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

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.

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

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 ◽  
Oligodendrocyte Precursor ◽  
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.

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 An Efficient Method for Generating Murine Hypothalamic Neurospheres for the Study of Regional Neural Progenitor Biology

Endocrinology ◽  
2020 ◽  
Vol 161 (4) ◽  
Author(s):  
Dinushan Nesan ◽  
Hayley F Thornton ◽  
Laronna C Sewell ◽  
Deborah M Kurrasch
Keyword(s):  
Progenitor Cells ◽  
Sonic Hedgehog ◽  
Cell Sorting ◽  
Seeding Density ◽  
Controlled Environment ◽  
Stem And Progenitor Cells ◽  
A New Technique ◽  
Primary Effector ◽  
Selection Of

Abstract The hypothalamus is a key homeostatic brain region and the primary effector of neuroendocrine signaling. Recent studies show that early embryonic developmental disruption of this region can lead to neuroendocrine conditions later in life, suggesting that hypothalamic progenitors might be sensitive to exogenous challenges. To study the behavior of hypothalamic neural progenitors, we developed a novel dissection methodology to isolate murine hypothalamic neural stem and progenitor cells at the early timepoint of embryonic day 12.5, which coincides with peak hypothalamic neurogenesis. Additionally, we established and optimized a culturing protocol to maintain multipotent hypothalamic neurospheres that are capable of sustained proliferation or differentiation into neurons, oligodendrocytes, and astrocytes. We characterized media requirements, appropriate cell seeding density, and the role of growth factors and sonic hedgehog (Shh) supplementation. Finally, we validated the use of fluorescence activated cell sorting of either Sox2GFPKI or Nkx2.1GFPKI transgenic mice as an alternate cellular isolation approach to enable enriched selection of hypothalamic progenitors for growth into neurospheres. Combined, we present a new technique that yields reliable culturing of hypothalamic neural stem and progenitor cells that can be used to study hypothalamic development in a controlled environment.

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 Sall4-Gli3 system in early limb progenitors is essential for the development of limb skeletal elements

2015 ◽  
Vol 112 (16) ◽  
pp. 5075-5080 ◽  
Author(s):  
Ryutaro Akiyama ◽  
Hiroko Kawakami ◽  
Julia Wong ◽  
Isao Oishi ◽  
Ryuichi Nishinakamura ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Sonic Hedgehog ◽  
Limb Development ◽  
Critical Role ◽  
Dependent Manner ◽  
Skeletal Element ◽  
Proximal Development ◽  
Limb Outgrowth ◽  
Common Regulator

Limb skeletal elements originate from the limb progenitor cells, which undergo expansion and patterning to develop each skeletal element. Posterior-distal skeletal elements, such as the ulna/fibula and posterior digits develop in a Sonic hedgehog (Shh)-dependent manner. However, it is poorly understood how anterior-proximal elements, such as the humerus/femur, the radius/tibia and the anterior digits, are developed. Here we show that the zinc finger factors Sall4 and Gli3 cooperate for proper development of the anterior-proximal skeletal elements and also function upstream of Shh-dependent posterior skeletal element development. Conditional inactivation of Sall4 in the mesoderm before limb outgrowth caused severe defects in the anterior-proximal skeletal elements in the hindlimb. We found that Gli3 expression is reduced in Sall4 mutant hindlimbs, but not in forelimbs. This reduction caused posteriorization of nascent hindlimb buds, which is correlated with a loss of anterior digits. In proximal development, Sall4 integrates Gli3 and the Plzf-Hox system, in addition to proliferative expansion of cells in the mesenchymal core of nascent hindlimb buds. Whereas forelimbs developed normally in Sall4 mutants, further genetic analysis identified that the Sall4-Gli3 system is a common regulator of the early limb progenitor cells in both forelimbs and hindlimbs. The Sall4-Gli3 system also functions upstream of the Shh-expressing ZPA and the Fgf8-expressing AER in fore- and hindlimbs. Therefore, our study identified a critical role of the Sall4-Gli3 system at the early steps of limb development for proper development of the appendicular skeletal elements.

scholarly journals EPH/EPHRIN SIGNALING CONTROLS PROGENITOR IDENTITIES IN THE VENTRAL SPINAL CORD

2016 ◽  
Author(s):  
Julien Laussu ◽  
Christophe Audouard ◽  
Anthony Kischel ◽  
Poincyane Assis-Nascimento ◽  
Nathalie Escalas ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Sonic Hedgehog ◽  
Cell Communication ◽  
Dependent Manner ◽  
Eph Receptors ◽  
Loss Of Function ◽  
Summary Statement ◽  
Dose Dependent ◽  
Ventral Spinal Cord

SUMMARY STATEMENTThis article by Laussu et al. describes a role for Eph:ephrin signaling in controlling the identity of neural progenitors in the ventral spinal cord.Early specification of progenitors of the ventral spinal cord involves the morphogen Sonic Hedgehog which induces distinct progenitor identities in a dose-dependent manner. Following these initial patterning events, progenitor identities have to be maintained in order to generate appropriate numbers of progeny. Here we provide evidence that communication via Eph:ephrin signaling is required to maintain progenitor identities in the ventral spinal cord. We show that ephrinB2 and ephrinB3 are expressed in restricted progenitor domains in the ventral spinal cord while several Eph receptors are more broadly expressed. Further, we provide evidence that expression of Efnb3 and EphA4 is controlled by Shh. Genetic loss-of-function analyses indicate that expression of ephrinB2 and ephrinB3 is required to control progenitor identities and in vitro experiments reveal that activation of Eph forward signaling in spinal progenitors up-regulates the expression of the identity transcription factor Nkx2.2. Altogether our results indicate that cell-to-cell communication is necessary to control progenitor identity in the ventral spinal cord.

scholarly journals Dual role of FGF in proliferation and endoreplication of Drosophila tracheal adult progenitor cells

2019 ◽  
Vol 12 (1) ◽  
pp. 32-41
Author(s):  
Cristina de Miguel ◽  
Josefa Cruz ◽  
David Martín ◽  
Xavier Franch-Marro
Keyword(s):  
Transcription Factor ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Progenitor Cells ◽  
Posterior Part ◽  
Dual Role ◽  
Fibroblast Growth ◽  
Fgf Signaling

Abstract Adult progenitor cells activation is a key event in the formation of adult organs. In Drosophila, formation of abdominal adult trachea depends on the specific activation of tracheal adult progenitors (tracheoblasts) at the Tr4 and Tr5 spiracular branches. Proliferation of these tracheoblasts generates a pool of tracheal cells that migrate toward the posterior part of the trachea by the activation of the branchless/fibroblast growth factor (Bnl/FGF) signaling to form the abdominal adult trachea. Here, we show that, in addition to migration, Bnl/FGF signaling, mediated by the transcription factor Pointed, is also required for tracheoblast proliferation. This tracheoblast activation relies on the expression of the FGF ligand bnl in their nearby branches. Finally, we show that, in the absence of the transcription factor Cut (Ct), Bnl/FGF signaling induces endoreplication of tracheoblasts partially by promoting fizzy-related expression. Altogether, our results suggest a dual role of Bnl/FGF signaling in tracheoblasts, inducing both proliferation and endoreplication, depending on the presence or absence of the transcription factor Ct, respectively.

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