disorders

Autism spectrum disorders (ASD) is a heterogeneous group of neurodevelopmental disorders characterized by synaptic dysfunction and defects in dendritic spine morphology. In the past decade, an extensive list of genes associated with ASD has been identified by genome-wide sequencing initiatives. Several of these genes functionally converge in the regulation of the Wnt/β-catenin signaling pathway, a conserved cascade essential for stem cell pluripotency and cell fate decisions during development. Here, we review current information regarding the transcriptional program of Wnt/β-catenin signaling in ASD. First, we discuss that Wnt/β-catenin gain and loss of function studies recapitulate brain developmental abnormalities associated with ASD. Second, transcriptomic approaches using patient-derived induced pluripotent stem cells (iPSC) cells, featuring mutations in high confidence ASD genes, reveal a significant dysregulation in the expression of Wnt signaling components. Finally, we focus on the activity of chromatin-remodeling proteins and transcription factors considered high confidence ASD genes, including CHD8, ARID1B, ADNP, and TBR1, that regulate Wnt/β-catenin-dependent transcriptional activity in multiple cell types, including pyramidal neurons, interneurons and oligodendrocytes, cells which are becoming increasingly relevant in the study of ASD. We conclude that the level of Wnt/β-catenin signaling activation could explain the high phenotypical heterogeneity of ASD and be instrumental in the development of new diagnostics tools and therapies.

scholarly journals Neuronal cell fate decisions

Worm ◽  
2013 ◽  
Vol 2 (4) ◽  
pp. e27284 ◽  
Author(s):  
Jakob Gramstrup Petersen ◽  
Roger Pocock
Keyword(s):  
Cell Fate ◽  
Neuronal Cell ◽  
Cell Fate Decisions

Single-cell protein analysis reveals metastable states during the transition to a sensory organ fate

2021 ◽  
Author(s):  
Ritika Giri ◽  
Shannon C Brady ◽  
Richard William Carthew
Keyword(s):  
Cell Fate ◽  
Single Cell Protein ◽  
Sensory Organ ◽  
Bistable System ◽  
Cell Protein ◽  
Organ Differentiation ◽  
Cell Fate Decisions ◽  
Number Variation ◽  
Drosophila Cells ◽  
Protein Number

Cell fate decisions can be envisioned as bifurcating dynamical systems, and the decision that Drosophila cells make to undergo sensory organ differentiation has been sucessfully described as such. We have extended these studies by focusing on the Senseless protein, which orchestrates the sensory fate transition. Wing cells contain intermediate Senseless numbers prior to their fate transition, after which they express much greater numbers of Senseless molecules as they differentiate. However, the dynamics are not consistent with it being a simple bistable system. Cells with intermediate Senseless are best modeled as residing in four discrete states, each with a distinct protein number and occupying a specific region of the tissue. Although the four states are stable over time, the number of molecules in each state vary with time. Remarkably, the fold-change in molecule number between adjacent states is invariant and robust to absolute protein number variation. Thus, cells transitioning to sensory fates exhibit metastability with relativistic properties.

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