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.

Early development and dispersal of oligodendrocyte precursors in the embryonic chick spinal cord

Development ◽  
1995 ◽  
Vol 121 (6) ◽  
pp. 1743-1754 ◽  
Author(s):  
K. Ono ◽  
R. Bansal ◽  
J. Payne ◽  
U. Rutishauser ◽  
R.H. Miller
Keyword(s):  
Spinal Cord ◽  
Ventricular Zone ◽  
General Characteristic ◽  
Central Canal ◽  
Vertebrate Development ◽  
Dorsal Spinal Cord ◽  
Oligodendrocyte Precursors ◽  
Dorsal Spinal ◽  
Chick Spinal Cord

Oligodendrocytes, the myelinating cells of the vertebrate CNS, originally develop from cells of the neuroepithelium. Recent studies suggest that spinal cord oligodendrocyte precursors are initially localized in the region of the ventral ventricular zone and subsequently disperse throughout the spinal cord. The characteristics of these early oligodendrocyte precursors and their subsequent migration has been difficult to assay directly in the rodent spinal cord due to a lack of appropriate reagents. In the developing chick spinal cord, we show that oligodendrocyte precursors can be specifically identified by labeling with O4 monoclonal antibody. In contrast to rodent oligodendrocyte precursors, which express O4 immunoreactivity only during the later stages of maturation, in the chick O4 immunoreactivity appears very early and its expression is retained through cellular maturation. In embryos older than stage 35, O4+ cells represent the most immature, self-renewing, cells of the chick spinal cord oligodendrocyte lineage. In the intact chick spinal cord, the earliest O4+ cells are located at the ventral ventricular zone where they actually contribute to the ventricular lining of the central canal. The subsequent migration of O4+ cells into the dorsal region of the spinal cord temporally correlates with the capacity of isolated dorsal spinal cord to generate oligodendrocytes in vitro. Biochemical analysis suggests O4 labels a POA-like antigen on the surface of chick spinal cord oligodendrocyte precursors. These studies provide direct evidence for the ventral ventricular origin of spinal cord oligodendrocytes, and suggest that this focal source of oligodendrocytes is a general characteristic of vertebrate development.

Oligodendrocyte precursors originate at the ventral ventricular zone dorsal to the ventral midline region in the embryonic rat spinal cord

Development ◽  
1993 ◽  
Vol 118 (2) ◽  
pp. 563-573 ◽  
Author(s):  
E. Noll ◽  
R.H. Miller
Keyword(s):  
Spinal Cord ◽  
Ventricular Zone ◽  
Rat Spinal Cord ◽  
Proliferating Cells ◽  
Dorsal Spinal Cord ◽  
Ventral Midline ◽  
Ventricular Cells ◽  
Oligodendrocyte Precursors ◽  
Dorsal Spinal ◽  
Ventral Spinal Cord

The precursors for oligodendrocytes, the myelinating cells of the vertebrate CNS, appear to be initially restricted to ventral regions of the embryonic rat spinal cord. These cells subsequently populate dorsal spinal cord regions where they acquire the mature characteristics of oligodendrocytes. To determine the location and timing of proliferation of oligodendrocyte precursors in the ventral spinal cord, and to map their pathways of migration in vivo, an assay that identifies mitotic cells was used in conjunction with antibodies that distinguish astrocytes, oligodendrocytes and their precursors. Between E16.5 and E18.5, two hours after a maternal injection of BrdU, the majority of proliferating cells were located in a discrete cluster at the ventral ventricular zone dorsal to the ventral midline region of the developing spinal cord. By contrast, 12–24 hours following a BrdU injection at E16.5, increasing numbers of labeled cells were seen in the dorsal and more lateral locations of the spinal cord. These observations suggest that BrdU-labeled ventral ventricular cells, or their progeny migrate dorsally and laterally during subsequent spinal cord development. To determine the nature of these proliferating cells, cultures of dorsal and ventral spinal cord from BrdU-labeled animals were double-labeled with antibodies that identify oligodendrocytes or astrocytes and anti-BrdU. In dorsal spinal cord cultures derived from animals that had received a single injection of BrdU at E16.5, the majority of proliferating cells differentiated into astrocytes while, in ventrally derived cultures from the same animals, the majority of proliferating cells differentiated into oligodendrocytes. In dorsal cultures prepared from animals that received multiple injections of BrdU between E16.5 and E18.5, many more cells were labeled with BrdU and approximately half of these differentiated into oligodendrocytes. These observations suggest that during embryonic development proliferating oligodendrocyte precursors are initially located at the ventral ventricular zone dorsal to the ventral midline region of the spinal cord and during subsequent maturation these cells or their progeny migrated dorsally in the ventricular region of the spinal cord, and laterally to reside in the developing white matter.

Sonic hedgehog-dependent emergence of oligodendrocytes in the telencephalon: evidence for a source of oligodendrocytes in the olfactory bulb that is independent of PDGFRα signaling

Development ◽  
2001 ◽  
Vol 128 (24) ◽  
pp. 4993-5004
Author(s):  
Nathalie Spassky ◽  
Katharina Heydon ◽  
Arnaud Mangatal ◽  
Alexandar Jankovski ◽  
Christelle Olivier ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Olfactory Bulb ◽  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
Molecular Mechanisms ◽  
Cell Contact ◽  
Sonic Hedgehog Signaling ◽  
Oligodendrocyte Progenitors

Most studies on the origin of oligodendrocyte lineage have been performed in the spinal cord. By contrast, molecular mechanisms that regulate the appearance of the oligodendroglial lineage in the brain have not yet attracted much attention. We provide evidence for three distinct sources of oligodendrocytes in the mouse telencephalon. In addition to two subpallial ventricular foci, the anterior entopeduncular area and the medial ganglionic eminence, the rostral telencephalon also gives rise to oligodendrocytes. We show that oligodendrocytes in the olfactory bulb are generated within the rostral pallium from ventricular progenitors characterized by the expression of Plp. We provide evidence that these Plp oligodendrocyte progenitors do not depend on signal transduction mediated by platelet-derived growth factor receptors (PDGFRs), and therefore propose that they belong to a different lineage than the PDGFRα-expressing progenitors. Moreover, induction of oligodendrocytes in the telencephalon is dependent on sonic hedgehog signaling, as in the spinal cord. In all these telencephalic ventricular territories, oligodendrocyte progenitors were detected at about the same developmental stage as in the spinal cord. However, both in vivo and in vitro, the differentiation into O4-positive pre-oligodendrocytes was postponed by 4-5 days in the telencephalon in comparison with the spinal cord. This delay between determination and differentiation appears to be intrinsic to telencephalic oligodendrocytes, as it was not shortened by diffusible or cell-cell contact factors present in the spinal cord.

scholarly journals Soluble Heparin and Heparan Sulfate Glycosaminoglycans Interfere with Sonic Hedgehog Solubilization and Receptor Binding

Molecules ◽  
2019 ◽  
Vol 24 (8) ◽  
pp. 1607 ◽  
Author(s):  
Manikowski ◽  
Jakobs ◽  
Jboor ◽  
Grobe
Keyword(s):  
Heparan Sulfate ◽  
Sonic Hedgehog ◽  
Receptor Binding ◽  
Feedback Loop ◽  
Cancer Cell Growth ◽  
Shh Signaling ◽  
Epithelial Cancers ◽  
And Function

Sonic hedgehog (Shh) signaling plays a tumor-promoting role in many epithelial cancers. Cancer cells produce soluble a Shh that signals to distant stromal cells that express the receptor Patched (Ptc). These receiving cells respond by producing other soluble factors that promote cancer cell growth, generating a positive feedback loop. To interfere with reinforced Shh signaling, we examined the potential of defined heparin and heparan sulfate (HS) polysaccharides to block Shh solubilization and Ptc receptor binding. We confirm in vitro and in vivo that proteolytic cleavage of the N-terminal Cardin–Weintraub (CW) amino acid motif is a prerequisite for Shh solubilization and function. Consistent with the established binding of soluble heparin or HS to the Shh CW target motif, both polysaccharides impaired proteolytic Shh processing and release from source cells. We also show that HS and heparin bind to, and block, another set of basic amino acids required for unimpaired Shh binding to Ptc receptors on receiving cells. Both modes of Shh activity downregulation depend more on HS size and overall charge than on specific HS sulfation modifications. We conclude that heparin oligosaccharide interference in the physiological roles of HS in Shh release and reception may be used to expand the field of investigation to pharmaceutical intervention of tumor-promoting Shh functions.

scholarly journals Cadherin-7 enhances Sonic Hedgehog signalling by preventing Gli3 repressor formation during neural tube patterning

Open Biology ◽  
2017 ◽  
Vol 7 (12) ◽  
pp. 170225 ◽  
Author(s):  
Rie Kawano ◽  
Kunimasa Ohta ◽  
Giuseppe Lupo
Keyword(s):  
Spinal Cord ◽  
Sonic Hedgehog ◽  
Neural Tube ◽  
Target Genes ◽  
Dorsoventral Patterning ◽  
Dorsal Spinal Cord ◽  
Suppressor Of Fused ◽  
Intracellular Movement ◽  
Sonic Hedgehog Signalling ◽  
Dorsal Spinal

Sonic Hedgehog (Shh) is a ventrally enriched morphogen controlling dorsoventral patterning of the neural tube. In the dorsal spinal cord, Gli3 protein bound to suppressor-of-fused (Sufu) is converted into Gli3 repressor (Gli3R), which inhibits Shh-target genes. Activation of Shh signalling prevents Gli3R formation, promoting neural tube ventralization. We show that cadherin-7 (Cdh7) expression in the intermediate spinal cord region is required to delimit the boundary between the ventral and the dorsal spinal cord. We demonstrate that Cdh7 functions as a receptor for Shh and enhances Shh signalling. Binding of Shh to Cdh7 promotes its aggregation on the cell membrane and association of Cdh7 with Gli3 and Sufu. These interactions prevent Gli3R formation and cause Gli3 protein degradation. We propose that Shh can act through Cdh7 to limit intracellular movement of Gli3 protein and production of Gli3R, thus eliciting more efficient activation of Gli-dependent signalling.

FoxF1 is Required for Ciliogenesis and Distribution of Sonic Hedgehog Signaling Components in Cilium

2019 ◽  
Vol 19 (5) ◽  
pp. 326-334
Author(s):  
Lu Huang ◽  
Marco Tjakra ◽  
Desha Luo ◽  
Lin Wen ◽  
Daoxi Lei ◽  
...  
Keyword(s):  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
3T3 Cells ◽  
Shh Signaling ◽  
Nih 3T3 ◽  
Signaling Components ◽  
Nih 3T3 Cells

Background: In vertebrates, cilium is crucial for Hedgehog signaling transduction. Forkhead box transcriptional factor FoxF1 is reported to be associated with Sonic Hedgehog (Shh) signaling in many cases. However, the role of FoxF1 in cilium remains unknown. Here, we showed an essential role of FoxF1 in the regulation of ciliogenesis and in the distribution of Shh signaling components in cilium. Methods: NIH/3T3 cells were serum starved for 24h to induce cilium. Meanwhile, shRNA was used to knockdown the FoxF1 expression in the cells and CRISPR/Cas9 was used to generate the FoxF1 zebrafish mutant. The mRNA and protein expression of indicated genes were detected by the qRT-PCR and western blot, respectively. Immunofluorescence staining was performed to detect the cilium and Shh components distribution. Results: FoxF1 knockdown decreased the cilium length in NIH/3T3 cells. Meanwhile, the disruption of FoxF1 function inhibited the expression of cilium-related genes and caused an abnormal distribution of Shh components in the cilium. Furthermore, homozygous FoxF1 mutants exhibited defective development of pronephric cilium in early zebrafish embryos. Conclusion: Together, our data illustrated that FoxF1 is required for ciliogenesis in vitro and in vivo and for the proper localization of Shh signaling components in cilium.

Gli1can rescue the in vivo function ofGli2

Development ◽  
2001 ◽  
Vol 128 (24) ◽  
pp. 5161-5172 ◽  
Author(s):  
Chunyang Brian Bai ◽  
Alexandra L. Joyner
Keyword(s):  
Spinal Cord ◽  
Sonic Hedgehog ◽  
Target Genes ◽  
Wild Type ◽  
Shh Signaling ◽  
Gli Proteins ◽  
Functional Differences ◽  
Expression Studies ◽  
Null Mutants

In mice, three Gli genes are thought to mediate sonic hedgehog (Shh) signaling collectively. Mis-expression studies and analysis of null mutants for each gene have indicated that the Gli proteins have different functions. In particular, Gli1 appears to be a constitutive activator, and Gli2 and Gli3 have repressor functions. To determine the precise functional differences between Gli1 and Gli2, we have expressed Gli1 in place of Gli2 from the endogenous Gli2 locus in mice. Strikingly, a low level of Gli1 can rescue all the Shh signaling defects in Gli2 mutants; however, only in the presence of a wild-type Shh gene. These studies demonstrate that only the activator function of Gli2 is actually required, and indicates that in specific situations, Shh can modulate the ability of Gli1 to activate target genes. Furthermore, expression of both copies of Gli1 in place of Gli2 does not disrupt spinal cord patterning, but does result in new gain-of-function defects that lead to lethality. We show that the defects are enhanced when Gli3 function is reduced, demonstrating that an important difference between Gli1 and Gli2 is the ability of Gli1 to antagonize Gli3 function.

Positive N-methyl-d-aspartate receptor modulation by selective glycine transporter-1 inhibition in the rat dorsal spinal cord in vivo

Neuroscience ◽  
2004 ◽  
Vol 126 (2) ◽  
pp. 381-390 ◽  
Author(s):  
K.J Whitehead ◽  
S.M Pearce ◽  
G Walker ◽  
H Sundaram ◽  
D Hill ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Dorsal Spinal Cord ◽  
Receptor Modulation ◽  
Glycine Transporter 1 ◽  
Aspartate Receptor ◽  
Glycine Transporter ◽  
Dorsal Spinal
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