Diminished ventral oligodendrocyte precursor generation results in the subsequent over-production of dorsal oligodendrocyte precursors of aberrant morphology and function

And Function ◽

Sod1 Mouse ◽

Lateral Sclerosis ◽

Ventral Spinal Cord

AbstractOligodendrocyte precursor cells (OPCs) arise sequentially first from a ventral and then from a dorsal precursor domain at the end of neurogenesis during spinal cord development. Whether the sequential production of OPCs is of physiological significance has not been examined. Here we show that ablating Shh signaling from nascent ventricular zone derivatives and partially from the floor plate results in a severe diminishment of ventral derived OPCs but normal numbers of motor neurons in the postnatal spinal cord. In the absence of ventral vOPCs, dorsal dOPCs populate the entire spinal cord resulting in an increased OPC density in the ventral horns. These OPCs take on an altered morphology, do not participate in the removal of excitatory vGlut1 synapses from injured motor neurons, and exhibit morphological features similar to those found in the vicinity of motor neurons in the SOD1 mouse model of Amyotrophic Lateral Sclerosis (ALS). Our data indicates that vOPCs prevent dOPCs from invading ventral spinal cord laminae and suggests that vOPCs have a unique ability to communicate with injured motor neurons.

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

Developmental Neuroscience ◽

10.1159/000464284 ◽

2017 ◽

Vol 39 (5) ◽

pp. 361-374 ◽

Cited By ~ 9

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 ◽

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.

Identification of a Sulf2-dependant astrocyte subtype that stands out through the expression of Olig2 in the ventral spinal cord

10.1101/430074 ◽

2018 ◽

Author(s):

David Ohayon ◽

Nathalie Escalas ◽

Philippe Cochard ◽

Bruno Glise ◽

Cathy Danesin ◽

...

Keyword(s):

Spinal Cord ◽

Extracellular Enzyme ◽

Oligodendrocyte Precursor Cells ◽

Spinal Cord Development ◽

Cell Diversity ◽

Editing Enzyme ◽

Ventral Spinal Cord ◽

Developing Spinal Cord

SummaryDuring spinal cord development, both spatial and temporal mechanisms operate to generate glial cell diversity. Here, we addressed the role of the Heparan Sulfate-editing enzyme Sulf2 in the control of gliogenesis in the mouse developing spinal cord and found an unanticipated function for this enzyme. Sulf2 is expressed in ventral spinal progenitors at initiation of gliogenesis, including in Olig2-expressing cells of the pMN domain known to generate most spinal cord oligodendrocyte precursor cells (OPCs). We found that Sulf2 is dispensable for OPC development but required for proper generation of an as-yet-unidentified astrocyte precursor cell (AP) subtype. These cells, like OPCs, express Olig2 while populating the spinal parenchyma at embryonic stages but also retain Olig2 expression as they differentiate into mature astrocytes. We therefore identify a spinal Olig2-expressing AP subtype that segregates early under the influence of the extracellular enzyme Sulf2.

Multiple sources of Shh are critical for the generation and scaling of ventral spinal cord oligodendrocyte precursor populations

10.1101/534750 ◽

2019 ◽

Cited By ~ 1

Author(s):

Lev Starikov ◽

Andreas H. Kottmann

Keyword(s):

Spinal Cord ◽

Motor Neurons ◽

Ventricular Zone ◽

Multiple Sources ◽

Shh Signaling ◽

Lateral Motor Column ◽

Dorsal Axis ◽

Sequential Activation ◽

Subsequent Phase ◽

Oligodendrocyte Precursor

AbstractGraded Sonic Hedgehog (Shh) signaling emanating from notochord and floorplate patterns the early neural tube. Soon thereafter, Shh signaling strength within the ventricular zone becomes dis-contiguous and discontinuous along the ventral to dorsal axis suggesting a distribution of Shh that cannot be achieved by diffusion alone. Here we discover that sequential activation of Shh expression by ventricular zone derivatives is critical for counteracting a precocious exhaustion of the Olig2 precursor cell population of the pMN domain at the end of motor neuron genesis and during the subsequent phase of ventral oligodendrocyte precursor production. Selective expression of Shh by motor neurons of the lateral motor column at the beginning of oligodendrogenesis ensures a more yielding pMN domain at limb levels compared to thoracic levels. Thus, patterned expression of Shh by ventricular zone derivatives including earlier born neurons contributes to the scaling of the spinal cord along the anterior - posterior axis by regulating the activity of a select ventricular zone precursor domain at later stages of development.

Abnormal Upregulation of GPR17 Receptor Contributes to Oligodendrocyte Dysfunction in SOD1 G93A Mice

International Journal of Molecular Sciences ◽

10.3390/ijms21072395 ◽

2020 ◽

Vol 21 (7) ◽

pp. 2395 ◽

Cited By ~ 2

Author(s):

Elisabetta Bonfanti ◽

Tiziana Bonifacino ◽

Stefano Raffaele ◽

Marco Milanese ◽

Erica Morgante ◽

...

Keyword(s):

Spinal Cord ◽

Motor Neurons ◽

Protein Levels ◽

Progressive Loss ◽

Abnormal Increase ◽

G Protein Coupled ◽

Lateral Sclerosis ◽

Immunohistochemical Analyses

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive loss of motor neurons (MN). Importantly, MN degeneration is intimately linked to oligodendrocyte dysfunction and impaired capacity of oligodendrocyte precursor cells (OPCs) to regenerate the myelin sheath enwrapping and protecting neuronal axons. Thus, improving OPC reparative abilities represents an innovative approach to counteract MN loss. A pivotal regulator of OPC maturation is the P2Y-like G protein-coupled receptor 17 (GPR17), whose role in ALS has never been investigated. In other models of neurodegeneration, an abnormal increase of GPR17 has been invariably associated to myelin defects and its pharmacological manipulation succeeded in restoring endogenous remyelination. Here, we analyzed GPR17 alterations in the SOD1G93A ALS mouse model and assessed in vitro whether this receptor could be targeted to correct oligodendrocyte alterations. Western-blot and immunohistochemical analyses showed that GPR17 protein levels are significantly increased in spinal cord of ALS mice at pre-symptomatic stage; this alteration is exacerbated at late symptomatic phases. Concomitantly, mature oligodendrocytes degenerate and are not successfully replaced. Moreover, OPCs isolated from spinal cord of SOD1G93A mice display defective differentiation compared to control cells, which is rescued by treatment with the GPR17 antagonist montelukast. These data open novel therapeutic perspectives for ALS management.

Cell-autonomous requirement of TDP-43, an ALS/FTD signature protein, for oligodendrocyte survival and myelination

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1809821115 ◽

2018 ◽

Vol 115 (46) ◽

pp. E10941-E10950 ◽

Cited By ~ 20

Author(s):

Jia Wang ◽

Wan Yun Ho ◽

Kenneth Lim ◽

Jia Feng ◽

Greg Tucker-Kellogg ◽

...

Keyword(s):

Spinal Cord ◽

White Matter ◽

Motor Neurons ◽

Oligodendrocyte Precursor Cells ◽

Progressive Reduction ◽

Disease Pathogenesis ◽

Neuromuscular Synapses ◽

Early Lethality ◽

TDP-43 aggregates in neurons and glia are the defining pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), raising the possibility of glial damage in the disease pathogenesis. However, the normal physiological functions of TDP-43 in glia are largely unknown. To address how TDP-43 may be required for oligodendroglial functions we selectively deleted TDP-43 in mature oligodendrocytes in mice. Although mice with TDP-43 deleted in oligodendrocytes are born in an expected Mendelian ratio, they develop progressive neurological phenotypes leading to early lethality accompanied by a progressive reduction in myelination. The progressive myelin reduction is likely due to a combination of the cell-autonomous RIPK1-mediated necroptosis of mature oligodendrocytes and the TDP-43–dependent reduction in the expression of myelin genes. Strikingly, enhanced proliferation of NG2-positive oligodendrocyte precursor cells within the white matter, but not the gray matter, was able to replenish the loss of mature oligodendrocytes, indicating an intrinsic regeneration difference between the gray and white matter oligodendrocytes. By contrast, there was no loss of spinal cord motor neurons and no sign of denervation at the neuromuscular synapses. Taken together, our data demonstrate that TDP-43 is indispensable for oligodendrocyte survival and myelination, and loss of TDP-43 in oligodendrocytes exerts no apparent toxicity on motor neurons.

RBM45 Modulates the Antioxidant Response in Amyotrophic Lateral Sclerosis through Interactions with KEAP1

Molecular and Cellular Biology ◽

10.1128/mcb.00087-15 ◽

2015 ◽

Vol 35 (14) ◽

pp. 2385-2399 ◽

Cited By ~ 12

Author(s):

Nadine Bakkar ◽

Arianna Kousari ◽

Tina Kovalik ◽

Yang Li ◽

Robert Bowser

Keyword(s):

Oxidative Stress ◽

Spinal Cord ◽

Amyotrophic Lateral Sclerosis ◽

Motor Neurons ◽

Rna Binding ◽

Binding Protein ◽

Rna Binding Protein ◽

Antioxidant Response ◽

Cytoplasmic Inclusions ◽

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the selective loss of motor neurons. Various factors contribute to the disease, including RNA binding protein dysregulation and oxidative stress, but their exact role in pathogenic mechanisms remains unclear. We have recently linked another RNA binding protein, RBM45, to ALS via increased levels of protein in the cerebrospinal fluid of ALS patients and its localization to cytoplasmic inclusions in ALS motor neurons. Here we show RBM45 nuclear exit in ALS spinal cord motor neurons compared to controls, a phenotype recapitulatedin vitroin motor neurons treated with oxidative stressors. We find that RBM45 binds and stabilizes KEAP1, the inhibitor of the antioxidant response transcription factor NRF2. ALS lumbar spinal cord lysates similarly show increased cytoplasmic binding of KEAP1 and RBM45. Binding of RBM45 to KEAP1 impedes the protective antioxidant response, thus contributing to oxidative stress-induced cellular toxicity. Our findings thus describe a novel link between a mislocalized RNA binding protein implicated in ALS (RBM45) and dysregulation of the neuroprotective antioxidant response seen in the disease.

A longitudinal DTI and histological study of the spinal cord reveals early pathological alterations in G93A-SOD1 mouse model of amyotrophic lateral sclerosis

Experimental Neurology ◽

10.1016/j.expneurol.2017.03.018 ◽

2017 ◽

Vol 293 ◽

pp. 43-52 ◽

Cited By ~ 12

Author(s):

Stefania Marcuzzo ◽

Silvia Bonanno ◽

Matteo Figini ◽

Alessandro Scotti ◽

Ileana Zucca ◽

...

Keyword(s):

Spinal Cord ◽

Amyotrophic Lateral Sclerosis ◽

Mouse Model ◽

Histological Study ◽

G93a Sod1 Mouse ◽

Sod1 Mouse ◽

G93a Sod1 ◽

S-100β protein is upregulated in astrocytes and motor neurons in the spinal cord of patients with amyotrophic lateral sclerosis

Neuroscience Letters ◽

10.1016/s0304-3940(98)01001-5 ◽

1999 ◽

Vol 261 (1-2) ◽

pp. 25-28 ◽

Cited By ~ 44

Author(s):

Antonio Migheli ◽

Susanna Cordera ◽

Caterina Bendotti ◽

Cristiana Atzori ◽

Roberto Piva ◽

...

Keyword(s):

Spinal Cord ◽

Amyotrophic Lateral Sclerosis ◽

Motor Neurons ◽

Selective neuronal degeneration in MATR3 S85C knock-in mouse model of early-stage ALS

Nature Communications ◽

10.1038/s41467-020-18949-w ◽

2020 ◽

Vol 11 (1) ◽

Author(s):

Ching Serena Kao ◽

Rebekah van Bruggen ◽

Jihye Rachel Kim ◽

Xiao Xiao Lily Chen ◽

Cadia Chan ◽

...

Keyword(s):

Spinal Cord ◽

Mouse Model ◽

Motor Neurons ◽

Neuronal Degeneration ◽

Early Stage ◽

Motor Impairment ◽

Preclinical Research ◽

Cell Degeneration ◽

Promising Tool ◽

Abstract A missense mutation, S85C, in the MATR3 gene is a genetic cause for amyotrophic lateral sclerosis (ALS). It is unclear how the S85C mutation affects MATR3 function and contributes to disease. Here, we develop a mouse model that harbors the S85C mutation in the endogenous Matr3 locus using the CRISPR/Cas9 system. MATR3 S85C knock-in mice recapitulate behavioral and neuropathological features of early-stage ALS including motor impairment, muscle atrophy, neuromuscular junction defects, Purkinje cell degeneration and neuroinflammation in the cerebellum and spinal cord. Our neuropathology data reveals a loss of MATR3 S85C protein in the cell bodies of Purkinje cells and motor neurons, suggesting that a decrease in functional MATR3 levels or loss of MATR3 function contributes to neuronal defects. Our findings demonstrate that the MATR3 S85C mouse model mimics aspects of early-stage ALS and would be a promising tool for future basic and preclinical research.

ALS-Associated SOD1(G93A) Decreases SERCA Pump Levels and Increases Store-Operated Ca2+ Entry in Primary Spinal Cord Astrocytes from a Transgenic Mouse Model

International Journal of Molecular Sciences ◽

10.3390/ijms20205151 ◽

2019 ◽

Vol 20 (20) ◽

pp. 5151 ◽

Cited By ~ 1

Author(s):

Norante ◽

Peggion ◽

Rossi ◽

Martorana ◽

De Mario ◽

...

Keyword(s):

Spinal Cord ◽

Mouse Model ◽

Motor Neurons ◽

Neurodegenerative Disorder ◽

Nervous System Function ◽

Serca Pump ◽

Selective Death ◽

First Time ◽

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the selective death of motor neurons (MNs), probably by a combination of cell- and non-cell-autonomous processes. The past decades have brought many important insights into the role of astrocytes in nervous system function and disease, including the implication in ALS pathogenesis possibly through the impairment of Ca2+-dependent astrocyte-MN cross-talk. In this respect, it has been recently proposed that altered astrocytic store-operated Ca2+ entry (SOCE) may underlie aberrant gliotransmitter release and astrocyte-mediated neurotoxicity in ALS. These observations prompted us to a thorough investigation of SOCE in primary astrocytes from the spinal cord of the SOD1(G93A) ALS mouse model in comparison with the SOD1(WT)-expressing controls. To this purpose, we employed, for the first time in the field, genetically-encoded Ca2+ indicators, allowing the direct assessment of Ca2+ fluctuations in different cell domains. We found increased SOCE, associated with decreased expression of the sarco-endoplasmic reticulum Ca2+-ATPase and lower ER resting Ca2+ concentration in SOD1(G93A) astrocytes compared to control cells. Such findings add novel insights into the involvement of astrocytes in ALS MN damage.