scholarly journals Ciliary phosphatidylinositol phosphatase Inpp5e plays positive and negative regulatory roles in Shh signaling

2019 ◽  
Author(s):  
Sandii Constable ◽  
Alyssa B. Long ◽  
Katharine A. Floyd ◽  
Stéphane Schurmans ◽  
Tamara Caspary
Keyword(s):  
Signal Transduction ◽  
Sonic Hedgehog ◽  
Neural Tube ◽  
Relative Timing ◽  
Neural Patterning ◽  
Cell Fates ◽  
Shh Signaling ◽  
Mouse Mutants ◽  
Summary Statement ◽  
Time Required

AbstractSonic hedgehog (Shh) signal transduction specifies ventral cell fates in the neural tube and is mediated by the Gli transcription factors that play both activator (GliA) and repressor (GliR) roles. Cilia are essential for Shh signal transduction and the ciliary phosphatidylinositol phosphatase, Inpp5e, is linked to Shh regulation. In the course of a forward genetic screen for recessive mouse mutants, we identified a functional null allele of Inpp5e, ridge top (rdg), with expanded ventral neural cell fates at E10.5. By E12.5, Inpp5erdg/rdg embryos displayed normal neural patterning and this correction over time required Gli3, the predominant repressor in neural patterning. Inpp5erdg function largely depended on the presence of cilia and on Smoothened, the obligate transducer of Shh signaling, indicating Inpp5e functions within the cilium to regulate the pathway. These data indicate that Inpp5e plays a more complicated role in Shh signaling than previously appreciated. We propose that Inpp5e attenuates Shh signaling in the neural tube through regulation of the relative timing of GliA and GliR production, which is important in understanding how duration of Shh signaling regulates neural tube patterning.Summary statementInpp5e attenuates Sonic hedgehog signal transduction through a combination of positive and negative regulatory roles that likely control the relative timing of Gli processing.

The teratogenic Veratrum alkaloid cyclopamine inhibits sonic hedgehog signal transduction

Development ◽  
1998 ◽  
Vol 125 (18) ◽  
pp. 3553-3562 ◽  
Author(s):  
J.P. Incardona ◽  
W. Gaffield ◽  
R.P. Kapur ◽  
H. Roelink
Keyword(s):  
Signal Transduction ◽  
Sonic Hedgehog ◽  
Neural Tube ◽  
Cholesterol Metabolism ◽  
Cell Types ◽  
Dependent Manner ◽  
Post Translational Modification ◽  
Shh Signaling ◽  
Exogenous Cholesterol ◽  
Ay 9944

The steroidal alkaloid cyclopamine produces cyclopia and holoprosencephaly when administered to gastrulation-stage amniote embryos. Cyclopamine-induced malformations in chick embryos are associated with interruption of Sonic hedgehog (Shh)-mediated dorsoventral patterning of the neural tube and somites. Cell types normally induced in the ventral neural tube by Shh are either absent or appear aberrantly at the ventral midline after cyclopamine treatment, while dorsal cell types normally repressed by Shh appear ventrally. Somites in cyclopamine-treated embryos show Pax7 expression throughout, indicating failure of sclerotome induction. Cyclopamine at concentrations of 20–100 nM blocks the response of neural plate explants to recombinant Shh-N in a dose-dependent manner. Similar concentrations have no effect on the post-translational modification of Shh by cholesterol in transfected COS-1 cells. Comparison of the effects of cyclopamine to those of the holoprosencephaly-inducing cholesterol synthesis inhibitor AY-9944 shows that cyclopamine does not induce malformations by interfering with cholesterol metabolism. Although AY-9944 does not interrupt Shh signaling in ovo, it blocks the response to Shh-N in explants cultured without an exogenous cholesterol source. As predicted by current models of the regulation of cholesterol metabolism, the response to Shh-N in AY-9944-treated explants is restored by providing exogenous cholesterol. However, exogenous cholesterol does not restore Shh signaling in cyclopamine-treated explants. These findings suggest that cyclopamine-induced teratogenesis is due to a more direct antagonism of Shh signal transduction.

scholarly journals Sonic hedgehog signaling directs patterned cell remodeling during cranial neural tube closure

2020 ◽  
Author(s):  
Eric R. Brooks ◽  
Mohammed T. Islam ◽  
Kathryn V. Anderson ◽  
Jennifer A. Zallen
Keyword(s):  
Sonic Hedgehog ◽  
Neural Tube ◽  
Hedgehog Signaling ◽  
Structural Changes ◽  
Neural Tube Closure ◽  
Mammalian Brain ◽  
Shh Signaling ◽  
Apical Constriction ◽  
Cell Remodeling ◽  
Tube Closure

AbstractNeural tube closure defects are a major cause of infant mortality, with exencephaly accounting for nearly one-third of cases. However, the mechanisms of cranial neural tube closure are not well understood. Here we show that this process involves a tissue-wide pattern of apical constriction controlled by Sonic hedgehog (Shh) signaling. Midline cells in the mouse midbrain neuroepithelium are short with large apical surfaces, whereas lateral cells are taller and undergo synchronous apical constriction, driving neural fold elevation. Embryos lacking the Shh effector Gli2 fail to produce appropriate midline cell architecture, whereas embryos with expanded Shh signaling, including the IFT-A complex mutants Ift122 and Ttc21b and embryos expressing activated Smoothened, display apical constriction defects in lateral cells. Disruption of lateral, but not midline, cell remodeling results in exencephaly. These results reveal a morphogenetic program of patterned apical constriction governed by Shh signaling that generates structural changes in the developing mammalian brain.

Zebrafishsmoothenedfunctions in ventral neural tube specification and axon tract formation

Development ◽  
2001 ◽  
Vol 128 (18) ◽  
pp. 3497-3509 ◽  
Author(s):  
Zoltán M. Varga ◽  
Angel Amores ◽  
Katharine E. Lewis ◽  
Yi-Lin Yan ◽  
John H. Postlethwait ◽  
...  
Keyword(s):  
Sonic Hedgehog ◽  
Neural Tube ◽  
Hedgehog Signaling ◽  
Floor Plate ◽  
Slow Muscle ◽  
Pituitary Cells ◽  
Shh Signaling ◽  
Ventral Neural Tube ◽  
Hypothalamic Cells

Sonic hedgehog (Shh) signaling patterns many vertebrate tissues. shh mutations dramatically affect mouse ventral forebrain and floor plate but produce minor defects in zebrafish. Zebrafish have two mammalian Shh orthologs, sonic hedgehog and tiggy-winkle hedgehog, and another gene, echidna hedgehog, that could have overlapping functions. To examine the role of Hedgehog signaling in zebrafish, we have characterized slow muscle omitted (smu) mutants. We show that smu encodes a zebrafish ortholog of Smoothened that transduces Hedgehog signals. Zebrafish smoothened is expressed maternally and zygotically and supports specification of motoneurons, pituitary cells and ventral forebrain. We propose that smoothened is required for induction of lateral floor plate and a subpopulation of hypothalamic cells and for maintenance of medial floor plate and hypothalamic cells.

scholarly journals The Role of Sonic Hedgehog Pathway in the Development of the Central Nervous System and Aging-Related Neurodegenerative Diseases

2021 ◽  
Vol 8 ◽  
Author(s):  
Chen Yang ◽  
Yan Qi ◽  
Zhitang Sun
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Neurodegenerative Diseases ◽  
Signaling Pathway ◽  
Sonic Hedgehog ◽  
Neural Patterning ◽  
Shh Signaling ◽  
Shh Pathway ◽  
The Central Nervous System

The Sonic hedgehog (SHH) pathway affects neurogenesis and neural patterning during the development of the central nervous system. Dysregulation of the SHH pathway in the brain contributes to aging-related neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. At present, the SHH signaling pathway can be divided into the canonical signaling pathway and non-canonical signaling pathway, which directly or indirectly mediates other related pathways involved in the development of neurodegenerative diseases. Hence, an in-depth knowledge of the SHH signaling pathway may open an avenue of possibilities for the treatment of neurodegenerative diseases. Here, we summarize the role and mechanism of the SHH signaling pathway in the development of the central nervous system and aging-related neurodegenerative diseases. In this review, we will also highlight the potential of the SHH pathway as a therapeutic target for treating neurodegenerative diseases.

scholarly journals Prdm8 regulates pMN progenitor specification for motor neuron and oligodendrocyte fates by modulating Shh signaling response

2020 ◽  
Author(s):  
Kayt Scott ◽  
Rebecca O’Rourke ◽  
Austin Gillen ◽  
Bruce Appel
Keyword(s):  
Spinal Cord ◽  
Motor Neuron ◽  
Cell Fate ◽  
Motor Neurons ◽  
Oligodendrocyte Precursor Cells ◽  
Cell Fate Specification ◽  
Cell Fates ◽  
Shh Signaling ◽  
Summary Statement ◽  
Oligodendrocyte Precursor

AbstractSpinal cord pMN progenitors sequentially produce motor neurons and oligodendrocyte precursor cells (OPCs). Some OPCs differentiate rapidly as myelinating oligodendrocytes whereas others remain into adulthood. How pMN progenitors switch from producing motor neurons to OPCs with distinct fates is poorly understood. pMN progenitors express prdm8, which encodes a transcriptional repressor, during motor neuron and OPC formation. To determine if prdm8 controls pMN cell fate specification, we used zebrafish as a model system to investigate prdm8 function. Our analysis revealed that prdm8 mutant embryos have a deficit of motor neurons resulting from a premature switch from motor neuron to OPC production. Additionally, prdm8 mutant larvae have excess oligodendrocytes and a concomitant deficit of OPCs. Notably, pMN cells of mutant embryos have elevated Shh signaling coincident with the motor neuron to OPC switch. Inhibition of Shh signaling restored the number of motor neurons to normal but did not rescue the proportion of oligodendrocytes. These data suggest that Prdm8 regulates the motor neuron-OPC switch by controlling the level of Shh activity in pMN progenitors and also regulates allocation of oligodendrocyte lineage cell fates.Summary StatementPrdm8 regulates the timing of a motor neuron-oligodendrocyte switch and oligodendrocyte lineage cell identity in the zebrafish spinal cord.

scholarly journals A Scube2-Shh feedback loop links morphogen release to morphogen signaling to enable scale invariant patterning of the ventral neural tube

2018 ◽  
Author(s):  
Zachary M. Collins ◽  
Kana Ishimatsu ◽  
Tony Y.C. Tsai ◽  
Sean G. Megason
Keyword(s):  
Neural Tube ◽  
Size Reduction ◽  
Morphogen Gradient ◽  
Neural Patterning ◽  
Scale Invariant ◽  
Shh Signaling ◽  
Size Dependent ◽  
Analysis Technique ◽  
Ventral Neural Tube ◽  
Tissue Size

AbstractTo enable robust patterning, morphogen systems should be resistant to variations in gene expression and tissue size. Here we explore how a Shh morphogen gradient in the ventral neural tube enables proportional patterning in embryos of varying sizes. Using a surgical technique to reduce the size of zebrafish embryos and quantitative confocal microscopy, we find that patterning of neural progenitors remains proportional after size reduction. Intriguingly, a protein necessary for Shh release, Scube2, is expressed far from the source of sonic hedgehog production. scube2 expression levels control Shh signaling extent during ventral neural patterning and conversely Shh signaling represses the expression of scube2, thereby restricting its own signaling. scube2 is disproportionately downregulated in size-reduced embryos, providing a potential mechanism for size-dependent regulation of Shh. This regulatory feedback is necessary for pattern scaling, as demonstrated by a loss of scaling in scube2 overexpressing embryos. In a manner akin to the expander-repressor model of morphogen scaling, we conclude that feedback between Shh signaling and scube2 expression enables proportional patterning in the ventral neural tube by encoding a tissue size dependent morphogen signaling gradient.Summary StatementThe Shh morphogen gradient can scale to different size tissues by feedback between Scube2 mediated release of Shh and Shh based inhibition of Scube2 expressionAuthor ContributionsZ.M.C. conducted experiments and data analysis. Z.M.C and S.G.M. conceived the study, designed the experiments, and wrote the paper. K.I and Z.M.C. developed the size reduction technique. T.Y.C.T helped develop the image analysis technique and generated the tg(shha:memCherry) reporter line. S.G.M. supervised the overall study.

scholarly journals Neural tube development depends on notochord-derived Sonic hedgehog released into the sclerotome

2019 ◽  
Author(s):  
Nitza Kahane ◽  
Chaya Kalcheim
Keyword(s):  
Sonic Hedgehog ◽  
Neural Tube ◽  
Direct Consequence ◽  
Floor Plate ◽  
Neural Progenitors ◽  
Interacting Protein ◽  
Potential Site ◽  
Summary Statement ◽  
Neural Tube Development ◽  
Mesodermal Development

AbstractSonic hedgehog (Shh), produced in notochord and floor plate, is necessary both for neural and mesodermal development. To reach the myotome, Shh has to traverse the sclerotome. By loss and gain of Shh function, and floor plate deletions, we report that sclerotomal Shh is also necessary for neural tube development. Reducing the amount of Shh in sclerotome by membrane-tethered hedgehog-interacting protein or by Patched1, but not by dominant active Patched, decreased motoneuron numbers while also compromising myotome differentiation. These effects were a specific and direct consequence of reducing Shh. In addition, grafting notochords in a basal, but not apical location vis-a-vis the tube, profoundly affected motoneuron development, suggesting that initial ligand presentation occurs at the basal side of epithelia corresponding to the sclerotome-neural tube interface.Collectively, our results reveal that the sclerotome is a potential site of a Shh gradient that coordinates development of mesodermal and neural progenitors.Summary statementShh that transits through the sclerotome is presented to the neuroepithelium from its basal aspect to affect motoneuron development.

scholarly journals Sonic hedgehog signaling directs patterned cell remodeling during cranial neural tube closure

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Eric R Brooks ◽  
Mohammed Tarek Islam ◽  
Kathryn V Anderson ◽  
Jennifer A Zallen
Keyword(s):  
Sonic Hedgehog ◽  
Neural Tube ◽  
Hedgehog Signaling ◽  
Structural Changes ◽  
Neural Tube Closure ◽  
Mammalian Brain ◽  
Shh Signaling ◽  
Apical Constriction ◽  
Cell Remodeling ◽  
Tube Closure

Neural tube closure defects are a major cause of infant mortality, with exencephaly accounting for nearly one-third of cases. However, the mechanisms of cranial neural tube closure are not well understood. Here, we show that this process involves a tissue-wide pattern of apical constriction controlled by Sonic hedgehog (Shh) signaling. Midline cells in the mouse midbrain neuroepithelium are flat with large apical surfaces, whereas lateral cells are taller and undergo synchronous apical constriction, driving neural fold elevation. Embryos lacking the Shh effector Gli2 fail to produce appropriate midline cell architecture, whereas embryos with expanded Shh signaling, including the IFT-A complex mutants Ift122 and Ttc21b and embryos expressing activated Smoothened, display apical constriction defects in lateral cells. Disruption of lateral, but not midline, cell remodeling results in exencephaly. These results reveal a morphogenetic program of patterned apical constriction governed by Shh signaling that generates structural changes in the developing mammalian brain.

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