scholarly journals ADNP promotes neural differentiation by modulating Wnt/β-catenin signaling

2019 ◽  
Author(s):  
Xiaoyun Sun ◽  
Xixia Peng ◽  
Yuqing Cao ◽  
Yan Zhou ◽  
Yuhua Sun
Keyword(s):  
Wnt Signaling ◽  
Neural Development ◽  
Neural Differentiation ◽  
Developmental Disorders ◽  
Embryonic Stem ◽  
Mouse Embryonic Stem Cell ◽  
Neural Induction ◽  
Neuron Death ◽  
Aberrant Expression ◽  
Protein Levels

AbstractADNP (Activity Dependent Neuroprotective Protein) is proposed as a neuroprotective protein whose aberrant expression has been frequently linked to neural developmental disorders, including the Helsmoortel-Van der Aa syndrome. However, its role in neural development and pathology remains unclear. Using mESC (mouse embryonic stem cell) directional neural differentiation as a model, we show that ADNP is required for ESC neural induction and neuronal differentiation by maintaining Wnt signaling. Mechanistically, ADNP functions to maintain the proper protein levels of β-Catenin through binding to its armadillo domain which prevents its association with key components of the degradation complex: Axin and APC. Loss of ADNP promotes the formation of the degradation complex and hyperphosphorylation of β-Catenin by GSK3β and subsequent degradation via ubiquitin-proteasome pathway, resulting in down-regulation of key neuroectoderm developmental genes. We further show that ADNP plays key role in cerebellar neuron formation. Finally, adnp gene disruption in zebrafish embryos recapitulates key features of the mouse phenotype, including the reduced Wnt signaling, defective embryonic cerebral neuron formation and the massive neuron death. Thus, our work provides important insights into the role of ADNP in neural development and the pathology of the Helsmoortel-Van der Aa syndrome caused by ADNP gene mutation.

scholarly journals Neural Induction, Neural Fate Stabilization, and Neural Stem Cells

2002 ◽  
Vol 2 ◽  
pp. 1147-1166 ◽  
Author(s):  
Sally A. Moody ◽  
Hyun-Soo Je
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Neural Stem Cells ◽  
Neural Development ◽  
Current Knowledge ◽  
Embryonic Stem ◽  
Neural Induction ◽  
Neural Plate ◽  
Natural Rate ◽  
Neural Fate

The promise of stem cell therapy is expected to greatly benefit the treatment of neurodegenerative diseases. An underlying biological reason for the progressive functional losses associated with these diseases is the extremely low natural rate of self-repair in the nervous system. Although the mature CNS harbors a limited number of self-renewing stem cells, these make a significant contribution to only a few areas of brain. Therefore, it is particularly important to understand how to manipulate embryonic stem cells and adult neural stem cells so their descendants can repopulate and functionally repair damaged brain regions. A large knowledge base has been gathered about the normal processes of neural development. The time has come for this information to be applied to the problems of obtaining sufficient, neurally committed stem cells for clinical use. In this article we review the process of neural induction, by which the embryonic ectodermal cells are directed to form the neural plate, and the process of neural�fate stabilization, by which neural plate cells expand in number and consolidate their neural fate. We will present the current knowledge of the transcription factors and signaling molecules that are known to be involved in these processes. We will discuss how these factors may be relevant to manipulating embryonic stem cells to express a neural fate and to produce large numbers of neurally committed, yet undifferentiated, stem cells for transplantation therapies.

scholarly journals Epsins Regulate Mouse Embryonic Stem Cell Exit from Pluripotency and Neural Commitment by Controlling Notch Activation

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Marina Cardano ◽  
Jacopo Zasso ◽  
Luca Ruggiero ◽  
Giuseppina Di Giacomo ◽  
Matteo Marcatili ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Embryonic Stem Cells ◽  
Notch Signaling ◽  
Neural Differentiation ◽  
Radial Glia ◽  
Embryonic Stem ◽  
Mouse Embryonic Stem Cell ◽  
Neural Progenitors ◽  
Notch Activation

Epsins are part of the internalization machinery pivotal to control clathrin-mediated endocytosis. Here, we report that epsin family members are expressed in mouse embryonic stem cells (mESCs) and that epsin1/2 knockdown alters both mESC exits from pluripotency and their differentiation. Furthermore, we show that epsin1/2 knockdown compromises the correct polarization and division of mESC-derived neural progenitors and their conversion into expandable radial glia-like neural stem cells. Finally, we provide evidence that Notch signaling is impaired following epsin1/2 knockdown and that experimental restoration of Notch signaling rescues the epsin-mediated phenotypes. We conclude that epsins contribute to control mESC exit from pluripotency and allow their neural differentiation by appropriate modulation of Notch signaling.

scholarly journals Bidirectional Wnt signaling between endoderm and mesoderm confer tracheal identity in mouse and human

2019 ◽  
Author(s):  
Keishi Kishimoto ◽  
Kana T. Furukawa ◽  
Agustin Luz Madrigal ◽  
Akira Yamaoka ◽  
Chisa Matsuoka ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Wnt Signaling ◽  
Embryonic Stem ◽  
Mouse Embryonic Stem Cell ◽  
Bmp Signaling ◽  
Lateral Plate ◽  
Tracheal Tissue ◽  
Canonical Wnt ◽  
Human And Mouse

AbstractThe periodic cartilage and smooth muscle structures in mammalian trachea are derived from tracheal mesoderm, and tracheal malformations result in serious respiratory defects in neonates. Here we show that canonical Wnt signaling in mesoderm is critical to confer trachea mesenchymal identity in human and mouse. Loss of β-catenin in fetal mouse mesoderm caused loss of Tbx4+ tracheal mesoderm and tracheal cartilage agenesis. The Tbx4 expression relied on endodermal Wnt activity and its downstream Wnt ligand but independent of known Nkx2.1-mediated respiratory development, suggesting that bidirectional Wnt signaling between endoderm and mesoderm promotes trachea development. Repopulating in vivo model, activating Wnt, Bmp signaling in mouse embryonic stem cell (ESC)-derived lateral plate mesoderm (LPM) generated tracheal mesoderm containing chondrocytes and smooth muscle cells. For human ESC-derived LPM, SHH activation was required along with Wnt to generate proper tracheal mesoderm. Together, these findings may contribute to developing applications for human tracheal tissue repair.

scholarly journals Dlk1-Dio3 locus-derived lncRNAs perpetuate postmitotic motor neuron cell fate and subtype identity

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Ya-Ping Yen ◽  
Wen-Fu Hsieh ◽  
Ya-Yin Tsai ◽  
Ya-Lin Lu ◽  
Ee Shan Liau ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Fate ◽  
Motor Neurons ◽  
Neural Development ◽  
Hox Genes ◽  
Critical Role ◽  
Embryonic Stem ◽  
Cell Types ◽  
Aberrant Expression ◽  
Spinal Cord Development

The mammalian imprinted Dlk1-Dio3 locus produces multiple long non-coding RNAs (lncRNAs) from the maternally inherited allele, including Meg3 (i.e., Gtl2) in the mammalian genome. Although this locus has well-characterized functions in stem cell and tumor contexts, its role during neural development is unknown. By profiling cell types at each stage of embryonic stem cell-derived motor neurons (ESC~MNs) that recapitulate spinal cord development, we uncovered that lncRNAs expressed from the Dlk1-Dio3 locus are predominantly and gradually enriched in rostral motor neurons (MNs). Mechanistically, Meg3 and other Dlk1-Dio3 locus-derived lncRNAs facilitate Ezh2/Jarid2 interactions. Loss of these lncRNAs compromises the H3K27me3 landscape, leading to aberrant expression of progenitor and caudal Hox genes in postmitotic MNs. Our data thus illustrate that these lncRNAs in the Dlk1-Dio3 locus, particularly Meg3, play a critical role in maintaining postmitotic MN cell fate by repressing progenitor genes and they shape MN subtype identity by regulating Hox genes.

scholarly journals Extracellular vesicles from neuronal cells promote neural induction of mESCs through cyclinD1

2021 ◽  
Author(s):  
Lu Song ◽  
Xinran Tian ◽  
Randy Schekman
Keyword(s):  
Cyclin D1 ◽  
Extracellular Vesicles ◽  
Neural Development ◽  
Neuronal Cells ◽  
Buoyant Density ◽  
Embryonic Stem ◽  
Neural Induction ◽  
Induction Effect ◽  
Differentiated Cells

Extracellular vesicles (EVs) that are thought to mediate the transport of proteins and RNAs involved in intercellular communication. Here, we show dynamic changes in the buoyant density and abundance of extracellular vesicles that are secreted by PC12 cells stimulated with nerve growth factor (NGF), N2A cells treated with retinoic acid to induce neural differentiation and mESCs differentiated into neuronal cells. EVs secreted from in vitro differentiated cells promote neural induction of mouse embryonic stem cells (mESCs). Cyclin D1 enriched within the EVs derived from differentiated neuronal cells contributes to this induction. EVs purified from cells overexpressing cyclin D1 are more potent in neural induction of mESC cells. Depletion of cyclin D1 from the EVs reduced the neural induction effect. Our results suggest that extracellular vesicles regulate neural development through sorting of cyclin D1.

scholarly journals Induction of recurrent break cluster genes in neural progenitor cells differentiated from embryonic stem cells in culture

2020 ◽  
Vol 117 (19) ◽  
pp. 10541-10546 ◽  
Author(s):  
Aseda Tena ◽  
Yuxiang Zhang ◽  
Nia Kyritsis ◽  
Anne Devorak ◽  
Jeffrey Zurita ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Neural Development ◽  
Large Fraction ◽  
Embryonic Stem ◽  
Mouse Embryonic Stem Cell ◽  
Neural Progenitor ◽  
Strand Break ◽  
Neuropsychiatric Diseases ◽  
Primary Mouse

Mild replication stress enhances appearance of dozens of robust recurrent genomic break clusters, termed RDCs, in cultured primary mouse neural stem and progenitor cells (NSPCs). Robust RDCs occur within genes (“RDC-genes”) that are long and have roles in neural cell communications and/or have been implicated in neuropsychiatric diseases or cancer. We sought to develop an in vitro approach to determine whether specific RDC formation is associated with neural development. For this purpose, we adapted a system to induce neural progenitor cell (NPC) development from mouse embryonic stem cell (ESC) lines deficient for XRCC4 plus p53, a genotype that enhances DNA double-strand break (DSB) persistence to enhance detection. We tested for RDCs by our genome-wide DSB identification approach that captures DSBs via their ability to join to specific genomic Cas9/single-guide RNA–generated bait DSBs. In XRCC4/p53-deficient ESCs, we detected seven RDCs, all of which were in genes and two of which were robust. In contrast, in NPCs derived from these ESC lines we detected 29 RDCs, a large fraction of which were robust and associated with long, transcribed neural genes that were also robust RDC-genes in primary NSPCs. These studies suggest that many RDCs present in NSPCs are developmentally influenced to occur in this cell type and indicate that induced development of NPCs from ESCs provides an approach to rapidly elucidate mechanistic aspects of NPC RDC formation.

scholarly journals Expression Profiles of Subtracted Genes During Neural Differentiation from Human Embryonic Stem Cells using Suppression Subtractive Hybridization

2021 ◽  
Author(s):  
Jung Ki Yoo ◽  
Hye Min Noh ◽  
Jonghyup Kim ◽  
Sehun Lim ◽  
Seong-Jun Choi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Human Embryonic Stem Cells ◽  
Neural Development ◽  
Neural Differentiation ◽  
Es Cells ◽  
Embryonic Stem ◽  
Subtractive Hybridization ◽  
Specific Gene ◽  
Gene Expressions ◽  
Human Es Cells

Abstract Human embryonic stem cells (human ES cells) are pluripotent and self-renewing cells that can be isolated from the inner cell mass at the blastocyst stage. Human ES cells differentiate into specific cell lineages according to the expression of related genes. During neural development, specific gene expressions induced human ES cells some morphological changes. We used suppression subtractive hybridization to identify genes which shows altered expression during neural differentiation from human ES cells. We identified 90 genes as downregulated and 64 genes as upregulated in neural precursor (NP) cells derived from human ES cells compared with human ES cells. To obtain further information about differentiation, we performed expression profiling of subtracted genes between human ES cells and NP cells. Of the subtracted genes in human ES cells, the 19 genes showed decreased expression in NP cells. Meanwhile, of the subtracted genes in NP cells, the 20 genes were upregulated. Among them, COPZ1, CPSF6, MATR3 and TOMD3 were specific gene expressions that they significantly expressed up and down-regulation during neural development derived from ES cells. These genes have not previously been associated with neural differentiation, but they may be potentially participated in neurogenesis.

scholarly journals A conserved acetylation switch enables pharmacological control of tubby-like protein stability

2020 ◽  
pp. jbc.RA120.015839 ◽  
Author(s):  
Evan M Kerek ◽  
Kevin H Yoon ◽  
Shu Y Luo ◽  
Jerry Chen ◽  
Robert Valencia ◽  
...  
Keyword(s):  
Protein Interaction ◽  
Developmental Disorders ◽  
Intracellular Transport ◽  
Interaction Network ◽  
Membrane Receptors ◽  
Aberrant Expression ◽  
Protein Protein Interaction ◽  
Protein Levels ◽  
Lysine Residues ◽  
The Stability

Tubby-like proteins (TULPs) are characterized by a conserved C-terminal domain that binds phosphoinositides. Collectively, mammalian TULP1-4 proteins play essential roles in intracellular transport, cell differentiation, signaling, and motility. Yet, little is known about how the function of these proteins is regulated in cells. Here, we present the protein-protein interaction network of TULP3, a protein that is responsible for the trafficking of G-protein coupled receptors to cilia, and whose aberrant expression is associated with severe developmental disorders and polycystic kidney disease. We identify several protein interaction nodes linked to TULP3 that include enzymes involved in acetylation and ubiquitination. We show that acetylation of two key lysine residues on TULP3 by p300 increases TULP3 protein abundance, and that deacetylation of these sites by HDAC1 decreases protein levels. Furthermore, we show that one of these sites is ubiquitinated in the absence of acetylation, and that acetylation inversely correlates with ubiquitination of TULP3. This mechanism is evidently conserved across species and is active in zebrafish during development. Finally, we identify this same regulatory module in TULP1, TULP2, and TULP4, and demonstrate that the stability of these proteins is similarly modulated by an acetylation switch. This study unveils a signaling pathway that links nuclear enzymes to ciliary membrane receptors via TULP3, describes a dynamic mechanism for the regulation of all tubby-like proteins, and explores how to exploit it pharmacologically using drugs.

How Wnt Signaling Builds the Brain: Bridging Development and Disease

2016 ◽  
Vol 23 (3) ◽  
pp. 314-329 ◽  
Author(s):  
Rivka Noelanders ◽  
Kris Vleminckx
Keyword(s):  
Wnt Signaling ◽  
Neural Development ◽  
Neurological Disorders ◽  
Neural Differentiation ◽  
Neurological Diseases ◽  
Physiological Role ◽  
Adult Brain ◽  
Neurological Dysfunction ◽  
The Brain

Wnt/β-catenin signaling plays a crucial role throughout all stages of brain development and remains important in the adult brain. Accordingly, many neurological disorders have been linked to Wnt signaling. Defects in Wnt signaling during neural development can give rise to birth defects or lead to neurological dysfunction later in life. Developmental signaling events can also be hijacked in the adult and result in disease. Moreover, knowledge about the physiological role of Wnt signaling in the brain might lead to new therapeutic strategies for neurological diseases. Especially, the important role for Wnt signaling in neural differentiation of pluripotent stem cells has received much attention as this might provide a cure for neurodegenerative disorders. In this review, we summarize the versatile role of Wnt/β-catenin signaling during neural development and discuss some recent studies linking Wnt signaling to neurological disorders.

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