The transition from G0 to GAlert is regulated by GLI3 processing by the primary cilia
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA605180 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR11035156.fastq.gz | Fastqsanger.gz | |||
| SRR11035157.fastq.gz | Fastqsanger.gz | |||
| SRR11035158.fastq.gz | Fastqsanger.gz | |||
| SRR11035159.fastq.gz | Fastqsanger.gz | |||
| SRR11035160.fastq.gz | Fastqsanger.gz |
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Project description:Satellite stem cells are required for the growth, maintenance, and regeneration of skeletal muscle. Quiescent satellite stem cells possess a primary cilium, a structure that regulates the processing of the GLI-family of transcription factors. We find that GLI3, specifically, plays a critical role in satellite cell activation. Strikingly, primary cilia-mediated processing of GLI3, independent of canonical Hedgehog signaling, is required to maintain satellite cells in a G0 dormant state, as satellite cells lacking GLI3 enter GAlert in absence of injury. Furthermore, GLI3 depletion or inhibition of its processing stimulates symmetrical division in satellite cells and expansion of the stem cell pool. As a result, satellite cells lacking GLI3 display rapid cell-cycle entry, increased proliferation and augmented self-renewal, and markedly enhanced long-term regenerative capacity. Therefore, our results reveal an essential role for primary cilia processing of GLI3 in regulating muscle stem cell activation.
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Project description:Ectodermal appendage formation requires hedgehog (HH) signal reception, its conduction through the primary cilium and activation of Gli transcription factors (TF). How HH signalling induces cell-type-specific responses through Gli TF in stem cells (SCs) and their ciliadependence remain open questions. Here, we use conditional mouse mutants to genetically dissect the roles of Gli and cilia HH mediators in the skin epithelium. Upon Gli2 depletion, hair follicle (HF) morphogenesis is delayed whereas sebaceous gland (SG) formation is enhanced, suggesting a dual role for Gli2 during appendage formation. By controlling proliferation of SG SCs, Gli2 impacts on the number and size of individual SG lobes. Whereas ablation of Gli3 shows no detectable phenotypes, HF cell fate is blocked in Gli2/3 double knockouts. In addition, loss of cilia phenocopies the loss of Gli2 but not the Gli2/3 mutants. Our study reveals that Gli3 exerts activator and cilia-independent functions in the absence of Gli2.
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2009-05-22 | E-MEXP-2188 | biostudies-arrayexpress
Project description:The functional activation of the androgen receptor (AR) and its interplay with the aberrant Hh/Gli cascade are pivotal in the progression of castration-resistant prostate cancer (CRPC) and resistance to AR-targeted therapies. Our study unveils a novel role of the truncated form of Gli (t-Gli3) in advancing CRPC. Investigation into Gli3 regulation revealed a Smo-independent mechanism for its activation. Despite lacking a transactivation domain, t-Gli3 relies on androgen receptor variant 7 (AR-V7) for its action. Mechanistically, Gsk3β activation leads to the t-Gli3 generation, and inhibition of Gsk3β supports the accumulation of full-length Gli3 through a non-canonical mechanism. Knockdown of Gsk3β (Gsk3β KD) reduces CRPC cell proliferation, induces apoptosis via mitochondrial fragmentation, and triggers metabolomic reprogramming. Orthotropic implantation of Gsk3β KD cells in the mouse prostate results in tumor growth retardation compared to scramble control cells. RNA-seq analysis of Gsk3β KD reveals upregulation of pathways associated with apoptosis, tumor suppressor pathway, and downregulation of oncogenic pathway relative to control. Furthermore, combinational use of a Gsk3β inhibitor with anti-Smo or Gli1 significantly inhibits the growth of CRPC cells, which are resistant to individual Smo or Gli1 inhibitor targeting. Intriguingly, solely targeting Gli3 proves effective in inhibiting CRPC cell growth. Overall, our study underscores the clinical significance of Gli3, emphasizing t-Gli3, and provides novel insights into the interplay of the Gsk3β/t-Gli3/AR-V7 axis in CRPC.
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Project description:Purpose: This study seeks to determine whether GLI3 is required to recruit the SMARCC1 complex to GLI enhancers in the limb. Methods: To determine if Gli3 is required to recruit SMARCC1 to its anhancers, we performed differential chromatin binding to compare SMARCC1 binding in control and Gli3 mutants. We performed Cut&Run for SMARCC1 binding on individually genotyped E11.5 (40-43s) anterior forelimb pairs from control (Gli3+/+; 3 replicates) and Gli3 mutant (Gli3-/-; 4 replicates) embryos. Results: We found that there is no major difference in SMARCC1 binding in Gli3-mutants compared to controls.
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Project description:Aim: To determine the major protein kinase pathways altered upon serum- or LPA-induced cilia disassembly Primary cilia are dynamic structures which must disassemble for a cell to go through mitosis and re-assemble in G0 to transduce essential signals. Also, in non-cycling cells (such as renal epithelial cells), there is evidence to suggest that deregulated cilia disassembly is of critical importance, for example in instances with an excess of a cilia disassembly stimuli (such as Aurora kinase A expression and activation, a key disassembly factor) which is associated with ciliopathy phenotypes and a net loss of ciliated cells. Serum, growth factor or lysophosphatidic acid (LPA) stimulation of ciliated cells are well established experimental paradigms for the induction of cilia disassembly. The signalling network activated by these stimuli that culminates in cilia disassembly is complex and poorly understood. Studies have generally focused on a single or small group of proteins of interest to define their roles in cilia disassembly and the key pathways and kinases activated upon serum stimulation to induce cilia disassembly have not been defined. Moreover, to the best of our knowledge an unbiased analysis of the major pathways activated during cilia disassembly has not been performed. Ciliated hTERT-RPE1 cells were treated with 10% serum or 2 M LPA for 15’ or 2 h to initiate cilia disassembly + pan-class I PI3K inhibitor GDC-0941, followed by label-free phosphoproteomics.
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