scholarly journals Prdm8 regulates pMN progenitor specification for motor neuron and oligodendrocyte fates by modulating Shh signaling response

2020 ◽  
Author(s):  
Kayt Scott ◽  
Rebecca O’Rourke ◽  
Austin Gillen ◽  
Bruce Appel
Keyword(s):  
Spinal Cord ◽  
Motor Neuron ◽  
Cell Fate ◽  
Motor Neurons ◽  
Oligodendrocyte Precursor Cells ◽  
Cell Fate Specification ◽  
Cell Fates ◽  
Shh Signaling ◽  
Summary Statement ◽  
Oligodendrocyte Precursor

AbstractSpinal cord pMN progenitors sequentially produce motor neurons and oligodendrocyte precursor cells (OPCs). Some OPCs differentiate rapidly as myelinating oligodendrocytes whereas others remain into adulthood. How pMN progenitors switch from producing motor neurons to OPCs with distinct fates is poorly understood. pMN progenitors express prdm8, which encodes a transcriptional repressor, during motor neuron and OPC formation. To determine if prdm8 controls pMN cell fate specification, we used zebrafish as a model system to investigate prdm8 function. Our analysis revealed that prdm8 mutant embryos have a deficit of motor neurons resulting from a premature switch from motor neuron to OPC production. Additionally, prdm8 mutant larvae have excess oligodendrocytes and a concomitant deficit of OPCs. Notably, pMN cells of mutant embryos have elevated Shh signaling coincident with the motor neuron to OPC switch. Inhibition of Shh signaling restored the number of motor neurons to normal but did not rescue the proportion of oligodendrocytes. These data suggest that Prdm8 regulates the motor neuron-OPC switch by controlling the level of Shh activity in pMN progenitors and also regulates allocation of oligodendrocyte lineage cell fates.Summary StatementPrdm8 regulates the timing of a motor neuron-oligodendrocyte switch and oligodendrocyte lineage cell identity in the zebrafish spinal cord.

scholarly journals Prdm8 regulates pMN progenitor specification for motor neuron and oligodendrocyte fates by modulating the Shh signaling response

Development ◽  
2020 ◽  
Vol 147 (16) ◽  
pp. dev191023 ◽  
Author(s):  
Kayt Scott ◽  
Rebecca O'Rourke ◽  
Austin Gillen ◽  
Bruce Appel
Keyword(s):  
Motor Neuron ◽  
Cell Fate ◽  
Motor Neurons ◽  
Oligodendrocyte Precursor Cells ◽  
Cell Fate Specification ◽  
Cell Fates ◽  
Shh Signaling ◽  
Fate Specification ◽  
The People ◽  
Oligodendrocyte Precursor

ABSTRACTSpinal cord pMN progenitors sequentially produce motor neurons and oligodendrocyte precursor cells (OPCs). Some OPCs differentiate rapidly as myelinating oligodendrocytes, whereas others remain into adulthood. How pMN progenitors switch from producing motor neurons to OPCs with distinct fates is poorly understood. pMN progenitors express prdm8, which encodes a transcriptional repressor, during motor neuron and OPC formation. To determine whether prdm8 controls pMN cell fate specification, we used zebrafish as a model system to investigate prdm8 function. Our analysis revealed that prdm8 mutant embryos have fewer motor neurons resulting from a premature switch from motor neuron to OPC production. Additionally, prdm8 mutant larvae have excess oligodendrocytes and a concomitant deficit of OPCs. Notably, pMN cells of mutant embryos have elevated Shh signaling, coincident with the motor neuron to OPC switch. Inhibition of Shh signaling restored the number of motor neurons to normal but did not rescue the proportion of oligodendrocytes. These data suggest that Prdm8 regulates the motor neuron-OPC switch by controlling the level of Shh activity in pMN progenitors, and also regulates the allocation of oligodendrocyte lineage cell fates.This article has an associated ‘The people behind the papers’ interview.

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

2019 ◽  
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.

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

2018 ◽  
Vol 115 (46) ◽  
pp. E10941-E10950 ◽  
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 ◽  
Oligodendrocyte Precursor ◽  
Early Lethality ◽  
Lateral Sclerosis

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.

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

2020 ◽  
Author(s):  
Lev Starikov ◽  
Andreas H. Kottmann
Keyword(s):  
Spinal Cord ◽  
Motor Neurons ◽  
Ventricular Zone ◽  
Normal Numbers ◽  
Spinal Cord Development ◽  
Oligodendrocyte Precursor ◽  
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.

The control of rostrocaudal pattern in the developing spinal cord: specification of motor neuron subtype identity is initiated by signals from paraxial mesoderm

Development ◽  
1998 ◽  
Vol 125 (6) ◽  
pp. 969-982 ◽  
Author(s):  
M. Ensini ◽  
T.N. Tsuchida ◽  
H.G. Belting ◽  
T.M. Jessell
Keyword(s):  
Spinal Cord ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Neural Tube ◽  
Motor Behavior ◽  
Neural Tube Closure ◽  
Paraxial Mesoderm ◽  
Homeodomain Protein ◽  
Mesodermal Cell ◽  
Developing Spinal Cord

The generation of distinct classes of motor neurons is an early step in the control of vertebrate motor behavior. To study the interactions that control the generation of motor neuron subclasses in the developing avian spinal cord we performed in vivo grafting studies in which either the neural tube or flanking mesoderm were displaced between thoracic and brachial levels. The positional identity of neural tube cells and motor neuron subtype identity was assessed by Hox and LIM homeodomain protein expression. Our results show that the rostrocaudal identity of neural cells is plastic at the time of neural tube closure and is sensitive to positionally restricted signals from the paraxial mesoderm. Such paraxial mesodermal signals appear to control the rostrocaudal identity of neural tube cells and the columnar subtype identity of motor neurons. These results suggest that the generation of motor neuron subtypes in the developing spinal cord involves the integration of distinct rostrocaudal and dorsoventral patterning signals that derive, respectively, from paraxial and axial mesodermal cell groups.

scholarly journals WNT signaling suppresses oligodendrogenesis via Ngn2-dependent direct inhibition of Olig2 expression

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Min Jiang ◽  
Dan Yu ◽  
Binghua Xie ◽  
Hao Huang ◽  
Wenwen Lu ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Motor Neurons ◽  
Promoter Activity ◽  
Neural Progenitor Cells ◽  
Luciferase Reporter ◽  
Oligodendrocyte Precursor Cells ◽  
Reporter Assay ◽  
Direct Inhibition ◽  
In Ovo ◽  
Oligodendrocyte Precursor

AbstractOlig2 transcription factor is essential for the maintenance of neural progenitor cells (NPCs) in the pMN domain and their sequential specification into motor neurons (MNs) and oligodendrocyte precursor cells (OPCs). The expression of Olig2 rapidly declines in newly generated MNs. However, Olig2 expression persists in later-born OPCs and antagonizes the expression of MN-related genes. The mechanism underlying the differential expression of Olig2 in MNs and oligodendrocytes remains unknown. Here, we report that activation of WNT/β-catenin signaling in pMN lineage cells abolished Olig2 expression coupled with a dramatic increase of Ngn2 expression. Luciferase reporter assay showed that Ngn2 inhibited Olig2 promoter activity. Overexpression of Ngn2-EnR transcription repressor blocked the expression of Olig2 in ovo. Our results suggest that down-regulation of WNT-Ngn2 signaling contributes to oligodendrogenesis from the pMN domain and the persistent Olig2 expression in OPCs.

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