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 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.

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 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 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 Critical roles of ARHGAP36 as a signal transduction mediator of Shh pathway in lateral motor columnar specification

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Heejin Nam ◽  
Shin Jeon ◽  
Hyejin An ◽  
Jaeyoung Yoo ◽  
Hyo-Jong Lee ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Sonic Hedgehog ◽  
Motor Neurons ◽  
Floor Plate ◽  
Spinal Cord Development ◽  
Shh Pathway ◽  
Downstream Effector ◽  
Lateral Motor Column ◽  
Ventral Neural Tube ◽  
Transcription Factor Complex

During spinal cord development, Sonic hedgehog (Shh), secreted from the floor plate, plays an important role in the production of motor neurons by patterning the ventral neural tube, which establishes MN progenitor identity. It remains unknown, however, if Shh signaling plays a role in generating columnar diversity of MNs that connect distinct target muscles. Here, we report that Shh, expressed in MNs, is essential for the formation of lateral motor column (LMC) neurons in vertebrate spinal cord. This novel activity of Shh is mediated by its downstream effector ARHGAP36, whose expression is directly induced by the MN-specific transcription factor complex Isl1-Lhx3. Furthermore, we found that AKT stimulates the Shh activity to induce LMC MNs through the stabilization of ARHGAP36 proteins. Taken together, our data reveal that Shh, secreted from MNs, plays a crucial role in generating MN diversity via a regulatory axis of Shh-AKT-ARHGAP36 in the developing mouse spinal cord.

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.

Sonic hedgehog signaling is required during the appearance of spinal cord oligodendrocyte precursors

Development ◽  
1999 ◽  
Vol 126 (11) ◽  
pp. 2419-2429 ◽  
Author(s):  
D.M. Orentas ◽  
J.E. Hayes ◽  
K.L. Dyer ◽  
R.H. Miller
Keyword(s):  
Spinal Cord ◽  
Sonic Hedgehog ◽  
Ventricular Zone ◽  
Developmental Period ◽  
Dorsal Spinal Cord ◽  
Shh Signaling ◽  
Oligodendrocyte Precursors ◽  
Dorsal Spinal

Spinal cord oligodendrocyte precursors arise in the ventral ventricular zone as a result of local signals. Ectopic oligodendrocyte precursors can be induced by sonic hedgehog (Shh) in explants of chick dorsal spinal cord over an extended developmental period. The role of Shh during normal oligodendrocyte development is, however, unclear. Here we demonstrate that Shh is localized to the ventral spinal cord immediately prior to, and during the appearance of oligodendrocyte precursors. Continued expression of Shh is required for the appearance of spinal cord oligodendrocyte precursors as neutralization of Shh signaling both in vivo and in vitro during a defined developmental period blocked their emergence. The inhibition of oligodendrocyte precursor emergence in the absence of Shh signaling was not the result of inhibiting precursor cell proliferation, and the neutralization of Shh signaling after the emergence of oligodendrocyte precursors had no effect on the appearance of additional cells or their subsequent differentiation. Similar concentrations of Shh induce motor neurons and oligodendrocytes in dorsal spinal cord explants. However, in explants from early embryos the motor neuron lineage is preferentially expanded while in explants from older embryos the oligodendrocyte lineage is preferentially expanded.

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