Establishing and Interpreting Graded Sonic Hedgehog Signaling during Vertebrate Neural Tube Patterning: The Role of Negative Feedback

Ribes, Vanessa; Briscoe, James

doi:10.1101/cshperspect.a002014

Cited by 212 publications

(219 citation statements)

References 87 publications

(167 reference statements)

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“…SMO and PTCH1 base level expression, much like that of GLI2 and GLI3, is independent of pathway activity. However, PTCH1 production is upregulated with increasing HH levels, thus forming a negative-feedback loop in the canonical signaling pathway (Ribes and Briscoe, 2009). Recent analysis of the cis-regulatory modules of HH-regulated genes has revealed that cells interpret the levels of HH signaling through differential affinity GLI-binding sites in target genes, whereas tissue specificity is achieved through the participation of co-activators (Balaskas et al, 2012;Oosterveen et al, 2012Oosterveen et al, , 2013.…”

Section: The Hh Signaling Pathway In Mammalsmentioning

confidence: 99%

Roles for Hedgehog signaling in adult organ homeostasis and repair

2014

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The hedgehog (HH) pathway is well known for its mitogenic and morphogenic functions during development, and HH signaling continues in discrete populations of cells within many adult mammalian tissues. Growing evidence indicates that HH regulates diverse quiescent stem cell populations, but the exact roles that HH signaling plays in adult organ homeostasis and regeneration remain poorly understood. Here, we review recently identified functions of HH in modulating the behavior of tissue-specific adult stem and progenitor cells during homeostasis, regeneration and disease. We conclude that HH signaling is a key factor in the regulation of adult tissue homeostasis and repair, acting via multiple different routes to regulate distinct cellular outcomes, including maintenance of plasticity, in a context-dependent manner.

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Section: The Hh Signaling Pathway In Mammalsmentioning

confidence: 99%

Roles for Hedgehog signaling in adult organ homeostasis and repair

2014

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“…11 Other Hh-Gli target genes code for PTC1 and Hedgehog-interacting protein (HHIP) that can also bind HH, mediating a negative feedback loop by limiting the quantity of available unbound ligand required for pathway activation. [11][12][13] The human PTCH1 gene (MIM 601309) is located on chromosome 9q22.32 and spans about 74 kilobases. 14 There are at least 7 major PTCH1 transcript variants with 24 exons, of which 23 are coding, and with the first exon being specific for each variant.…”

Section: Introductionmentioning

confidence: 99%

Regulation of humanPTCH1bexpression by different 5' untranslated regioncis-regulatory elements

et al. 2015

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Inga (2015) Regulation of human PTCH1b expression by different 5' untranslated region cis-regulatory elements, RNA Biology, 12:3, 290-304, DOI: 10.1080/15476286.2015 PTCH1 gene codes for a 12-pass transmembrane receptor with a negative regulatory role in the Hedgehog-Gli signaling pathway. PTCH1 germline mutations cause Gorlin syndrome, a disorder characterized by developmental abnormalities and tumor susceptibility. The autosomal dominant inheritance, and the evidence for PTCH1 haploinsufficiency, suggests that fine-tuning systems of protein patched homolog 1 (PTC1) levels exist to properly regulate the pathway. Given the role of 5' untranslated region (5'UTR) in protein expression, our aim was to thoroughly explore cis-regulatory elements in the 5'UTR of PTCH1 transcript 1b. The (CGG) n polymorphism was the main potential regulatory element studied so far but with inconsistent results and no clear association between repeat number and disease risk. Using luciferase reporter constructs in human cell lines here we show that the number of CGG repeats has no strong impact on gene expression, both at mRNA and protein levels. We observed variability in the length of 5'UTR and changes in abundance of the associated transcripts after pathway activation. We show that upstream AUG codons (uAUGs) present only in longer 5'UTRs could negatively regulate the amount of PTC1 isoform L (PTC1-L). The existence of an internal ribosome entry site (IRES) observed using different approaches and mapped in the region comprising the CGG repeats, would counteract the effect of the uAUGs and enable synthesis of PTC1-L under stressful conditions, such as during hypoxia. Higher relative translation efficiency of PTCH1b mRNA in HEK 293T cultured hypoxia was observed by polysomal profiling and Western blot analyses. All our results point to an exceptionally complex and so far unexplored role of 5'UTR PTCH1b cis-element features in the regulation of the Hedgehog-Gli signaling pathway.

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“…During the early stages of spinal cord development, Shh is synthesized and secreted by the notochord and floor plate to form a ventrodorsal concentration gradient, imprinting a spatiotemporal profile of Gli activity (4,5) that specifies neural progenitors (6)(7)(8)(9). Despite persistence of Shh gradient and increased Shh levels as spinal cord development progresses (3,10), Gli activity is switched off (3,4) by unknown mechanisms.…”

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confidence: 99%

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

Belgacem

Borodinsky

2015

Proc. Natl. Acad. Sci. U.S.A.

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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.

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Establishing and Interpreting Graded Sonic Hedgehog Signaling during Vertebrate Neural Tube Patterning: The Role of Negative Feedback

Cited by 212 publications

References 87 publications

Roles for Hedgehog signaling in adult organ homeostasis and repair

Roles for Hedgehog signaling in adult organ homeostasis and repair

Regulation of humanPTCH1bexpression by different 5' untranslated regioncis-regulatory elements

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

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