Regulation Of Hedgehog Signaling Research Articles

Arih2 regulates Hedgehog signaling through smoothened ubiquitylation and ER-associated degradation.

During Hedgehog signaling, the ciliary levels of Ptch1 and Smo are regulated by the pathway. At the basal state, Ptch1 localizes to cilia and prevents the ciliary accumulation and activation of Smo. Upon binding a Hedgehog ligand, Ptch1 exits cilia, relieving inhibition of Smo. Smo then concentrates in cilia, becomes activated and activates downstream signaling. Loss of the ubiquitin E3 ligase Arih2 elevates basal Hedgehog signaling, elevates the cellular level of Smo and increases basal levels of ciliary Smo. Mice express two isoforms of Arih2 with Arih2α found primarily in the nucleus and Arih2β found on the cytoplasmic face of the endoplasmic reticulum (ER). Re-expression of ER-localized Arih2β but not nuclear-localized Arih2α rescues the Arih2 mutant phenotypes. When Arih2 is defective, protein aggregates accumulate in the ER and the unfolded protein response is activated. Arih2β appears to regulate the ER-associated degradation (ERAD) of Smo preventing excess and potentially misfolded Smo from reaching the cilium and interfering with pathway regulation.

Dissection of the microRNA Network Regulating Hedgehog Signaling in Drosophila.

The evolutionarily conserved Hedgehog (Hh) signaling plays a critical role in embryogenesis and adult tissue homeostasis. Aberrant Hh signaling often leads to various forms of developmental anomalies and cancer. Since altered microRNA (miRNA) expression is associated with developmental defects and tumorigenesis, it is not surprising that several miRNAs have been found to regulate Hh signaling. However, these miRNAs are mainly identified through small-scale in vivo screening or in vitro assays. As miRNAs preferentially reduce target gene expression via the 3′ untranslated region, we analyzed the effect of reduced expression of core components of the Hh signaling cascade on downstream signaling activity, and generated a transgenic Drosophila toolbox of in vivo miRNA sensors for core components of Hh signaling, including hh, patched (ptc), smoothened (smo), costal 2 (cos2), fused (fu), Suppressor of fused (Su(fu)), and cubitus interruptus (ci). With these tools in hand, we performed a genome-wide in vivo miRNA overexpression screen in the developing Drosophila wing imaginal disc. Of the twelve miRNAs identified, seven were not previously reported in the in vivo Hh regulatory network. Moreover, these miRNAs may act as general regulators of Hh signaling, as their overexpression disrupts Hh signaling-mediated cyst stem cell maintenance during spermatogenesis. To identify direct targets of these newly discovered miRNAs, we used the miRNA sensor toolbox to show that miR-10 and miR-958 directly target fu and smo, respectively, while the other five miRNAs act through yet-to-be-identified targets other than the seven core components of Hh signaling described above. Importantly, through loss-of-function analysis, we found that endogenous miR-10 and miR-958 target fu and smo, respectively, whereas deletion of the other five miRNAs leads to altered expression of Hh signaling components, suggesting that these seven newly discovered miRNAs regulate Hh signaling in vivo. Given the powerful effects of these miRNAs on Hh signaling, we believe that identifying their bona fide targets of the other five miRNAs will help reveal important new players in the Hh regulatory network.

Ptch2 is a Potential Regulator of Mesenchymal Stem Cells.

Ptch receptors 1 and 2 mediate Hedgehog signaling pivotal for organ development and homeostasis. In contrast to embryonic lethal Ptch1 −/− phenotype, Ptch2 −/− mice display no effect on gross phenotype. In this brief report, we provide evidence of changes in the putative incisor mesenchymal stem cell (MSC) niches that contribute to accelerated incisor growth, as well as intriguing changes in the bones and skin which suggest a role for Ptch2 in the regulation of MSCs and their regenerative potential. We employed histological, immunostaining, and computed tomography (µCT) analyses to analyze morphological differences between Ptch2 −/− and wild-type incisors, long bones, and skins. In vitro CFU and differentiation assays were used to demonstrate the MSC content and differentiation potential of Ptch2 −/− bone marrow stromal cells. Wound healing assay was performed in vivo and in vitro on 8-week-old mice to assess the effect of Ptch2 on the wound closure. Loss of Ptch2 causes increases in the number of putative MSCs in the continuously growing incisor, associated with increased vascularization observed in the tooth mesenchyme and the neurovascular bundle. Increased length and volume of Ptch2 −/− bones is linked with the increased number and augmented in vitro differentiation potential of MSCs in the bone marrow. Dynamic changes in the Ptch2 −/− skin thickness relate to changes in the mesenchymal compartment and impact the wound closure potential. The effects of Ptch2 abrogation on the postnatal MSCs suggest a crucial role for Ptch2 in Hedgehog signaling regulation of the organ regenerative potential.

Pregnane X receptor (PXR) represses osteoblast differentiation through repression of the Hedgehog signaling pathway

The pregnane X receptor (PXR, NR1I2) belongs to the nuclear receptor family and functions as a xenobiotic and endobiotic sensor by binding to various molecules through its relatively flexible ligand-binding domain. In addition to these well-known canonical roles, we previously reported that PXR represses osteoblast differentiation. However, the mechanisms underlying the PXR-mediated repression of osteoblast differentiation remains unknown. In this study, we analyzed the changes in global gene expression profiles induced by PXR in calvarial osteoblasts cultured in standard fetal bovine serum (in which PXR induces repression of differentiation), and in those cultured in charcoal-stripped fetal bovine serum (in which PXR does not induce repression of differentiation). The comparison revealed that PXR attenuated the Hedgehog-mediated signaling in culture conditions that induced PXR-mediated repression of differentiation. Real-time PCR analysis showed that PXR repressed the Hedgehog signaling-induced genes such as Gli1 and Hhip, and conversely induced the Hedgehog signaling-repressed genes such as Cdon, Boc, and Gas1. Activation of Smo-mediated signaling in osteoblasts following treatment with a Smo agonist (SAG) significantly restored Gli-mediated transcriptional activity and osteoblast differentiation. Our results demonstrate the osteoblast-autonomous effects of PXR and identify a novel regulation of Hedgehog signaling by nuclear receptors.

Hedgehog pathway modulation by glypican 3-conjugated heparan sulfate.

Glypicans are a family of cell surface heparan sulfate proteoglycans that play critical roles in multiple cell signaling pathways. Glypicans consist of a globular core, an unstructured stalk modified with sulfated glycosaminoglycan chains, and a glycosylphosphatidylinositol anchor. Though these structural features are conserved, their individual contribution to glypican function remains obscure. Here, we investigate how glypican 3 (GPC3), which is mutated in Simpson-Golabi-Behmel tissue overgrowth syndrome, regulates Hedgehog signaling. We find that GPC3 is necessary for the Hedgehog response, surprisingly controlling a downstream signal transduction step. Purified GPC3 ectodomain rescues signaling when artificially recruited to the surface of GPC3-deficient cells but has dominant-negative activity when unattached. Strikingly, the purified stalk, modified with heparan sulfate but not chondroitin sulfate, is necessary and sufficient for activity. Our results demonstrate a novel function for GPC3-associated heparan sulfate and provide a framework for the functional dissection of glycosaminoglycans by in vivo biochemical complementation. This article has an associated First Person interview with the first author of the paper.

Cepharanthine hydrochloride inhibits the Wnt/β‑catenin/Hedgehog signaling axis in liver cancer.

Cepharanthine, a biscoclaurine alkaloid isolated from the roots of Stephania cephalantha Hayata, has been reported to demonstrate antitumor activity across multiple cancer types; however, the mechanisms are still under investigation. High transcriptional responses by both the Hedgehog and Wnt pathways are frequently associated with specific human cancers, including liver cancer. To investigate whether these signaling pathways are involved in the pharmaceutical action of cepharanthine, we investigated Hedgehog and Wnt signaling in models of liver cancer treated with a semi-synthetic cepharanthine derivative, cepharanthine hydrochloride (CH), in vitro and in vivo. By using MTT cytotoxic, scratch, Transwell, colony formation and flow cytometry assays, the pharmaceutical effect of CH was assessed. The compound was found to inhibit cellular proliferation and invasion, and promote apoptosis. Subsequent mechanistic investigations revealed that CH suppressed the Hedgehog/Gli1 signaling pathway by inhibiting Gli1 transcription and its transcriptional activity. CH also inhibited Wnt/β-catenin signaling, and the pathway was found to be an upstream regulator of Hedgehog signaling in CH-treated liver cancer cells. Finally, the antitumor effects of CH were demonstrated in an in vivo xenograft tumor model. Immunohistochemical analysis indicated that Gli1 protein levels were diminished in CH-treated xenografts, compared with that noted in the controls. In summary, our results highlight a novel pharmaceutical antitumor mechanism of cepharanthine and provide support for CH as a clinical therapy for refractory liver cancer and other Wnt/Hedgehog-driven cancers.

Unique lingual expression of the Hedgehog pathway antagonist Hedgehog-interacting protein in filiform papillae during homeostasis and ectopic expression in fungiform papillae during Hedgehog signaling inhibition.

Hedgehog (HH) signaling is essential for homeostasis in gustatory fungiform papillae (FP) and taste buds. However, activities of HH antagonists in these tissues remain unexplored. We investigated a potential role for HH-interacting protein (HHIP), an endogenous pathway antagonist, in regulating HH signaling during taste organ homeostasis. We found a restricted pattern of Hhip-expressing cells in the anterior epithelium of each nongustatory filiform papilla (FILIF) only. To test for roles in antagonism of HH signaling, we investigated HHIP after pathway inhibition with SMO inhibition via sonidegib and Smo deletion, Gli2 deletion/suppression, or with chorda tympani/lingual nerve cut. In all approaches, the HHIP expression pattern was retained in FILIF suggesting HH-independent regulation of HHIP. Remarkably, after pathway inhibition, HHIP expression was detected also in the conical, FILIF-like atypical FP. We found a close association of de novo expression of HHIP in atypical FP with loss of Gli1+, HH-responding cells. Further, we report that PTCH1 is another potential HH antagonist in FILIF that co-localizes with HHIP. After HH pathway inhibition the ectopic expression of HHIP correlates with a FILIF-like morphology in atypical FP and we propose that localized expression of the HH antagonist HHIP regulates pathway inhibition to maintain FILIF during tongue homeostasis.

Effect of kaempferol on hedgehog signaling pathway in rats with ‐‐chronic atrophic gastritis – Based on network pharmacological screening and experimental verification

The effect of active ingredients of Chaishaoliujun Decoction (CD) on chronic atrophic gastritis (CAG) was screened by network pharmacological method and verified by preliminary experiment.Firstly, the active ingredients and drug targets of CD were retrieved in TCMSP database; CAG-related targets from PharmGkb, OMIM, GeneCards and DrugBank databases were collected as well. Secondly, the drug targets and disease targets were mapped to obtain the intersection targets. PPI network and active ingredient-common target network were constructed for the intersection targets obtained and KEGG enrichment analysis was also carried out. Finally, the core active ingredient (kaempferol), effective targets (IL-1β、IL-6) and hedgehog signaling pathway were verified by animal experiments.There were 137 active ingredients, 243 potential target so and 48 intersection targets with CAG in CD. 147 KEGG enrichment pathways were obtained, mainly involving JAK/STAT signaling pathway, PI3K/Akt signaling pathway, hedgehog signaling pathway, etc. The results of animal experiments showed: The content of IL-1β and IL-6 in model group was significantly increased compared with the normal group, while the mRNA and protein expressions of Shh, Ptch1 and Gli1 were also significantly decreased (P < 0.05); compared with model group, the content of IL-1β and IL-6 in the vitacoenzyme group, the CD group and the kaempferol group were significantly decreased, while the mRNA and protein expressions of Shh, Ptch1 and Gli1 were significantly increased (P < 0.05).Kaempferol, the active ingredient of CD, could reduce the levels of IL-6 and IL-1β by regulating hedgehog signaling pathway so as to play a role in the treatment of CAG. Hence this paper could provide the methodological basis and theoretical basis for further revealing the pharmacological mechanism of CD.

Gas1 Regulates Patterning of the Murine and Human Dentitions through Sonic Hedgehog

The mammalian dentition is a serially homogeneous structure that exhibits wide numerical and morphological variation among multiple different species. Patterning of the dentition is achieved through complex reiterative molecular signaling interactions that occur throughout the process of odontogenesis. The secreted signaling molecule Sonic hedgehog (Shh) plays a key role in this process, and the Shh coreceptor growth arrest-specific 1 (Gas1) is expressed in odontogenic mesenchyme and epithelium during multiple stages of tooth development. We show that mice engineered with Gas1 loss-of-function mutation have variation in number, morphology, and size of teeth within their molar dentition. Specifically, supernumerary teeth with variable morphology are present mesial to the first molar with high penetrance, while molar teeth are characterized by the presence of both additional and absent cusps, combined with reduced dimensions and exacerbated by the presence of a supernumerary tooth. We demonstrate that the supernumerary tooth in Gas1 mutant mice arises through proliferation and survival of vestigial tooth germs and that Gas1 function in cranial neural crest cells is essential for the regulation of tooth number, acting to restrict Wnt and downstream FGF signaling in odontogenic epithelium through facilitation of Shh signal transduction. Moreover, regulation of tooth number is independent of the additional Hedgehog coreceptors Cdon and Boc, which are also expressed in multiple regions of the developing tooth germ. Interestingly, further reduction of Hedgehog pathway activity in Shhtm6Amc hypomorphic mice leads to fusion of the molar field and reduced prevalence of supernumerary teeth in a Gas1 mutant background. Finally, we demonstrate defective coronal morphology and reduced coronal dimensions in the molar dentition of human subjects identified with pathogenic mutations in GAS1 and SHH/GAS1, suggesting that regulation of Hedgehog signaling through GAS1 is also essential for normal patterning of the human dentition.

LncRNA MEG3 restrained pulmonary fibrosis induced by NiO NPs via regulating hedgehog signaling pathway-mediated autophagy.

Long noncoding RNA maternally expressed gene 3 (lncRNA MEG3) was down-regulated in pulmonary fibrosis of rats induced by Nickel oxide nanoparticles (NiO NPs), while the downstream regulatory mechanisms of MEG3 remain unclear. This study aimed to investigate the relationship among MEG3, Hedgehog (Hh) signaling pathway and autophagy in pulmonary fibrosis caused by NiO NPs. The pulmonary fibrosis model in rats was constructed by intratracheal instillation of 0.015, 0.06, and 0.24 mg/kg NiO NPs twice a week for 9 weeks. Collagen deposition model was established by treating A549 cells with 25, 50, and 100 μg/mL NiO NPs for 24 h. Our results indicated that NiO NPs activated Hh pathway, down-regulated the expression of MEG3, and reduced autophagy activity in vivo and in vitro. Meanwhile, the autophagy process was promoted by Hh pathway inhibitor (CDG-0449), while the collagen formation in A549 cells was reduced by autophagy activator (Rapamycin). Furthermore, the overexpressed MEG3 inhibited the activation of Hh pathway, resulting in autophagy activity enhancement along with collagen formation reduction. In summary, lncRNA MEG3 can restrain pulmonary fibrosis induced by NiO NPs via regulating hedgehog signaling pathway-mediated autophagy, which may serve as a potential therapeutic strategy for pulmonary fibrosis.

SLITRK5 is a negative regulator of hedgehog signaling in osteoblasts

Hedgehog signaling is essential for bone formation, including functioning as a means for the growth plate to drive skeletal mineralization. However, the mechanisms regulating hedgehog signaling specifically in bone-forming osteoblasts are largely unknown. Here, we identified SLIT and NTRK-like protein-5(Slitrk5), a transmembrane protein with few identified functions, as a negative regulator of hedgehog signaling in osteoblasts. Slitrk5 is selectively expressed in osteoblasts and loss of Slitrk5 enhanced osteoblast differentiation in vitro and in vivo. Loss of SLITRK5 in vitro leads to increased hedgehog signaling and overexpression of SLITRK5 in osteoblasts inhibits the induction of targets downstream of hedgehog signaling. Mechanistically, SLITRK5 binds to hedgehog ligands via its extracellular domain and interacts with PTCH1 via its intracellular domain. SLITRK5 is present in the primary cilium, and loss of SLITRK5 enhances SMO ciliary enrichment upon SHH stimulation. Thus, SLITRK5 is a negative regulator of hedgehog signaling in osteoblasts that may be attractive as a therapeutic target to enhance bone formation.

Wdpcp regulates cellular proliferation and differentiation in the developing limb via hedgehog signaling

BackgroundMice with a loss of function mutation in Wdpcp were described previously to display severe birth defects in the developing heart, neural tube, and limb buds. Further characterization of the skeletal phenotype of Wdpcp null mice was limited by perinatal lethality.ResultsWe utilized Prx1-Cre mice to generate limb bud mesenchyme specific deletion of Wdpcp. These mice recapitulated the appendicular skeletal phenotype of the Wdpcp null mice including polydactyl and limb bud signaling defects. Examination of late stages of limb development demonstrated decreased size of cartilage anlagen, delayed calcification, and abnormal growth plates. Utilizing in vitro assays, we demonstrated that loss of Wdpcp in skeletal progenitors lead to loss of hedgehog signaling responsiveness and associated proliferative response. In vitro chondrogenesis assays showed this loss of hedgehog and proliferative response was associated with decreased expression of early chondrogenic marker N-Cadherin. E14.5 forelimbs demonstrated delayed ossification and expression of osteoblast markers Runx2 and Sp7. P0 growth plates demonstrated loss of hedgehog signaling markers and expansion of the hypertrophic zones of the growth plate. In vitro osteogenesis assays demonstrated decreased osteogenic differentiation of Wdpcp null mesenchymal progenitors in response to hedgehog stimulation.ConclusionsThese findings demonstrate how Wdpcp and associated regulation of the hedgehog signaling pathway plays an important role at multiple stages of skeletal development. Wdpcp is necessary for positive regulation of hedgehog signaling and associated proliferation is key to the initiation of chondrogenesis. At later stages, Wdpcp facilitates the robust hedgehog response necessary for chondrocyte hypertrophy and osteogenic differentiation.

Cholesterol as a Second Messenger in the Hedgehog Signaling Pathway

The Hedgehog (HH) pathway is a cell-cell communication system essential for embryonic development; loss of proper HH signaling results in birth defects and cancer. Signaling is initiated when HH ligands are received on target cells by their receptor, Patched-1 (PTCH1). This relieves the inhibitory effect of PTCH1 on the G protein-coupled receptor Smoothened (SMO), allowing the HH signal to be transmitted across the membrane. The question of how PTCH1 inhibits SMO has remained a central mystery in developmental signaling for 25 years. Prior work implicated cholesterol as an endogenous lipid regulator of SMO. However, a major conundrum is presented by the abundance of cholesterol: how can a lipid that makes up 30%-50% of the plasma membrane be used to regulate a key signaling pathway? Using a custom CRISPR library focused on genes involved in lipid regulation, we asked the more general question of which lipids regulate HH signaling in target cells. We found that Sphingomyelin (SM) levels negatively regulate HH signaling. We show that SM exerts its effect by sequestering cholesterol into complexes, altering the chemical activity (or “accessibility”) of cholesterol. This highlights a key concept in membrane biology: only the accessible pool of cholesterol is available to interact with proteins and engage in signaling reactions. Using toxin-based sensors to measure accessible and sequestered cholesterol in cells, we find that HH ligands change cholesterol accessibility selectively in the membrane of the primary cilium. Primary cilia are antenna-like organelles required for HH signaling in all vertebrates. By compartmentalizing HH signaling in cilia, cells can use accessible cholesterol to communicate between PTCH1 and SMO without interfering with overall cellular cholesterol homeostasis. Our work suggests that the second messenger that communicates the signal between PTCH1 and SMO is the accessibility of cholesterol in a membrane compartment.

Time-resolved proteomics profiling of the ciliary Hedgehog response.

The primary cilium is a signaling compartment that interprets Hedgehog signals through changes of its protein, lipid, and second messenger compositions. Here, we combine proximity labeling of cilia with quantitative mass spectrometry to unbiasedly profile the time-dependent alterations of the ciliary proteome in response to Hedgehog. This approach correctly identifies the three factors known to undergo Hedgehog-regulated ciliary redistribution and reveals two such additional proteins. First, we find that a regulatory subunit of the cAMP-dependent protein kinase (PKA) rapidly exits cilia together with the G protein-coupled receptor GPR161 in response to Hedgehog, and we propose that the GPR161/PKA module senses and amplifies cAMP signals to modulate ciliary PKA activity. Second, we identify the phosphatase Paladin as a cell type-specific regulator of Hedgehog signaling that enters primary cilia upon pathway activation. The broad applicability of quantitative ciliary proteome profiling promises a rapid characterization of ciliopathies and their underlying signaling malfunctions.

Primary Cilia as a Biomarker in Mesenchymal Stem Cells Senescence: Influencing Osteoblastic Differentiation Potency Associated with Hedgehog Signaling Regulation.

Bone tissue engineering-based therapy for bone lesions requires the expansion of seeding cells, such as autologous mesenchymal stem cells (MSCs). A major obstacle to this process is the loss of the phenotype and differentiation capacity of MSCs subjected to passage. Recent studies have suggested that primary cilia, primordial organelles that transduce multiple signals, particularly hedgehog signals, play a role in senescence. Therefore, we explored the relationships among senescence, primary cilia, and hedgehog signaling in MSCs. Ageing of MSCs by expansion in vitro was accompanied by increased cell doubling time. The osteogenic capacity of aged MSCs at passage 4 was compromised compared to that of primary cells. P4 MSCs exhibited reductions in the frequency and length of primary cilia associated with decreased intensity of Arl13b staining on cilia. Senescence also resulted in downregulation of the expression of hedgehog components and CDKN2A. Suppression of ciliogenesis reduced the gene expression of both Gli1, a key molecule in the hedgehog signaling pathway and ALP, a marker of osteoblastic differentiation. This study demonstrated that the senescence of MSCs induced the loss of osteoblastic differentiation potency and inactivated hedgehog signaling associated with attenuated ciliogenesis, indicating that primary cilia play a mediating role in and are biomarkers of MSC senescence; thus, future antisenescence strategies involving manipulation of primary cilia could be developed.

Primary cilium-mediated MSC mechanotransduction is dependent on Gpr161 regulation of hedgehog signalling.

The benefits of physical loading to skeletal mass are well known. The primary cilium has emerged as an important organelle in bone mechanobiology/mechanotransduction, particularly in mesenchymal stem/stromal cells, yet the molecular mechanisms of cilium mechanotransduction are poorly understood. In this study, we demonstrate that Gpr161 is a mechanoresponsive GPCR, that localises to the cilium, and is involved in fluid shear-induced cAMP signalling and downstream osteogenesis. This Gpr161-mediated mechanotransduction is dependent on IFT88/cilium and may act through adenylyl cyclase 6 (AC6) to regulate cAMP and MSC osteogenesis. Moreover, we demonstrate that Hh signalling is positively associated with osteogenesis and that Hh gene expression is mechanically regulated and required for loading-induced osteogenic differentiation through a mechanism that involves IFT88, Gpr161, AC6, and cAMP. Therefore, we have delineated a molecular mechanism of MSC mechanotransduction which likely occurs at the cilium, leading to MSC osteogenesis, highlighting novel mechanotherapeutic targets to enhance osteogenesis.

Regulation of Hedgehog Signaling by miRNAs and Nanoformulations: A Possible Therapeutic Solution for Colorectal Cancer

Hedgehog (Hh) signaling aberrations trigger differentiation and proliferation in colorectal cancer (CRC). However, the current approaches which inhibit this vital cellular pathway provoke some side effects. Therefore, it is necessary to look for new therapeutic options. MicroRNAs are small molecules that modulate expression of the target genes and can be utilized as a potential therapeutic option for CRC. On the other hand, nanoformulations have been implemented in the treatment of plethora of diseases. Owing to their excessive bioavailability, limited cytotoxicity and high specificity, nanoparticles may be considered as an alternative drug delivery platform for the Hh signaling mediated CRC. This article reviews the Hh signaling and its involvement in CRC with focus on miRNAs, nanoformulations as potential diagnostic/prognostic and therapeutics for CRC.

Xpo7 negatively regulates Hedgehog signaling by exporting Gli2 from the nucleus

Dynamic bidirectional transport between the nucleus and the cytoplasm is critical for the regulation of many transcription factors, whose levels inside the nucleus must be tightly controlled. Efficient shuttling across the nuclear membrane is especially crucial with regard to the Hedgehog (Hh) pathway, where the transcriptional signal depends on the fine balance between the amounts of Gli protein activator and repressor forms in the nucleus. The nuclear export machinery prevents the unchecked nuclear accumulation of Gli proteins, but the mechanistic insight into this process is limited. We show that the atypical exportin Xpo7 functions as a major nuclear export receptor that actively excludes Gli2 from the nucleus and controls the outcome of Hh signaling. We show that Xpo7 interacts with several domains of Gli2 and that this interaction is modulated by SuFu, a key negative regulator of Hh signaling. Our data pave the way for a more complete understanding of the nuclear shuttling of Gli proteins and the regulation of their transcriptional activity.

Camphor Inhibits Adipocyte Differentiation via Its Impact on SMO-dependent Regulation of Hedgehog Signaling

Camphor Inhibits Adipocyte Differentiation via Its Impact on SMO-dependent Regulation of Hedgehog Signaling

High-Fat Diet Induced Hedgehog Signaling Modifications during Chronic Kidney Damage.

Excessive consumption of dietary fats leads to the deposition of unnecessary metabolites and multiple organ damage. Lipids, important key regulators of Hedgehog signaling, are involved in triggering fibrotic chronic kidney disease. The present study encompasses the assessment of renal morphofunctional modifications and alteration of lipid metabolism influencing the changes in gene expression of hedgehog signaling pathway genes. Fifteen male Rattus norvegicus of 200 ± 25 grams weight were equally divided into three groups: control (standard rat chow), D-1 (unsaturated high-fat diet) and D-2 (saturated high-fat diet). Animals were provided with respective diets and were followed for 16 weeks. Both HFD-fed groups did not show overall body weight gain as compared to the control. While significant downregulation of hedgehog pathway genes was found in fatty diet groups. In comparison with the control group, Shh, Gli1, Gli2, and Gli3 were downregulated after the consumption of both unsaturated and saturated fatty diets. Ihh and Smo exhibit a similar downregulation in the D-1 group, but an upregulation was detected in the D-2 group. D-2 group also had an increased serum urea concentration as compared to the control (P = 0.0023). Furthermore, renal histopathology revealed tubular necrosis, glomerular edema, glomerular shrinkage, and hypocellularity. Collagen deposition in both HFD groups marks the extent of fibrosis summary figure. Extravagant intake of dietary fats impaired normal kidney functioning and morphofunctionally anomalous kidney triggers on Hh signaling in adult rats. These anomalies can be linked to an escalated risk of chronic kidney disease in adults strongly recommending the reduced uptake of fatty diets to prevent impaired metabolism and renal lipotoxicity.