scholarly journals FZD10 regulates cell proliferation and mediates Wnt1 induced neurogenesis in the developing spinal cord

2019 ◽  
Author(s):  
Abdulmajeed Fahad Alrefaei ◽  
Andrea E. Münsterberg ◽  
Grant N. Wheeler
Keyword(s):  
Spinal Cord ◽  
Cell Proliferation ◽  
Neural Tube ◽  
Spinal Cord Development ◽  
Dorsal Neural Tube ◽  
Wnt Ligands ◽  
Frizzled Receptors ◽  
Developmental Contexts ◽  
Developing Spinal Cord

AbstractWnt/FZD signalling activity is required for spinal cord development, including the dorsal-ventral patterning of the neural tube, where it affects proliferation and specification of neurons. Wnt ligands initiate canonical, β-catenin-dependent, signaling by binding to Frizzled receptors. However, in many developmental contexts the cognate FZD receptor for a particular Wnt ligand remains to be identified. Here, we characterized FZD10 expression in the dorsal neural tube where it overlaps with both Wnt1 and Wnt3a, as well as markers of dorsal progenitors and interneurons. We show FZD10 expression is sensitive to Wnt1, but not Wnt3a expression, and FZD10 plays a role in neural tube patterning. Knockdown approaches show that Wnt1 induced ventral expansion of dorsal neural markes, Pax6 and Pax7, requires FZD10. In contrast, Wnt3a induced dorsalization of the neural tube is not affected by FZD10 knockdown. Gain of function experiments show that FZD10 is not sufficient on its own to mediate Wnt1 activity in vivo. Indeed excess FZD10 inhibits the dorsalizing activity of Wnt1. However, addition of the Lrp6 co-receptor dramatically enhances the Wnt1/FZD10 mediated activation of dorsal markers. This suggests that the mechanism by which Wnt1 regulates proliferation and patterning in the neural tube requires both FZD10 and Lrp6.

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 FZD10 regulates cell proliferation and mediates Wnt1 induced neurogenesis in the developing spinal cord

PLoS ONE ◽  
2020 ◽  
Vol 15 (6) ◽  
pp. e0219721
Author(s):  
Abdulmajeed Fahad Alrefaei ◽  
Andrea E. Münsterberg ◽  
Grant N. Wheeler
Keyword(s):  
Spinal Cord ◽  
Cell Proliferation ◽  
Developing Spinal Cord

scholarly journals Differentiation and localization of interneurons in the developing spinal cord depends on DOT1L expression

2020 ◽  
Author(s):  
Angelica Gray de Cristoforis ◽  
Francesco Ferrari ◽  
Frédéric Clotman ◽  
Tanja Vogel
Keyword(s):  
Spinal Cord ◽  
Neural Tube ◽  
Transcriptional Activation ◽  
Neural Tube Closure ◽  
Epigenetic Factors ◽  
Late Developmental Stage ◽  
Neural Tube Closure Defect ◽  
H3k79 Methylation ◽  
Tube Closure ◽  
Developing Spinal Cord

Abstract Genetic and epigenetic factors contribute to the development of the spinal cord. Failure in correct exertion of the developmental programs, including neurulation, neural tube closure and neurogenesis of the diverse spinal cord neuronal subtypes results in clinical phenotypes with variable severity. The histone methyltransferase Disruptor of Telomeric 1 Like (DOT1L), which mediates histone H3 lysine 79 (H3K79) methylation, is fundamental for proper development of the cerebral cortex and cerebellum, and here we report on its essential role for development of the spinal cord. Conditional inactivation of DOT1L using Wnt1-cre as driver in the developing murine spinal cord did not result in neural tube closure defect (NTCD). Transcriptome analysis revealed that DOT1L deficiency favored differentiation over progenitor proliferation. Dot1l -cKO mainly decreased the numbers of dI1 interneurons expressing Lhx2 . Loss of DOT1L affected localization but not generation of dI2, dI3, and dI5 interneurons. The resulting derailed interneuron patterns might be responsible for increased cell death that occurred at the late developmental stage E18.5. Together our data indicate that DOT1L is essential for subtype- specific neurogenesis, migration and localization of interneurons in the developing spinal cord, in part by regulating transcriptional activation of Lhx2 .

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 Sustained experimental activation of FGF8/ERK in the developing chicken spinal cord reproducibly models early events in ERK-mediated tumorigenesis

2021 ◽  
Author(s):  
Axelle Wilmerding ◽  
Lauranne Bouteille ◽  
Nathalie Caruso ◽  
Ghislain Bidaut ◽  
Heather Corbett Etchevers ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Chicken Embryo ◽  
Active Form ◽  
In Vivo Model ◽  
Signal Attenuation ◽  
Transcriptional Signature ◽  
Undifferentiated State ◽  
Vertebrate Embryos ◽  
Developing Spinal Cord

Most human cancers demonstrate activated MAPK/ERK pathway signaling as a key tumor initiation step, but the immediate steps of further oncogenic progression are poorly understood due to a lack of appropriate models. Spinal cord differentiation follows caudal elongation in vertebrate embryos; both processes are regulated by a FGF8 gradient highest in neuromesodermal progenitors (NMP), where kinase effectors ERK1/2 maintain an undifferentiated state. FGF8/ERK signal attenuation is necessary for NMPs to progress to differentiation. We show that sustained ERK1/2 activity, using a constitutively active form of the kinase MEK1 (MEK1ca) in the chicken embryo, reproducibly provokes neopasia in the developing spinal cord. Transcriptomic data show that neoplasia not only relies on the maintenance of NMP gene expression, and the inhibition of genes expressed in the differentiating spinal cord, but also on a profound change in the transcriptional signature of the spinal cord cells leading to a complete loss of cell-type identity. MEK1ca expression in the developing spinal cord of the chicken embryo is therefore a tractable in vivo model to identify the critical factors fostering malignancy in ERK-induced tumorigenesis.

Regulation of the onset of neural crest migration by coordinated activity of BMP4 and Noggin in the dorsal neural tube

Development ◽  
1999 ◽  
Vol 126 (21) ◽  
pp. 4749-4762 ◽  
Author(s):  
D. Sela-Donenfeld ◽  
C. Kalcheim
Keyword(s):  
Neural Crest ◽  
Neural Tube ◽  
Specific Inhibitor ◽  
Neural Crest Cells ◽  
Concomitant Treatment ◽  
Neural Tubes ◽  
Dorsal Neural Tube ◽  
Dependent Inhibition ◽  
Neural Crest Migration

For neural crest cells to engage in migration, it is necessary that epithelial premigratory crest cells convert into mesenchyme. The mechanisms that trigger cell delamination from the dorsal neural tube remain poorly understood. We find that, in 15- to 40-somite-stage avian embryos, BMP4 mRNA is homogeneously distributed along the longitudinal extent of the dorsal neural tube, whereas its specific inhibitor noggin exists in a gradient of expression that decreases caudorostrally. This rostralward reduction in signal intensity coincides with the onset of emigration of neural crest cells. Hence, we hypothesized that an interplay between Noggin and BMP4 in the dorsal tube generates graded concentrations of the latter that in turn triggers the delamination of neural crest progenitors. Consistent with this suggestion, disruption of the gradient by grafting Noggin-producing cells dorsal to the neural tube at levels opposite the segmental plate or newly formed somites, inhibited emigration of HNK-1-positive crest cells, which instead accumulated within the dorsal tube. Similar results were obtained with explanted neural tubes from the same somitic levels exposed to Noggin. Exposure to Follistatin, however, had no effect. The Noggin-dependent inhibition was overcome by concomitant treatment with BMP4, which when added alone, also accelerated cell emigration compared to untreated controls. Furthermore, the observed inhibition of neural crest emigration in vivo was preceded by a partial or total reduction in the expression of cadherin-6B and rhoB but not in the expression of slug mRNA or protein. Altogether, these results suggest that a coordinated activity of Noggin and BMP4 in the dorsal neural tube triggers delamination of specified, slug-expressing neural crest cells. Thus, BMPs play multiple and discernible roles at sequential stages of neural crest ontogeny, from specification through delamination and later differentiation of specific neural crest derivatives.

Differential activation of Myf5 and MyoD by different Wnts in explants of mouse paraxial mesoderm and the later activation of myogenesis in the absence of Myf5

Development ◽  
1998 ◽  
Vol 125 (21) ◽  
pp. 4155-4162 ◽  
Author(s):  
S. Tajbakhsh ◽  
U. Borello ◽  
E. Vivarelli ◽  
R. Kelly ◽  
J. Papkoff ◽  
...  
Keyword(s):  
Neural Tube ◽  
Muscle Development ◽  
Early Embryo ◽  
Paraxial Mesoderm ◽  
Dorsal Neural Tube ◽  
Muscle Formation ◽  
Correct Pattern ◽  
Dorsal Ectoderm ◽  
Dependent Pathway

Activation of myogenesis in newly formed somites is dependent upon signals derived from neighboring tissues, namely axial structures (neural tube and notochord) and dorsal ectoderm. In explants of paraxial mesoderm from mouse embryos, axial structures preferentially activate myogenesis through a Myf5-dependent pathway and dorsal ectoderm preferentially through a MyoD-dependent pathway. Here we report that cells expressing Wnt1 will preferentially activate Myf5 while cells expressing Wnt7a will preferentially activate MyoD. Wnt1 is expressed in the dorsal neural tube and Wnt7a in dorsal ectoderm in the early embryo, therefore both can potentially act in vivo to activate Myf5 and MyoD, respectively. Wnt4, Wnt5a and Wnt6 exert an intermediate effect activating both Myf5 and MyoD equivalently in paraxial mesoderm. Sonic Hedgehog synergises with both Wnt1 and Wnt7a in explants from E8.5 paraxial mesoderm but not in explants from E9.5 embryos. Signaling through different myogenic pathways may explain the rescue of muscle formation in Myf5 null embryos, which do not form an early myotome but later develop both epaxial and hypaxial musculature. Explants of unsegmented paraxial mesoderm contain myogenic precursors capable of expressing MyoD in response to signaling from a neural tube isolated from E10.5 embryos, the developmental stage when MyoD is present throughout the embryo. Myogenic cells cannot activate MyoD in response to signaling from a less mature neural tube. Together these data suggest that different Wnt molecules can activate myogenesis through different pathways such that commitment of myogenic precursors is precisely regulated in space and time to achieve the correct pattern of skeletal muscle development.

scholarly journals N-cadherin–mediated cell adhesion restricts cell proliferation in the dorsal neural tube

2011 ◽  
Vol 22 (9) ◽  
pp. 1505-1515 ◽  
Author(s):  
Kavita Chalasani ◽  
Rachel M. Brewster
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Neural Tube ◽  
Neural Progenitor ◽  
Neural Progenitors ◽  
Cell Cycle Exit ◽  
Dorsal Neural Tube ◽  
Binding Partners ◽  
Hh Signaling ◽  
Cell Cycle Length

Neural progenitors are organized as a pseudostratified epithelium held together by adherens junctions (AJs), multiprotein complexes composed of cadherins and α- and β-catenin. Catenins are known to control neural progenitor division; however, it is not known whether they function in this capacity as cadherin binding partners, as there is little evidence that cadherins themselves regulate neural proliferation. We show here that zebrafish N-cadherin (N-cad) restricts cell proliferation in the dorsal region of the neural tube by regulating cell-cycle length. We further reveal that N-cad couples cell-cycle exit and differentiation, as a fraction of neurons are mitotic in N-cad mutants. Enhanced proliferation in N-cad mutants is mediated by ligand-independent activation of Hedgehog (Hh) signaling, possibly caused by defective ciliogenesis. Furthermore, depletion of Hh signaling results in the loss of junctional markers. We therefore propose that N-cad restricts the response of dorsal neural progenitors to Hh and that Hh signaling limits the range of its own activity by promoting AJ assembly. Taken together, these observations emphasize a key role for N-cad–mediated adhesion in controlling neural progenitor proliferation. In addition, these findings are the first to demonstrate a requirement for cadherins in synchronizing cell-cycle exit and differentiation and a reciprocal interaction between AJs and Hh signaling.

scholarly journals Spatiotemporal contribution of neuromesodermal progenitor-derived neural cells in the elongation of developing mouse spinal cord

2020 ◽  
Author(s):  
Mohammed R Shaker ◽  
Ju-Hyun Lee ◽  
Kyung Hyun Kim ◽  
Veronica Jihyun Kim ◽  
Joo Yeon Kim ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Neural Tube ◽  
Dorsal Side ◽  
Lineage Tracing ◽  
The Body ◽  
Lumbar Spinal Cord ◽  
Genetic Lineage ◽  
Mouse Development ◽  
Axial Elongation

ABSTRACTDuring vertebrate development, the posterior end of the embryo progressively elongates in a head-to-tail direction to form the body plan. Recent lineage tracing experiments revealed that bi-potent progenitors, called neuromesodermal progenitors (NMPs), produce caudal neural and mesodermal tissues during axial elongation. However, their precise location and contribution to spinal cord development remain elusive. Here we used NMP-specific markers (Sox2 and BraT) and a genetic lineage tracing system to localize NMP progeny in vivo. NMPs were initially located at the tail tip, but were later found in the caudal neural tube, which is a unique feature of mouse development. In the neural tube, they produced neural stem cells (NSCs) and contributed to the spinal cord gradually along the AP axis during axial elongation. Interestingly, NMP-derived NSCs preferentially contributed to the ventral side first and later to the dorsal side at the lumbar spinal cord level, which may be associated with atypical junctional neurulation in mice. Our current observations detail the contribution of NMP progeny to spinal cord elongation and provide insights into how different species uniquely execute caudal morphogenesis.

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