Comparison of the kidney transcriptome of 28 days old principal cell-specific Tsc1 knockout (Tsc1f/f/Aqp2 Cre) vs wild-type (WT) mice
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE311308 | GEO | 2026/02/18
REPOSITORIES: GEO
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Project description:Tuberous sclerosis complex is a genetic disorder that affects multiple organs. In the kidney, it presents as hamartomas and cysts. The epithelium of TSC renal cysts is primarily composed of A-intercalated cells. In these studies, we compared the renal transcriptomes of 45 days old principal cell-specific Tsc1 knockout (Tsc1f/f/Aqp2 Cre; Tsc1 KO) and WT mice.
2026-02-18 | GSE311309 | GEO
Project description:Tuberous sclerosis complex is a genetic disorder that affects multiple organs. In the kidney, it presents as hamartomas and cysts. The epithelium of TSC renal cysts is primarily composed of A-intercalated cells. The transcription factor FOXI1 is indispensable in the development of intercalated cells. The expression of Foxi1 mRNA is significantly upregulated in the kidneys of various mouse models of TSC. The simultaneous ablation of Tsc1 and Foxi1 prevents the formation of cysts in the kidneys of Tsc1 KO mice. In these studies, we compared the renal transcriptomes of 45 days old principal cell-specific Tsc1 knockout, Tsc1/Foxi1 double knockout, and WT mice.
2026-02-18 | GSE311307 | GEO
Project description:The mechanisms that regulate T cell quiescence are poorly understood. We report that tuberous sclerosis complex 1 (Tsc1) establishes a quiescent program in naïve T cells by controlling cell size, cell cycle entry, and responses to T cell receptor stimulation. Loss of quiescence predisposed Tsc1-deficient T cells to apoptosis that depleted conventional T cells and invariant natural killer T cells. Loss of Tsc1 function dampened in vivo immune responses to bacterial infection. Tsc1-deficient T cells exhibited increased mTORC1 but diminished mTORC2 activities, with mTORC1 activation essential for the disruption of immune homeostasis. Therefore, Tsc1-dependent control of mTOR is crucial in establishing naïve T cell quiescence to facilitate adaptive immune function. Naïve CD4 and CD8 T cells from wild-type and Tsc1-deficient mice (in triplicates each group) were stimulated with or without TCR signaling. RNA was analyzed by microarrays. WT/KO for 0 and 4 hr for CD4 (triplicates), and WT/KO for 0 hr for CD8 (duplicates).
2011-07-11 | E-GEOD-29797 | biostudies-arrayexpress
Project description:Tuberous sclerosis complex (TSC) is a multisystem tumor-forming disorder caused by loss of TSC1 or TSC2. Renal manifestations predominately include cysts and angiomyolipomas. Despite a well-described monogenic etiology, the cellular pathogenesis has remained elusive. Here, we report a novel genetically-engineered human renal organoid model which recapitulates pleiotropic features of TSC kidney disease in vitro and upon orthotopic xenotransplantation. We find that loss of TSC1/2 affects multiple developmental processes in the renal epithelial, stromal, and glial compartments. First, loss of TSC1/2 leads to an expanded stroma by favouring stromal cell fate acquisition and alters terminal stromal cell identity. Second, epithelial cells in the TSC1/2-/- organoids exhibit a rapamycin-insensitive epithelial-to-mesenchymal transition. Third, a melanocytic population forms exclusively in TSC1/2-/- organoids, branching from MITF+ Schwann cell precursors of a bona fide neural crest-to-Schwann cell differentiation trajectory. Together, these results illustrate the pleiotropic developmental consequences of biallelic inactivation of TSC1/2 and offer insight into the pathogenesis of TSC kidney lesions.
2022-07-05 | GSE182632 | GEO
Project description:Memory CD8+ T cells are an essential component of protective immunity. Signaling via mechanistic target of rapamycin (mTOR) has been implicated in the regulation of the differentiation of effector and memory T cells. However, little is understood about the mechanisms that control mTOR activity, or the effector pathways regulated by mTOR, in this process. We describe here that tuberous sclerosis 1 (Tsc1), a regulator of mTOR signaling, plays a crucial role in promoting the differentiation and function of memory CD8+ T cells in response to Listeria monocytogenes infection. Mice with specific deletion of Tsc1 in antigen-experienced CD8+ T cells evoked normal effector responses, but were markedly impaired in the generation of memory T cells and their recall responses to antigen re-exposure in a cell-intrinsic manner. Tsc1 deficiency suppressed the generation of memory-precursor effector cells (MPECs) while promoting short-lived effector cell (SLEC) differentiation. Functional genomic analysis indicated that Tsc1 coordinated gene expression programs underlying immune function, transcriptional regulation and cell metabolism. Furthermore, Tsc1 deletion led to excessive mTORC1 activity and dysregulated cellular metabolism including glycolytic and oxidative metabolism. These findings establish a Tsc1-mediated checkpoint in linking immune signaling and cell metabolism to orchestrate memory CD8+ T cell development and function. We used microarrays to explore the gene expression profiles differentially expressed in OVA-specific CD8+ T-cells from wild-type (WT; Tsc1-fl/fl and cre-negative) and Tsc1-/- (Tsc1-fl/fl and Granzyme B-cre-positive) mice
2014-09-20 | E-GEOD-61591 | biostudies-arrayexpress
Project description:The tuberous sclerosis complex (TSC) family of tumor suppressors, TSC1 and TSC2, function together in an evolutionarily conserved protein complex that is a point of convergence for major cell signaling pathways that regulate mTOR complex 1 (mTORC1). Mutation or aberrant inhibition of the TSC complex is common in various human tumor syndromes and cancers. The discovery of novel therapeutic strategies to selectively target cells with functional loss of this complex is therefore of substantial clinical relevance to TSC and sporadic cancers. We developed a CRISPR-based method to generate homogenous mutant Drosophila cell lines. By combining TSC1 and TSC2 mutant cell lines with RNAi screens against all kinases and phosphatases, we identified synthetic interactions with TSC1 and TSC2. Knockdown of three candidate genes (mRNA-cap, Pitslre and CycT; orthologs of RNGTT, CDK11 and CCNT1 in humans) reduced the population growth rate of both Drosophila TSC1 and TSC2 mutant cells but not that of wild-type cells. Moreover, knockdown of all three genes displayed similar selective effects in mammalian TSC2-deficient cell lines, including human tumor-derived cells, illustrating the power of this cross species screening strategy to identify potential drug targets.
2018-10-24 | PXD002670 | Pride
Project description:Water homeostasis is regulated by the peptide hormone arginine vasopressin (AVP), which promotes water reabsorption in the renal collecting duct. The regulation of Aqp2 gene transcription is a key mechanism through which AVP modulates water transport as disruption of this mechanism leads to water balance disorders. Therefore, an important goal is to understand the regulatory processes that control Aqp2 gene transcription. While CREB (CREB1) has been proposed as the primary transcription factor responsible for Aqp2 transcription, recent evidence challenges this view, suggesting that other CREB-like transcription factors, including ATF1 and CREM, may play a role. We employed the CRISPR/Cas9 gene-editing system to delete Atf1, Creb1, and Crem in mpkCCD cells, an immortalized collecting duct cell line. These cell lines were then exposed to the vasopressin analog dDAVP to assess the role of these transcription factors in regulating Aqp2 expression. Deletion of all three transcription factors (ATF1, CREB1, and CREM) led to a significant reduction in the vasopressin-induced upregulation of AQP2 protein, confirming their role in regulating Aqp2 expression. Rescue experiments in triple knockout cells showed that expressing any of the three transcription factors restored the response to vasopressin. RNA-seq data showed that Aqp2 mRNA levels mirrored changes in protein abundance, supporting the idea that these transcription factors affect Aqp2 transcription. Our findings demonstrate that ATF1, CREB1, and CREM have redundant roles in regulating Aqp2 transcription. Our results suggest that these transcription factors might regulate the expression of other unidentified transcription factors involved in Aqp2 regulation.
2025-06-25 | GSE291084 | GEO
Project description:The mechanisms that regulate T cell quiescence are poorly understood. We report that tuberous sclerosis complex 1 (Tsc1) establishes a quiescent program in naïve T cells by controlling cell size, cell cycle entry, and responses to T cell receptor stimulation. Loss of quiescence predisposed Tsc1-deficient T cells to apoptosis that depleted conventional T cells and invariant natural killer T cells. Loss of Tsc1 function dampened in vivo immune responses to bacterial infection. Tsc1-deficient T cells exhibited increased mTORC1 but diminished mTORC2 activities, with mTORC1 activation essential for the disruption of immune homeostasis. Therefore, Tsc1-dependent control of mTOR is crucial in establishing naïve T cell quiescence to facilitate adaptive immune function.
2011-07-12 | GSE29797 | GEO
Project description:Chronic kidney disease is the main cause of mortality in patients with tuberous sclerosis complex disease (TSC). The mechanisms underlying TSC cystic kidney disease remain unclear with no available interventions to prevent cyst formation. Using targeted deletion of TSC1 in nephron progenitor cells, we showed that cysts in TSC1 null embryonic kidneys originate from injured proximal tubular cells with high mTOR complex 1 activity. Injection of rapamycin to pregnant mice inhibited the mTOR pathway and tubular cell proliferation in kidneys of TSC1 null offspring. Rapamycin also prevented renal cystogenesis and prolonged the life span of TSC newborns. Gene expression analysis of proximal tubule cells, identified sets of genes and pathways that were modified secondary to TSC1 deletion and rescued by rapamycin administration during nephrogenesis. Inflammation with mononuclear infiltration was observed in the cystic areas of TSC1 null kidneys. Dexamethasone administration during pregnancy decreased cyst formation not only by inhibiting the inflammatory response but also by interfering with the mTORC1 pathway. These results reveal novel mechanisms of cystogenesis in TSC disease and suggest new interventions prior to birth to ameliorate cystic disease in offspring.
2020-06-10 | GSE152165 | GEO
Project description:Tuberous sclerosis complex (TSC) is a relatively common autosomal dominant disorder characterized by multiple dysplastic organ lesions and neuropsychiatric symptoms, caused by loss-of-function mutation of either TSC1 or TSC2. Target-capture full-length double-stranded cDNA sequencing using long-read sequencer Nanopore (Nanopore Long-read Target Sequencing) revealed that the various kinds of the TSC1 and TSC2 full-length transcripts and the novel intron retention transcripts of TSC2 in TSC patient. Our results indicate that the Nanopore Long-read Target Sequencing is useful for the detection of mutations and confers information on the full-length alternative splicing transcripts for the genetic diagnosis.
2023-09-04 | GSE241410 | GEO