Transcriptional regulation of graded Hedgehog signaling

Falkenstein, Kristin N.; Vokes, Steven A.

doi:10.1016/j.semcdb.2014.05.010

Cited by 59 publications

(54 citation statements)

References 103 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…1B= and C=), as expected (7). This differential expression pattern of Gli1 and Gli3 in the EGL is consistent with their roles as a transcriptional activator and a repressor, respectively (27). However, we were surprised to find a very high level of Sufu in P7 EGL (Fig.…”

Section: Resultssupporting

confidence: 81%

“…Downstream from the Ptch1-Smo receptor system, the signaling responses are orchestrated by three Krüppel family transcription factors, Gli1, Gli2, and Gli3, each of which uses a highly conserved zinc finger DNA-binding domain to bind a common cis-acting DNA element in target gene promoters (24)(25)(26)(27). Early data from Drosophila showed that the fly Gli-homologous protein encoded by cubitus interruptus (Ci) undergoes a partial proteolysis that converts the full-length 150-kDa protein into a carboxylterminally truncated 75-kDa transcriptional repressor, Ci 75D , in unstimulated cells (28).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Suppressor of Fused Chaperones Gli Proteins To Generate Transcriptional Responses to Sonic Hedgehog Signaling

Zhang

Shen

Law

et al. 2017

Molecular and Cellular Biology

View full text Add to dashboard Cite

Cellular responses to the graded Sonic Hedgehog (Shh) morphogenic signal are orchestrated by three Gli genes that give rise to both transcription activators and repressors. An essential downstream regulator of the pathway, encoded by the tumor suppressor gene Suppressor of fused (Sufu), plays critical roles in the production, trafficking, and function of Gli proteins, but the mechanism remains controversial. Here, we show that Sufu is upregulated in active Shh responding tissues and accompanies Gli activators translocating into and Gli repressors out of the nucleus. Trafficking of Sufu to the primary cilium, potentiated by Gli activators but not repressors, was found to be coupled to its nuclear import. We have identified a nuclear export signal (NES) motif of Sufu in juxtaposition to the protein kinase A (PKA) and glycogen synthase kinase 3 (GSK3) dual phosphorylation sites and show that Sufu binds the chromatin with both Gli1 and Gli3. Close comparison of neural tube development among individual Ptch1 Ϫ/Ϫ , Sufu Ϫ/Ϫ , and Ptch1 Ϫ/Ϫ ; Sufu Ϫ/Ϫ double mutant embryos indicates that Sufu is critical for the maximal activation of Shh signaling essential to the specification of the most-ventral neurons. These data define Sufu as a novel class of molecular chaperone required for every aspect of Gli regulation and function.

show abstract

Section: Resultssupporting

confidence: 81%

mentioning

confidence: 99%

Suppressor of Fused Chaperones Gli Proteins To Generate Transcriptional Responses to Sonic Hedgehog Signaling

Zhang

Shen

Law

et al. 2017

Molecular and Cellular Biology

View full text Add to dashboard Cite

show abstract

“…The increased GLIFL to GLIR ratio posed two possible molecular mechanisms for producing HH-dependent midfacial widening: (1) a loss of GLIR activity (de-repression) [44], or (2) a gain of GLIA activity. Using genetic and biochemical approaches, we attempted to determine which mechanism was responsible for midfacial widening in ciliopathic mutants.…”

Section: Resultsmentioning

confidence: 99%

Craniofacial Ciliopathies Reveal Specific Requirements for GLI Proteins during Development of the Facial Midline

Chang

Millington

et al. 2016

PLoS Genet

View full text Add to dashboard Cite

Ciliopathies represent a broad class of disorders that affect multiple organ systems. The craniofacial complex is among those most severely affected when primary cilia are not functional. We previously reported that loss of primary cilia on cranial neural crest cells, via a conditional knockout of the intraflagellar transport protein KIF3a, resulted in midfacial widening due to a gain of Hedgehog (HH) activity. Here, we examine the molecular mechanism of how a loss of primary cilia can produce facial phenotypes associated with a gain of HH function. We show that loss of intraflagellar transport proteins (KIF3a or IFT88) caused aberrant GLI processing such that the amount of GLI3FL and GLI2FL was increased, thus skewing the ratio of GLIFL to GLIR in favor of the FL isoform. Genetic addition of GLI3R partially rescued the ciliopathic midfacial widening. Interestingly, despite several previous studies suggesting midfacial development relies heavily on GLI3R activity, the conditional loss of GLI3 alone did not reproduce the ciliopathic phenotype. Only the combined loss of both GLI2 and GLI3 was able to phenocopy the ciliopathic midfacial appearance. Our findings suggest that ciliopathic facial phenotypes are generated via loss of both GLI3R and GLI2R and that this pathology occurs via a de-repression mechanism. Furthermore, these studies suggest a novel role for GLI2R in craniofacial development.

show abstract

“…How various combinations of Gli activators and repressors control Hh target gene expression and confer graded Hh responses in the nucleus is a major unresolved issue in Hh signaling (Hui and Angers 2011;Rabinowitz and Vokes 2012;Falkenstein and Vokes 2014). This task is particularly challenging because different tissues use a unique combination of Gli activator/repressor to produce specific Hh outputs (i.e., a specific set of Hh targets) necessary for patterning.…”

mentioning

confidence: 99%

Regulation of Sufu activity by p66β and Mycbp provides new insight into vertebrate Hedgehog signaling

et al. 2014

View full text Add to dashboard Cite

Control of Gli function by Suppressor of Fused (Sufu), a major negative regulator, is a key step in mammalian Hedgehog (Hh) signaling, but how this is achieved in the nucleus is unknown. We found that Hh signaling results in reduced Sufu protein levels and Sufu dissociation from Gli proteins in the nucleus, highlighting critical functions of Sufu in the nucleus. Through a proteomic approach, we identified several Sufu-interacting proteins, including p66b (a member of the NuRD [nucleosome remodeling and histone deacetylase] repressor complex) and Mycbp (a Myc-binding protein). p66b negatively and Mycbp positively regulate Hh signaling in cell-based assays and zebrafish. They function downstream from the membrane receptors, Patched and Smoothened, and the primary cilium. Sufu, p66b, Mycbp, and Gli are also detected on the promoters of Hh targets in a dynamic manner. Our results support a new model of Hh signaling in the nucleus. Sufu recruits p66b to block Gli-mediated Hh target gene expression. Meanwhile, Mycbp forms a complex with Gli and Sufu without Hh stimulation but remains inactive. Hh pathway activation leads to dissociation of Sufu/p66b from Gli, enabling Mycbp to promote Gli protein activity and Hh target gene expression. These studies provide novel insight into how Sufu controls Hh signaling in the nucleus.

show abstract

Transcriptional regulation of graded Hedgehog signaling

Cited by 59 publications

References 103 publications

Suppressor of Fused Chaperones Gli Proteins To Generate Transcriptional Responses to Sonic Hedgehog Signaling

Suppressor of Fused Chaperones Gli Proteins To Generate Transcriptional Responses to Sonic Hedgehog Signaling

Craniofacial Ciliopathies Reveal Specific Requirements for GLI Proteins during Development of the Facial Midline

Regulation of Sufu activity by p66β and Mycbp provides new insight into vertebrate Hedgehog signaling

Contact Info

Product

Resources

About