scholarly journals Zebrafish spinal cord oligodendrocyte formation requires boc function

Genetics ◽  
2021 ◽  
Author(s):  
Christina A Kearns ◽  
Macie Walker ◽  
Andrew M Ravanelli ◽  
Kayt Scott ◽  
Madeline R Arzbecker ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Motor Neurons ◽  
Transmembrane Protein ◽  
Fluorescent Detection ◽  
Bhlh Transcription Factor ◽  
Type I ◽  
Shh Signaling ◽  
Fibronectin Type Iii ◽  
The Central Nervous System ◽  
Fibronectin Type Iii Domain

Abstract The axis of the vertebrate neural tube is patterned, in part, by a ventral to dorsal gradient of Shh signaling. In the ventral spinal cord, Shh induces concentration-dependent expression of transcription factors, subdividing neural progenitors into distinct domains that subsequently produce distinct neuronal and glial subtypes. In particular, progenitors of the pMN domain express the bHLH transcription factor Olig2 and produce motor neurons followed by oligodendrocytes, the myelinating glial cell type of the central nervous system. In addition to its role in patterning ventral progenitors, Shh signaling must be maintained through development to specify pMN progenitors for oligodendrocyte fate. Using a forward genetic screen in zebrafish for mutations that disrupt development of oligodendrocytes, we identified a new mutant allele of boc, which encodes a type I transmembrane protein that functions as a coreceptor for Shh. Embryos homozygous for the bocco25 allele, which creates a missense mutation in a Fibronectin type III domain that binds Shh, have normally patterned spinal cords but fail to maintain pMN progenitors, resulting in a deficit of oligodendrocytes. Using a sensitive fluorescent detection method for in situ RNA hybridization, we found that spinal cord cells express boc in a graded fashion that is inverse to the gradient of Shh signaling activity and that boc function is necessary to maintain pMN progenitors by shaping the Shh signaling gradient.

scholarly journals Zebrafish spinal cord oligodendrocyte formation requires boc function

2021 ◽  
Author(s):  
Christina A. Kearns ◽  
Macie Walker ◽  
Andrew M. Ravanelli ◽  
Kayt Scott ◽  
Madeline R. Arzbecker ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Motor Neurons ◽  
Transmembrane Protein ◽  
Fluorescent Detection ◽  
Bhlh Transcription Factor ◽  
Type I ◽  
Shh Signaling ◽  
Fibronectin Type Iii ◽  
The Central Nervous System ◽  
Fibronectin Type Iii Domain

AbstractThe axis of the vertebrate neural tube is patterned, in part, by a ventral to dorsal gradient of Shh signaling. In the ventral spinal cord, Shh induces concentration-dependent expression of transcription factors, subdividing neural progenitors into distinct domains that subsequently produce distinct neuronal and glial subtypes. In particular, progenitors of the pMN domain express the bHLH transcription factor Olig2 and produce motor neurons followed by oligodendrocytes, the myelinating glial cell type of the central nervous system. In addition to its role in patterning ventral progenitors, Shh signaling must be maintained through development to specify pMN progenitors for oligodendrocyte fate. Using a forward genetic screen in zebrafish for mutations that disrupt development of oligodendrocytes, we identified a new mutant allele of boc, which encodes a type I transmembrane protein that functions as a coreceptor for Shh. Embryos homozygous for the bocco25 allele, which creates a missense mutation in a Fibronectin type III domain that binds Shh, have normally patterned spinal cords but fail to maintain pMN progenitors, resulting in a deficit of oligodendrocytes. Using a sensitive fluorescent detection method for in situ RNA hybridization, we found that spinal cord cells express boc in a graded fashion that is inverse to the gradient of Shh signaling activity and that boc function is necessary to maintain pMN progenitors by shaping the Shh signaling gradient.

scholarly journals Targeted axonal import (TAxI) peptide delivers functional proteins into spinal cord motor neurons after peripheral administration

2016 ◽  
Vol 113 (9) ◽  
pp. 2514-2519 ◽  
Author(s):  
Drew L. Sellers ◽  
Jamie M. Bergen ◽  
Russell N. Johnson ◽  
Heidi Back ◽  
John M. Ravits ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Motor Neurons ◽  
Unmet Need ◽  
Nerve Roots ◽  
Biologic Drugs ◽  
Administration Routes ◽  
Macromolecular Drugs ◽  
The Central Nervous System ◽  
Clinical Potential

A significant unmet need in treating neurodegenerative disease is effective methods for delivery of biologic drugs, such as peptides, proteins, or nucleic acids into the central nervous system (CNS). To date, there are no operative technologies for the delivery of macromolecular drugs to the CNS via peripheral administration routes. Using an in vivo phage-display screen, we identify a peptide, targeted axonal import (TAxI), that enriched recombinant bacteriophage accumulation and delivered protein cargo into spinal cord motor neurons after intramuscular injection. In animals with transected peripheral nerve roots, TAxI delivery into motor neurons after peripheral administration was inhibited, suggesting a retrograde axonal transport mechanism for delivery into the CNS. Notably, TAxI-Cre recombinase fusion proteins induced selective recombination and tdTomato-reporter expression in motor neurons after intramuscular injections. Furthermore, TAxI peptide was shown to label motor neurons in the human tissue. The demonstration of a nonviral-mediated delivery of functional proteins into the spinal cord establishes the clinical potential of this technology for minimally invasive administration of CNS-targeted therapeutics.

scholarly journals Clobetasol Modulates Adult Neural Stem Cell Growth via Canonical Hedgehog Pathway Activation

2019 ◽  
Vol 20 (8) ◽  
pp. 1991 ◽  
Author(s):  
Nunzio Vicario ◽  
Joshua D. Bernstock ◽  
Federica M. Spitale ◽  
Cesarina Giallongo ◽  
Maria A.S. Giunta ◽  
...  
Keyword(s):  
Nuclear Translocation ◽  
Transmembrane Protein ◽  
Clonal Expansion ◽  
Target System ◽  
Shh Signaling ◽  
Adult Neural Stem Cell ◽  
Pathway Activation ◽  
The Central Nervous System ◽  
Cellular Thermal Shift Assay ◽  
The Impact

Sonic hedgehog (Shh) signaling is a key pathway within the central nervous system (CNS), during both development and adulthood, and its activation via the 7-transmembrane protein Smoothened (Smo) may promote neuroprotection and restoration during neurodegenerative disorders. Shh signaling may also be activated by selected glucocorticoids such as clobetasol, fluocinonide and fluticasone, which therefore act as Smo agonists and hold potential utility for regenerative medicine. However, despite its potential role in neurodegenerative diseases, the impact of Smo-modulation induced by these glucocorticoids on adult neural stem cells (NSCs) and the underlying signaling mechanisms are not yet fully elucidated. The aim of the present study was to evaluate the effects of Smo agonists (i.e., purmorphamine) and antagonists (i.e., cyclopamine) as well as of glucocorticoids (i.e., clobetasol, fluocinonide and fluticasone) on NSCs in terms of proliferation and clonal expansion. Purmorphamine treatment significantly increased NSC proliferation and clonal expansion via GLI-Kruppel family member 1 (Gli1) nuclear translocation and such effects were prevented by cyclopamine co-treatment. Clobetasol treatment exhibited an equivalent pharmacological effect. Moreover, cellular thermal shift assay suggested that clobetasol induces the canonical Smo-dependent activation of Shh signaling, as confirmed by Gli1 nuclear translocation and also by cyclopamine co-treatment, which abolished these effects. Finally, fluocinonide and fluticasone as well as control glucocorticoids (i.e., prednisone, corticosterone and dexamethasone) showed no significant effects on NSCs proliferation and clonal expansion. In conclusion, our data suggest that Shh may represent a druggable target system to drive neuroprotection and promote restorative therapies.

scholarly journals Sulfatase 2 Modulates Fate Change from Motor Neurons to Oligodendrocyte Precursor Cells through Coordinated Regulation of Shh Signaling with Sulfatase 1

2017 ◽  
Vol 39 (5) ◽  
pp. 361-374 ◽  
Author(s):  
Wen Jiang ◽  
Yugo Ishino ◽  
Hirokazu Hashimoto ◽  
Kazuko Keino-Masu ◽  
Masayuki Masu ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Expression Pattern ◽  
Motor Neurons ◽  
Expression Patterns ◽  
Precursor Cells ◽  
Oligodendrocyte Precursor Cells ◽  
Shh Signaling ◽  
Sulfatase Activity ◽  
Oligodendrocyte Precursor ◽  
Ventral Spinal Cord

Sulfatases (Sulfs) are a group of endosulfatases consisting of Sulf1 and Sulf2, which specifically remove sulfate from heparan sulfate proteoglycans. Although several studies have shown that Sulf1 acts as a regulator of sonic hedgehog (Shh) signaling during embryonic ventral spinal cord development, the detailed expression pattern and function of Sulf2 in the spinal cord remains to be determined. In this study, we found that Sulf2 also modulates the cell fate change from motor neurons (MNs) to oligodendrocyte precursor cells (OPCs) by regulating Shh signaling in the mouse ventral spinal cord in coordination with Sulf1. In the mouse, Sulf mRNAs colocalize with Shh mRNA and gradually expand dorsally from embryonic day (E) 10.5 to E12.5, following strong Patched1 signals (a target gene of Shh signaling). This coordinated expression pattern led us to hypothesize that in the mouse, strong Shh signaling is induced when Shh is released by Sulf1/2, and this strong Shh signaling subsequently induces the dorsal expansion of Shh and Sulf1/2 expression. Consistent with this hypothesis, in the ventral spinal cord of Sulf1 knockout (KO) or Sulf2 KO mice, the expression patterns of Shh and Patched1 differed from that in wild-type mice. Moreover, the position of the pMN and p3 domains were shifted ventrally, MN generation was prolonged, and OPC generation was delayed at E12.5 in both Sulf1 KO and Sulf2 KO mice. These results demonstrated that in addition to Sulf1, Sulf2 also plays an important and overlapping role in the MN-to-OPC fate change by regulating Shh signaling in the ventral spinal cord. However, neither Sulf1 nor Sulf2 could compensate for the loss of the other in the developing mouse spinal cord. In vitro studies showed no evidence of an interaction between Sulf1 and Sulf2 that could increase sulfatase activity. Furthermore, Sulf1/2 double heterozygote and Sulf1/2 double KO mice exhibited phenotypes similar to the Sulf1 KO and Sulf2 KO mice. These results indicate that there is a threshold for sulfatase activity (which is likely reflected in the dose of Shh) required to induce the MN-to-OPC fate change, and Shh signaling requires the coordinated activity of Sulf1 and Sulf2 in order to reach that threshold in the mouse ventral spinal cord.

scholarly journals A Comprehensive Profile of ChIP-Seq-Based Olig2 Target Genes in Motor Neuron Progenitor Cells Suggests the Possible Involvement of Olig2 in the Pathogenesis of Amyotrophic Lateral Sclerosis

2015 ◽  
Vol 7 ◽  
pp. JCNSD.S23210 ◽  
Author(s):  
Jun-Ichi Satoh ◽  
Naohiro Asahina ◽  
Shouta Kitano ◽  
Yoshihiro Kino
Keyword(s):  
Spinal Cord ◽  
Amyotrophic Lateral Sclerosis ◽  
Motor Neuron ◽  
Progenitor Cells ◽  
Motor Neurons ◽  
Target Genes ◽  
Molecular Networks ◽  
Bhlh Transcription Factor ◽  
Wide Range ◽  
Lateral Sclerosis

Background Amyotrophic lateral sclerosis (ALS) is an intractable neurodegenerative disease that primarily affects motor neurons in the cerebral cortex and the spinal cord. Recent evidence indicates that dysfunction of oligodendrocytes is implicated in the pathogenesis of ALS. The basic helix–loop–helix (bHLH) transcription factor Olig2 plays a pivotal role in the development of both motor neurons and oligodendrocytes in the progenitor of motor neuron (pMN) domain of the spinal cord, supporting evidence for the shared motor neuron/oligodendrocyte lineage. However, a comprehensive profile of Olig2 target genes in pMNs and oligodendrocyte progenitor cells (OPCs) with relevance to the pathogenesis of ALS remains to be characterized. Methods By analyzing the ChIP-Seq datasets numbered SRP007566 and SRP015333 with the Strand NGS program, we identified genome-wide Olig2 target genes in pMNs and OPCs, followed by molecular network analysis using three distinct bioinformatics tools. Results We identified 5966 Olig2 target genes in pMNs, including Nkx2.2, Pax6, Irx3, Ngn2, Zep2 (Cip1), Trp3, Mnx1 (Hb9), and Cdkn1a, and 1553 genes in OPCs. The genes closely related to the keyword “alternative splicing” were enriched in the set of 740 targets overlapping between pMNs and OPCs. Furthermore, approximately one-third of downregulated genes in purified motor neurons of presymptomatic mutant SOD1 transgenic mice and in lumbar spinal cord tissues of ALS patients corresponded to Olig2 target genes in pMNs. Molecular networks of Olig2 target genes indicate that Olig2 regulates a wide range of genes essential for diverse neuronal and glial functions. Conclusions These observations lead to a hypothesis that aberrant regulation of Olig2 function, by affecting biology of both motor neurons and oligodendrocytes, might be involved in the pathogenesis of ALS.

scholarly journals Hierarchical control of locomotion by distinct types of spinal V2a interneurons in zebrafish

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Evdokia Menelaou ◽  
David L. McLean
Keyword(s):  
Spinal Cord ◽  
Motor Neurons ◽  
Hierarchical Control ◽  
Higher Order ◽  
Type I ◽  
Type Ii ◽  
Timing Control ◽  
Amplitude Control ◽  
Spinal Interneurons ◽  
Larval Zebrafish

Abstract In all vertebrates, excitatory spinal interneurons execute dynamic adjustments in the timing and amplitude of locomotor movements. Currently, it is unclear whether interneurons responsible for timing control are distinct from those involved in amplitude control. Here, we show that in larval zebrafish, molecularly, morphologically and electrophysiologically distinct types of V2a neurons exhibit complementary patterns of connectivity. Stronger higher-order connections from type I neurons to other excitatory V2a and inhibitory V0d interneurons provide timing control, while stronger last-order connections from type II neurons to motor neurons provide amplitude control. Thus, timing and amplitude are coordinated by distinct interneurons distinguished not by their occupation of hierarchically-arranged anatomical layers, but rather by differences in the reliability and probability of higher-order and last-order connections that ultimately form a single anatomical layer. These findings contribute to our understanding of the origins of timing and amplitude control in the spinal cord.

scholarly journals Genetic risk score based on fat mass and obesity-associated, transmembrane protein 18 and fibronectin type III domain containing 5 polymorphisms is associated with anthropometric characteristics in South Brazilian children and adolescents

2018 ◽  
Vol 121 (1) ◽  
pp. 93-99 ◽  
Author(s):  
Pâmela F. Todendi ◽  
Elisa I. Klinger ◽  
Ana C. R. Geraldo ◽  
Lucas Brixner ◽  
Cézane P. Reuter ◽  
...  
Keyword(s):  
Children And Adolescents ◽  
Genetic Risk ◽  
Transmembrane Protein ◽  
Genetic Risk Score ◽  
Additive Effect ◽  
Anthropometric Parameters ◽  
Anthropometric Characteristics ◽  
Fibronectin Type Iii ◽  
Fibronectin Type Iii Domain ◽  
Fibronectin Type

AbstractThe prevalence of childhood obesity has increased worldwide. Although it is considered a polygenic inheritance disease, little is known about its susceptibility when the additive effect is considered. The aim of this study is to investigate whether the genetic risk score (GRS) based on previously associated obesity polymorphisms (SNP) rs9939609 (fat mass and obesity-associated (FTO)), rs6548238 (transmembrane protein 18 (TMEM18)) and rs16835198 (fibronectin type III domain containing 5 (FNDC5)) could serve as a predictor for anthropometric characteristics in a sample of Brazilian children and adolescents. This is a cross-sectional study with 1471 children and adolescents aged 6–17 years. BMI, waist circumference (WC) and percentage of body fat and metabolic parameters were verified. In all, three SNP were genotyped by TaqMan™ allelic discrimination. The metabolic and anthropometric parameters were compared between the genotypes, and the unweighted and weighted GRS (GRS and wGRS, respectively) were created to test the additive effect of these genetic polymorphisms on anthropometric parameters. The prevalence of overweight plus obesity was 41 %. Significant associations were identified forFTOrs9939609,TMEM18rs6548238 andFNDC5rs16835198 and for GRS and wGRS with anthropometric phenotypes. The higher score of wGRS was associated with obesity (OR: 2·65, 95 % CI 1·40, 5·04,P=0·003) and with greater WC (OR: 2·91, 95 % CI 1·57, 5·40,P=0·001). Our results suggest that these genetic variants contribute to obesity susceptibility in children and adolescents and reinforce the idea that the additive effect may be useful to elucidate the genetic component of obesity.

scholarly journals The Temporal Mechanisms Guiding Interneuron Differentiation in the Spinal Cord

2021 ◽  
Vol 22 (15) ◽  
pp. 8025
Author(s):  
Dylan Deska-Gauthier ◽  
Ying Zhang
Keyword(s):  
Spinal Cord ◽  
Motor Neurons ◽  
The Other ◽  
Neuronal Diversity ◽  
Collective Knowledge ◽  
Mouse Spinal Cord ◽  
Developmental Mechanism ◽  
State Dependent ◽  
The Central Nervous System

Neurogenesis timing is an essential developmental mechanism for neuronal diversity and organization throughout the central nervous system. In the mouse spinal cord, growing evidence is beginning to reveal that neurogenesis timing acts in tandem with spatial molecular controls to diversify molecularly and functionally distinct post-mitotic interneuron subpopulations. Particularly, in some cases, this temporal ordering of interneuron differentiation has been shown to instruct specific sensorimotor circuit wirings. In zebrafish, in vivo preparations have revealed that sequential neurogenesis waves of interneurons and motor neurons form speed-dependent locomotor circuits throughout the spinal cord and brainstem. In the present review, we discuss temporal principals of interneuron diversity taken from both mouse and zebrafish systems highlighting how each can lend illuminating insights to the other. Moving forward, it is important to combine the collective knowledge from different systems to eventually understand how temporally regulated subpopulation function differentially across speed- and/or state-dependent sensorimotor movement tasks.

scholarly journals Distinct Spinal V2a and V0d Microcircuits Distribute Locomotor Control in Larval Zebrafish

2019 ◽  
Author(s):  
Evdokia Menelaou ◽  
Sandeep Kishore ◽  
David L. McLean
Keyword(s):  
Spinal Cord ◽  
Conceptual Framework ◽  
Distributed Control ◽  
Motor Neurons ◽  
Type I ◽  
Type Ii ◽  
Spinal Interneurons ◽  
Larval Zebrafish ◽  
Locomotor Control ◽  
Pattern Control

SUMMARYSpinal interneurons coordinate adjustments in the rhythm and pattern of locomotor movements. Two prevailing models predict that interneurons either share or hierarchically distribute control of these key parameters. Here, we have tested each model in the coordination of swimming in larval zebrafish by circumferential excitatory V2a and commissural inhibitory V0d interneurons. We define two types of V2a neuron based on morphology, electrophysiology and connectivity. Type I V2as primarily propagate and amplify rhythmic signals biased to interneurons, while type II V2as primarily segregate and expedite patterning signals biased to motor neurons. Distributed control arises by differences in the likelihood of connections within types and the relative weights of connections between them, but not by a strict anatomical hierarchy. Heterogeneity among V0d neurons supports a similar functional distinction. Our findings provide a hybrid conceptual framework to better understand the origins of rhythm and pattern control in the spinal cord.

scholarly journals A direct excitatory action of lactate ions in the central respiratory network of bullfrogs, Lithobates catesbeianus

2020 ◽  
Vol 223 (24) ◽  
pp. jeb235705
Author(s):  
Michael T. Burton ◽  
Joseph M. Santin
Keyword(s):  
Spinal Cord ◽  
Central Nervous System ◽  
Motor Neurons ◽  
Motor Output ◽  
Pyruvate Metabolism ◽  
Respiratory Network ◽  
The Central Nervous System ◽  
Excitatory Action ◽  
Per Se ◽  
Excitatory Drive

ABSTRACTChemoreceptors that detect O2 and CO2/pH regulate ventilation. However, recent work shows that lactate ions activate arterial chemoreceptors independent of pH to stimulate breathing. Although lactate rises in the central nervous system (CNS) during metabolic challenges, the ability of lactate ions to enhance ventilation by directly targeting the central respiratory network remains unclear. To address this possibility, we isolated the amphibian brainstem–spinal cord and found that small increases in CNS lactate stimulate motor output that causes breathing. In addition, lactate potentiated the excitatory postsynaptic strength of respiratory motor neurons, thereby coupling central lactate to the excitatory drive of neurons that trigger muscle contraction. Lactate did not affect motor output through pH or pyruvate metabolism, arguing for sensitivity to lactate anions per se. In sum, these results introduce a mechanism whereby lactate ions in the CNS match respiratory motor output to metabolic demands.

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