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

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

10.1101/2020.03.09.983908 ◽

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.

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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 ◽

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.

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FGFs are orchestra conductors of Shh-dependent oligodendroglial fate specification in the ventral spinal cord

10.1101/233775 ◽

2017 ◽

Author(s):

Marie-Amélie Farreny ◽

Eric Agius ◽

Sophie Bel-Vialar ◽

Nathalie Escalas ◽

Nagham Khouri-Farah ◽

...

Keyword(s):

Spinal Cord ◽

Progenitor Cells ◽

Sonic Hedgehog ◽

Fgf Signaling ◽

Oligodendrocyte Precursor Cell ◽

Signaling Center ◽

Oligodendrocyte Precursor ◽

Prevailing View ◽

Ventral Spinal Cord

AbstractMost oligodendrocytes of the spinal cord originate from ventral progenitor cells of the pMN domain, characterized by expression of the transcription factor Olig2. A minority of oligodendrocytes is also recognized to emerge from dorsal progenitors during fetal development. The prevailing view is that generation of ventral oligodendrocytes depends on Sonic hedgehog (Shh) while dorsal oligodendrocytes develop under the influence of Fibroblast Growth Factors (FGFs). Using the well-established model of the chicken embryo, we evidence that ventral spinal progenitor cells activate FGF signaling at the onset of oligodendrocyte precursor cell (OPC) generation, as do they dorsal counterpart. Inhibition of FGF receptors at that time appears sufficient to prevent generation of ventral OPCs, highlighting that, in addition to Shh, FGF signaling is required also for generation of ventral OPCs. We further reveal an unsuspected interplay between Shh and FGF signaling by showing that FGFs serve dual essential functions in ventral OPC specification. FGFs are responsible for timely induction of a secondary Shh signaling center, the lateral floor plate, a crucial step to create the burst of Shh required for OPC specification. At the same time, FGFs prevent down-regulation of Olig2 in pMN progenitor cells as these cells receive higher threshold of the Shh signal. Finally, we bring arguments favoring a key role of newly differentiated neurons acting as providers of the FGF signal required to trigger OPC generation in the ventral spinal cord.

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Oligodendrocyte Precursor Cells in Spinal Cord Injury Repair

Cellular Therapy for Neurological Injury ◽

10.1201/b19533-7 ◽

2016 ◽

pp. 58-97

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Precursor Cells ◽

Oligodendrocyte Precursor Cells ◽

Injury Repair ◽

Cord Injury ◽

Oligodendrocyte Precursor

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Netrin-1 Is a Chemorepellent for Oligodendrocyte Precursor Cells in the Embryonic Spinal Cord

Journal of Neuroscience ◽

10.1523/jneurosci.23-09-03735.2003 ◽

2003 ◽

Vol 23 (9) ◽

pp. 3735-3744 ◽

Cited By ~ 85

Author(s):

Andrew A. Jarjour ◽

Colleen Manitt ◽

Simon W. Moore ◽

Katherine M. Thompson ◽

Sung-Joo Yuh ◽

...

Keyword(s):

Spinal Cord ◽

Precursor Cells ◽

Oligodendrocyte Precursor Cells ◽

Embryonic Spinal Cord ◽

Oligodendrocyte Precursor

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White Matter and Neuroprotection in Alzheimer’s Dementia

Molecules ◽

10.3390/molecules25030503 ◽

2020 ◽

Vol 25 (3) ◽

pp. 503 ◽

Cited By ~ 2

Author(s):

Luca Lorenzini ◽

Mercedes Fernandez ◽

Vito Antonio Baldassarro ◽

Andrea Bighinati ◽

Alessandro Giuliani ◽

...

Keyword(s):

White Matter ◽

Alzheimer’S Dementia ◽

Oligodendrocyte Precursor Cells ◽

Resonance Imaging ◽

Alzheimer's Dementia ◽

The Central Nervous System ◽

Oligodendrocyte Precursor ◽

Main Component ◽

Preclinical And Clinical Studies

Myelin is the main component of the white matter of the central nervous system (CNS), allowing the proper electrical function of the neurons by ensheathing and insulating the axons. The extensive use of magnetic resonance imaging has highlighted the white matter alterations in Alzheimer’s dementia (AD) and other neurodegenerative diseases, alterations which are early, extended, and regionally selective. Given that the white matter turnover is considerable in the adulthood, and that myelin repair is currently recognized as being the only true reparative capability of the mature CNS, oligodendrocyte precursor cells (OPCs), the cells that differentiate in oligodendrocyte, responsible for myelin formation and repair, are regarded as a potential target for neuroprotection. In this review, several aspects of the OPC biology are reviewed. The histology and functional role of OPCs in the neurovascular-neuroglial unit as described in preclinical and clinical studies on AD is discussed, such as the OPC vulnerability to hypoxia-ischemia, neuroinflammation, and amyloid deposition. Finally, the position of OPCs in drug discovery strategies for dementia is discussed.

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