scholarly journals Inversion of Sonic hedgehog action on its canonical pathway by electrical activity

2015 ◽  
Vol 112 (13) ◽  
pp. 4140-4145 ◽  
Author(s):  
Yesser H. Belgacem ◽  
Laura N. Borodinsky
Keyword(s):  
Spinal Cord ◽  
Electrical Activity ◽  
Sonic Hedgehog ◽  
Wide Spectrum ◽  
Canonical Pathway ◽  
Regulatory Mechanisms ◽  
Spatiotemporal Resolution ◽  
Spinal Cord Development ◽  
Shh Pathway ◽  
Element Binding Protein

Sonic hedgehog (Shh) is a morphogenic protein that operates through the Gli transcription factor-dependent canonical pathway to orchestrate normal development of many tissues. Because aberrant levels of Gli activity lead to a wide spectrum of diseases ranging from neurodevelopmental defects to cancer, understanding the regulatory mechanisms of Shh canonical pathway is paramount. During early stages of spinal cord development, Shh specifies neural progenitors through the canonical signaling. Despite persistence of Shh as spinal cord development progresses, Gli activity is switched off by unknown mechanisms. In this study we find that Shh inverts its action on Gli during development. Strikingly, Shh decreases Gli signaling in the embryonic spinal cord by an electrical activity- and cAMP-dependent protein kinase-mediated pathway. The inhibition of Gli activity by Shh operates at multiple levels. Shh promotes cytosolic over nuclear localization of Gli2, induces Gli2 and Gli3 processing into repressor forms, and activates cAMP-responsive element binding protein that in turn represses gli1 transcription. The regulatory mechanisms identified in this study likely operate with different spatiotemporal resolution and ensure effective down-regulation of the canonical Shh signaling as spinal cord development progresses. The developmentally regulated intercalation of electrical activity in the Shh pathway may represent a paradigm for switching from canonical to noncanonical roles of developmental cues during neuronal differentiation and maturation.

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 Sonic Hedgehog modulates the inflammatory response and improves functional recovery after spinal cord injury in a thoracic contusion–compression model

2021 ◽  
Author(s):  
Hao Zhang ◽  
Alexander Younsi ◽  
Guoli Zheng ◽  
Mohamed Tail ◽  
Anna-Kathrin Harms ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Sonic Hedgehog ◽  
Functional Recovery ◽  
Intrathecal Administration ◽  
Neuroprotective Effects ◽  
Thoracic Spinal Cord ◽  
Shh Pathway ◽  
Thoracic Spinal ◽  
Cord Injury

Abstract Purpose The Sonic Hedgehog (Shh) pathway has been associated with a protective role after injury to the central nervous system (CNS). We, therefore, investigated the effects of intrathecal Shh-administration in the subacute phase after thoracic spinal cord injury (SCI) on secondary injury processes in rats. Methods Twenty-one Wistar rats were subjected to thoracic clip-contusion/compression SCI at T9. Animals were randomized into three treatment groups (Shh, Vehicle, Sham). Seven days after SCI, osmotic pumps were implanted for seven-day continuous intrathecal administration of Shh. Basso, Beattie and Bresnahan (BBB) score, Gridwalk test and bodyweight were weekly assessed. Animals were sacrificed six weeks after SCI and immunohistological analyses were conducted. The results were compared between groups and statistical analysis was performed (p < 0.05 was considered significant). Results The intrathecal administration of Shh led to significantly increased polarization of macrophages toward the anti-inflammatory M2-phenotype, significantly decreased T-lymphocytic invasion and significantly reduced resident microglia six weeks after the injury. Reactive astrogliosis was also significantly reduced while changes in size of the posttraumatic cyst as well as the overall macrophagic infiltration, although reduced, remained insignificant. Finally, with the administration of Shh, gain of bodyweight (216.6 ± 3.65 g vs. 230.4 ± 5.477 g; p = 0.0111) and BBB score (8.2 ± 0.2 vs. 5.9 ± 0.7 points; p = 0.0365) were significantly improved compared to untreated animals six weeks after SCI as well. Conclusion Intrathecal Shh-administration showed neuroprotective effects with attenuated neuroinflammation, reduced astrogliosis and improved functional recovery six weeks after severe contusion/compression SCI.

Cadherin-20 expression by motor neurons is regulated by Sonic hedgehog during spinal cord development

Neuroreport ◽  
2009 ◽  
Vol 20 (4) ◽  
pp. 365-370 ◽  
Author(s):  
Jiankai Luo ◽  
Min Jeong Ju ◽  
Juntang Lin ◽  
Xin Yan ◽  
Annett Markus ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Sonic Hedgehog ◽  
Motor Neurons ◽  
Spinal Cord Development

Left-right pattern of cardiac BMP4 may drive asymmetry of the heart in zebrafish

Development ◽  
1997 ◽  
Vol 124 (21) ◽  
pp. 4373-4382 ◽  
Author(s):  
J.N. Chen ◽  
F.J. van Eeden ◽  
K.S. Warren ◽  
A. Chin ◽  
C. Nusslein-Volhard ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Sonic Hedgehog ◽  
Dominant Negative ◽  
Heart Tube ◽  
Dorsoventral Axis ◽  
Spinal Cord Development ◽  
Bmp4 Expression ◽  
The Right ◽  
Zebrafish Heart ◽  
Ventral Spinal Cord

The first evident break in left-right symmetry of the primitive zebrafish heart tube is the shift in pattern of BMP4 expression from radially symmetric to left-predominant. The midline heart tube then ‘jogs’ to the left and subsequently loops to the right. We examined 279 mutations, affecting more than 200 genes, and found 21 mutations that perturb this process. Some cause BMP4 to remain radially symmetric. Others randomize the asymmetric BMP4 pattern. Retention of BMP4 symmetry is associated with failure to jog: right-predominance of the BMP4 pattern is associated with reversal of the direction of jogging and looping. Raising BMP4 diffusely throughout the heart, via sonic hedgehog injection, or the blocking of its action by injection of a dominant negative BMP4 receptor, prevent directional jogging or looping. The genes crucial to directing cardiac asymmetry include a subset of those needed for patterning the dorsoventral axis and for notochord and ventral spinal cord development. Thus, the pattern of cardiac BMP4 appears to be in the pathway by which the heart interprets lateralizing signals from the midline.

scholarly journals Sonic Hedgehog Pathway Modulation Normalizes Expression of Olig2 in Rostrally Patterned NPCs With Trisomy 21

2022 ◽  
Vol 15 ◽  
Author(s):  
Jenny A. Klein ◽  
Zhen Li ◽  
Sanjeev Rampam ◽  
Jack Cardini ◽  
Amara Ayoub ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Down Syndrome ◽  
Sonic Hedgehog ◽  
Trisomy 21 ◽  
Neural Progenitor Cells ◽  
Neural Lineage ◽  
Shh Pathway ◽  
Gene Dysregulation ◽  
Induced Pluripotent ◽  
The Brain

The intellectual disability found in people with Down syndrome is associated with numerous changes in early brain development, including the proliferation and differentiation of neural progenitor cells (NPCs) and the formation and maintenance of myelin in the brain. To study how early neural precursors are affected by trisomy 21, we differentiated two isogenic lines of induced pluripotent stem cells derived from people with Down syndrome into brain-like and spinal cord-like NPCs and promoted a transition towards oligodendroglial fate by activating the Sonic hedgehog (SHH) pathway. In the spinal cord-like trisomic cells, we found no difference in expression of OLIG2 or NKX2.2, two transcription factors essential for commitment to the oligodendrocyte lineage. However, in the brain-like trisomic NPCs, OLIG2 is significantly upregulated and is associated with reduced expression of NKX2.2. We found that this gene dysregulation and block in NPC transition can be normalized by increasing the concentration of a SHH pathway agonist (SAG) during differentiation. These results underscore the importance of regional and cell type differences in gene expression in Down syndrome and demonstrate that modulation of SHH signaling in trisomic cells can rescue an early perturbed step in neural lineage specification.

An Early Developmental Marker for Radial Glia in Rat Spinal Cord

1996 ◽  
Vol 54 ◽  
pp. 36-37
Author(s):  
V. Kriho ◽  
H.-Y. Yang ◽  
C.-M. Lue ◽  
N. Lieska ◽  
G. D. Pappas
Keyword(s):  
Spinal Cord ◽  
Intermediate Filament ◽  
Radial Glia ◽  
Rat Spinal Cord ◽  
Future Studies ◽  
Spinal Cord Development ◽  
Median Septum ◽  
Differentiation Marker ◽  
Early Developmental ◽  
Developing Rat

Radial glia have been classically defined as those early glial cells that radially span their thin processes from the ventricular to the pial surfaces in the developing central nervous system. These radial glia constitute a transient cell population, disappearing, for the most part, by the end of the period of neuronal migration. Traditionally, it has been difficult to definitively identify these cells because the principal criteria available were morphologic only.Using immunofluorescence microscopy, we have previously defined a phenotype for radial glia in rat spinal cord based upon the sequential expression of vimentin, glial fibrillary acidic protein and an intermediate filament-associated protein, IFAP-70/280kD. We report here the application of another intermediate filament-associated protein, IFAP-300kD, originally identified in BHK-21 cells, to the immunofluorescence study of radial glia in the developing rat spinal cord.Results showed that IFAP-300kD appeared very early in rat spinal cord development. In fact by embryonic day 13, IFAP-300kD immunoreactivity was already at its peak and was observed in most of the radial glia which span the spinal cord from the ventricular to the subpial surfaces (Fig. 1). Interestingly, from this time, IFAP-300kD immunoreactivity diminished rapidly in a dorsal to ventral manner, so that by embryonic day 16 it was detectable only in the maturing macroglial cells in the marginal zone of the spinal cord and the dorsal median septum (Fig. 2). By birth, the spinal cord was essentially immuno-negative for this IFAP. Thus, IFAP-300kD appears to be another differentiation marker available for future studies of gliogenesis, especially for the early stages of radial glia differentiation.

scholarly journals Sonic Hedgehog and Triiodothyronine Pathway Interact in Mouse Embryonic Neural Stem Cells

2020 ◽  
Vol 21 (10) ◽  
pp. 3672
Author(s):  
Pavel Ostasov ◽  
Jan Tuma ◽  
Pavel Pitule ◽  
Jiri Moravec ◽  
Zbynek Houdek ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Sonic Hedgehog ◽  
Shh Pathway ◽  
Proliferation Activity ◽  
The Central Nervous System ◽  
Beta Gene ◽  
Potential Tool ◽  
Receptor Beta ◽  
Transplantation Therapy

Neural stem cells are fundamental to development of the central nervous system (CNS)—as well as its plasticity and regeneration—and represent a potential tool for neuro transplantation therapy and research. This study is focused on examination of the proliferation dynamic and fate of embryonic neural stem cells (eNSCs) under differentiating conditions. In this work, we analyzed eNSCs differentiating alone and in the presence of sonic hedgehog (SHH) or triiodothyronine (T3) which play an important role in the development of the CNS. We found that inhibition of the SHH pathway and activation of the T3 pathway increased cellular health and survival of differentiating eNSCs. In addition, T3 was able to increase the expression of the gene for the receptor smoothened (Smo), which is part of the SHH signaling cascade, while SHH increased the expression of the T3 receptor beta gene (Thrb). This might be the reason why the combination of SHH and T3 increased the expression of the thyroxine 5-deiodinase type III gene (Dio3), which inhibits T3 activity, which in turn affects cellular health and proliferation activity of eNSCs.

scholarly journals Cleavage activates Dispatched for Sonic Hedgehog ligand release

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Daniel P Stewart ◽  
Suresh Marada ◽  
William J Bodeen ◽  
Ashley Truong ◽  
Sadie Miki Sakurada ◽  
...  
Keyword(s):  
Sonic Hedgehog ◽  
Membrane Trafficking ◽  
Developmental Disorders ◽  
Transmembrane Protein ◽  
Regulatory Mechanisms ◽  
Extracellular Loop ◽  
Site Mutation ◽  
Evolutionarily Conserved ◽  
Processing Site

Hedgehog ligands activate an evolutionarily conserved signaling pathway that provides instructional cues during tissue morphogenesis, and when corrupted, contributes to developmental disorders and cancer. The transmembrane protein Dispatched is an essential component of the machinery that deploys Hedgehog family ligands from producing cells, and is absolutely required for signaling to long-range targets. Despite this crucial role, regulatory mechanisms controlling Dispatched activity remain largely undefined. Herein, we reveal vertebrate Dispatched is activated by proprotein convertase-mediated cleavage at a conserved processing site in its first extracellular loop. Dispatched processing occurs at the cell surface to instruct its membrane re-localization in polarized epithelial cells. Cleavage site mutation alters Dispatched membrane trafficking and reduces ligand release, leading to compromised pathway activity in vivo. As such, convertase-mediated cleavage is required for Dispatched maturation and functional competency in Hedgehog ligand-producing cells.

scholarly journals Glycine Release from Radial Cells Modulates the Spontaneous Activity and Its Propagation during Early Spinal Cord Development

2010 ◽  
Vol 30 (1) ◽  
pp. 390-403 ◽  
Author(s):  
A.-L. Scain ◽  
H. Le Corronc ◽  
A.-E. Allain ◽  
E. Muller ◽  
J.-M. Rigo ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spontaneous Activity ◽  
Spinal Cord Development ◽  
Glycine Release
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