scholarly journals Transcriptional reprogramming of distinct peripheral sensory neuron subtypes after axonal injury

2019 ◽  
Author(s):  
William Renthal ◽  
Ivan Tochitsky ◽  
Lite Yang ◽  
Yung-Chih Cheng ◽  
Emmy Li ◽  
...  
Keyword(s):  
Cell Fate ◽  
Axonal Regeneration ◽  
Cell Function ◽  
Sensory Information ◽  
Neuronal Cell ◽  
Transcriptional Response ◽  
Cell Identity ◽  
Transcriptional Reprogramming ◽  
Somatosensory Neurons ◽  
Peripheral Sensory

SummaryPrimary somatosensory neurons are specialized to transmit specific types of sensory information through differences in cell size, myelination, and the expression of distinct receptors and ion channels, which together define their transcriptional and functional identity. By transcriptionally profiling sensory ganglia at single-cell resolution, we find that different somatosensory neuronal subtypes undergo a remarkably consistent and dramatic transcriptional response to peripheral nerve injury that both promotes axonal regeneration and suppresses cell identity. Successful axonal regeneration leads to a restoration of neuronal cell identity and the deactivation of the growth program. This injury-induced transcriptional reprogramming requires Atf3, a transcription factor which is induced rapidly after injury and is necessary for axonal regeneration and functional recovery. While Atf3 and other injury-induced transcription factors are known for their role in reprogramming cell fate, their function in mature neurons is likely to facilitate major adaptive changes in cell function in response to damaging environmental stimuli.

scholarly journals Glycans and glycosaminoglycans in neurobiology: key regulators of neuronal cell function and fate

2018 ◽  
Vol 475 (15) ◽  
pp. 2511-2545 ◽  
Author(s):  
Anthony J. Hayes ◽  
James Melrose
Keyword(s):  
Cell Fate ◽  
Information Transfer ◽  
Cell Function ◽  
Dermatan Sulfate ◽  
Neuronal Cell ◽  
Keratan Sulfate ◽  
Neural Function ◽  
Cellular Survival ◽  
Downstream Signaling ◽  
Blood Group Substances

The aim of the present study was to examine the roles of l-fucose and the glycosaminoglycans (GAGs) keratan sulfate (KS) and chondroitin sulfate/dermatan sulfate (CS/DS) with selected functional molecules in neural tissues. Cell surface glycans and GAGs have evolved over millions of years to become cellular mediators which regulate fundamental aspects of cellular survival. The glycocalyx, which surrounds all cells, actuates responses to growth factors, cytokines and morphogens at the cellular boundary, silencing or activating downstream signaling pathways and gene expression. In this review, we have focused on interactions mediated by l-fucose, KS and CS/DS in the central and peripheral nervous systems. Fucose makes critical contributions in the area of molecular recognition and information transfer in the blood group substances, cytotoxic immunoglobulins, cell fate-mediated Notch-1 interactions, regulation of selectin-mediated neutrophil extravasation in innate immunity and CD-34-mediated new blood vessel development, and the targeting of neuroprogenitor cells to damaged neural tissue. Fucosylated glycoproteins regulate delivery of synaptic neurotransmitters and neural function. Neural KS proteoglycans (PGs) were examined in terms of cellular regulation and their interactive properties with neuroregulatory molecules. The paradoxical properties of CS/DS isomers decorating matrix and transmembrane PGs and the positive and negative regulatory cues they provide to neurons are also discussed.

scholarly journals miRNA suppression of a Notch repressor directs non-neuronal fate in Drosophila mechanosensory organs

2017 ◽  
Vol 217 (2) ◽  
pp. 571-583 ◽  
Author(s):  
Joshua Kavaler ◽  
Hong Duan ◽  
Rajaguru Aradhya ◽  
Luis F. de Navas ◽  
Brian Joseph ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Cell Fate ◽  
Large Scale ◽  
Notch Pathway ◽  
Neuronal Cell ◽  
Loss Of Function ◽  
Cell Specification ◽  
Neuronal Fate ◽  
Fate Decision ◽  
Peripheral Sensory

Although there is abundant evidence that individual microRNA (miRNA) loci repress large cohorts of targets, large-scale knockout studies suggest that most miRNAs are phenotypically dispensable. Here, we identify a rare case of developmental cell specification that is highly dependent on miRNA control of an individual target. We observe that binary cell fate choice in the Drosophila melanogaster peripheral sensory organ lineage is controlled by the non-neuronally expressed mir-279/996 cluster, with a majority of notum sensory organs exhibiting transformation of sheath cells into ectopic neurons. The mir-279/996 defect phenocopies Notch loss of function during the sheath–neuron cell fate decision, suggesting the miRNAs facilitate Notch signaling. Consistent with this, mir-279/996 knockouts are strongly enhanced by Notch heterozygosity, and activated nuclear Notch is impaired in the miRNA mutant. Although Hairless (H) is the canonical nuclear Notch pathway inhibitor, and H heterozygotes exhibit bristle cell fate phenotypes reflecting gain-of-Notch signaling, H/+ does not rescue mir-279/996 mutants. Instead, we identify Insensible (Insb), another neural nuclear Notch pathway inhibitor, as a critical direct miR-279/996 target. Insb is posttranscriptionally restricted to neurons by these miRNAs, and its heterozygosity strongly suppresses ectopic peripheral nervous system neurons in mir-279/996 mutants. Thus, proper assembly of multicellular mechanosensory organs requires a double-negative circuit involving miRNA-mediated suppression of a Notch repressor to assign non-neuronal cell fate.

scholarly journals Cadherins in early neural development

2021 ◽  
Author(s):  
Karolina Punovuori ◽  
Mattias Malaguti ◽  
Sally Lowell
Keyword(s):  
Adhesion Molecules ◽  
Cell Fate ◽  
Neural Development ◽  
Ex Vivo ◽  
Directed Differentiation ◽  
Culture Dish ◽  
Cell Identity ◽  
Cell Fate Decisions ◽  
Neural Tissues ◽  
And Function

AbstractDuring early neural development, changes in signalling inform the expression of transcription factors that in turn instruct changes in cell identity. At the same time, switches in adhesion molecule expression result in cellular rearrangements that define the morphology of the emerging neural tube. It is becoming increasingly clear that these two processes influence each other; adhesion molecules do not simply operate downstream of or in parallel with changes in cell identity but rather actively feed into cell fate decisions. Why are differentiation and adhesion so tightly linked? It is now over 60 years since Conrad Waddington noted the remarkable "Constancy of the Wild Type” (Waddington in Nature 183: 1654–1655, 1959) yet we still do not fully understand the mechanisms that make development so reproducible. Conversely, we do not understand why directed differentiation of cells in a dish is sometimes unpredictable and difficult to control. It has long been suggested that cells make decisions as 'local cooperatives' rather than as individuals (Gurdon in Nature 336: 772–774, 1988; Lander in Cell 144: 955–969, 2011). Given that the cadherin family of adhesion molecules can simultaneously influence morphogenesis and signalling, it is tempting to speculate that they may help coordinate cell fate decisions between neighbouring cells in the embryo to ensure fidelity of patterning, and that the uncoupling of these processes in a culture dish might underlie some of the problems with controlling cell fate decisions ex-vivo. Here we review the expression and function of cadherins during early neural development and discuss how and why they might modulate signalling and differentiation as neural tissues are formed.

scholarly journals Development in the Mammalian Auditory System Depends on Transcription Factors

2021 ◽  
Vol 22 (8) ◽  
pp. 4189
Author(s):  
Karen L. Elliott ◽  
Gabriela Pavlínková ◽  
Victor V. Chizhikov ◽  
Ebenezer N. Yamoah ◽  
Bernd Fritzsch
Keyword(s):  
Transcription Factors ◽  
Cell Fate ◽  
Auditory System ◽  
Hair Cells ◽  
System Development ◽  
Neuronal Cell ◽  
Spiral Ganglion Neuron ◽  
Cochlear Hair Cells ◽  
Cochlear Nuclei ◽  
Bhlh Genes

We review the molecular basis of several transcription factors (Eya1, Sox2), including the three related genes coding basic helix–loop–helix (bHLH; see abbreviations) proteins (Neurog1, Neurod1, Atoh1) during the development of spiral ganglia, cochlear nuclei, and cochlear hair cells. Neuronal development requires Neurog1, followed by its downstream target Neurod1, to cross-regulate Atoh1 expression. In contrast, hair cells and cochlear nuclei critically depend on Atoh1 and require Neurod1 expression for interactions with Atoh1. Upregulation of Atoh1 following Neurod1 loss changes some vestibular neurons’ fate into “hair cells”, highlighting the significant interplay between the bHLH genes. Further work showed that replacing Atoh1 by Neurog1 rescues some hair cells from complete absence observed in Atoh1 null mutants, suggesting that bHLH genes can partially replace one another. The inhibition of Atoh1 by Neurod1 is essential for proper neuronal cell fate, and in the absence of Neurod1, Atoh1 is upregulated, resulting in the formation of “intraganglionic” HCs. Additional genes, such as Eya1/Six1, Sox2, Pax2, Gata3, Fgfr2b, Foxg1, and Lmx1a/b, play a role in the auditory system. Finally, both Lmx1a and Lmx1b genes are essential for the cochlear organ of Corti, spiral ganglion neuron, and cochlear nuclei formation. We integrate the mammalian auditory system development to provide comprehensive insights beyond the limited perception driven by singular investigations of cochlear neurons, cochlear hair cells, and cochlear nuclei. A detailed analysis of gene expression is needed to understand better how upstream regulators facilitate gene interactions and mammalian auditory system development.

scholarly journals Set1 Targets Genes with Essential Identity and Tumor-Suppressing Functions in Planarian Stem Cells

Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1182
Author(s):  
Prince Verma ◽  
Court K. M. Waterbury ◽  
Elizabeth M. Duncan
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Mammalian Cells ◽  
Cell Function ◽  
Genotoxic Stress ◽  
Specific Gene ◽  
Cell Identity ◽  
Chromatin Signature ◽  
Lysine Methyltransferase

Tumor suppressor genes (TSGs) are essential for normal cellular function in multicellular organisms, but many TSGs and tumor-suppressing mechanisms remain unknown. Planarian flatworms exhibit particularly robust tumor suppression, yet the specific mechanisms underlying this trait remain unclear. Here, we analyze histone H3 lysine 4 trimethylation (H3K4me3) signal across the planarian genome to determine if the broad H3K4me3 chromatin signature that marks essential cell identity genes and TSGs in mammalian cells is conserved in this valuable model of in vivo stem cell function. We find that this signature is indeed conserved on the planarian genome and that the lysine methyltransferase Set1 is largely responsible for creating it at both cell identity and putative TSG loci. In addition, we show that depletion of set1 in planarians induces stem cell phenotypes that suggest loss of TSG function, including hyperproliferation and an abnormal DNA damage response (DDR). Importantly, this work establishes that Set1 targets specific gene loci in planarian stem cells and marks them with a conserved chromatin signature. Moreover, our data strongly suggest that Set1 activity at these genes has important functional consequences both during normal homeostasis and in response to genotoxic stress.

scholarly journals Histone Acetyltransferases and Stem Cell Identity

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2407
Author(s):  
Ruicen He ◽  
Arthur Dantas ◽  
Karl Riabowol
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Fate ◽  
Epigenetic Modification ◽  
Cell Types ◽  
Histone Acetyltransferases ◽  
Specific Cell ◽  
Cell Fates ◽  
Cell Identity ◽  
Hematopoietic Stem

Acetylation of histones is a key epigenetic modification involved in transcriptional regulation. The addition of acetyl groups to histone tails generally reduces histone-DNA interactions in the nucleosome leading to increased accessibility for transcription factors and core transcriptional machinery to bind their target sequences. There are approximately 30 histone acetyltransferases and their corresponding complexes, each of which affect the expression of a subset of genes. Because cell identity is determined by gene expression profile, it is unsurprising that the HATs responsible for inducing expression of these genes play a crucial role in determining cell fate. Here, we explore the role of HATs in the maintenance and differentiation of various stem cell types. Several HAT complexes have been characterized to play an important role in activating genes that allow stem cells to self-renew. Knockdown or loss of their activity leads to reduced expression and or differentiation while particular HATs drive differentiation towards specific cell fates. In this study we review functions of the HAT complexes active in pluripotent stem cells, hematopoietic stem cells, muscle satellite cells, mesenchymal stem cells, neural stem cells, and cancer stem cells.

split ends encodes large nuclear proteins that regulate neuronal cell fate and axon extension in the Drosophila embryo

Development ◽  
2000 ◽  
Vol 127 (7) ◽  
pp. 1517-1529 ◽  
Author(s):  
B. Kuang ◽  
S.C. Wu ◽  
Y. Shin ◽  
L. Luo ◽  
P. Kolodziej
Keyword(s):  
Cell Fate ◽  
Egf Receptor ◽  
Neuronal Cell ◽  
Drosophila Embryo ◽  
Neuronal Precursors ◽  
Split Ends ◽  
Recognition Motifs ◽  
Midline Cells ◽  
Wrong Number ◽  
Nuclear Levels

split ends (spen) encodes nuclear 600 kDa proteins that contain RNA recognition motifs and a conserved C-terminal sequence. These features define a new protein family, Spen, which includes the vertebrate MINT transcriptional regulator. Zygotic spen mutants affect the growth and guidance of a subset of axons in the Drosophila embryo. Removing maternal and zygotic protein elicits cell-fate and more general axon-guidance defects that are not seen in zygotic mutants. The wrong number of chordotonal neurons and midline cells are generated, and we identify defects in precursor formation and EGF receptor-dependent inductive processes required for cell-fate specification. The number of neuronal precursors is variable in embryos that lack Spen. The levels of Suppressor of Hairless, a key transcriptional effector of Notch required for precursor formation, are reduced, as are the nuclear levels of Yan, a transcriptional repressor that regulates cell fate and proliferation downstream of the EGF receptor. We propose that Spen proteins regulate the expression of key effectors of signaling pathways required to specify neuronal cell fate and morphology.

scholarly journals Gene-free methodology for cell fate dynamics during development

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Francis Corson ◽  
Eric D Siggia
Keyword(s):  
Cell Fate ◽  
Cell Function ◽  
Geometric Model ◽  
Model Fit ◽  
Vulval Development ◽  
Epistatic Interactions ◽  
Compact Representations ◽  
Special Points ◽  
Unexpected Outcomes

Models of cell function that assign a variable to each gene frequently lead to systems of equations with many parameters whose behavior is obscure. Geometric models reduce dynamics to intuitive pictorial elements that provide compact representations for sparse in vivo data and transparent descriptions of developmental transitions. To illustrate, a geometric model fit to vulval development in Caenorhabditis elegans, implies a phase diagram where cell-fate choices are displayed in a plane defined by EGF and Notch signaling levels. This diagram defines allowable and forbidden cell-fate transitions as EGF or Notch levels change, and explains surprising observations previously attributed to context-dependent action of these signals. The diagram also reveals the existence of special points at which minor changes in signal levels lead to strong epistatic interactions between EGF and Notch. Our model correctly predicts experiments near these points and suggests specific timed perturbations in signals that can lead to additional unexpected outcomes.

Sign in / Sign up

Export Citation Format

Share Document