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Negative control of keratinocyte differentiation by Rho/CRIK signaling coupled with up-regulation of KyoT1/2 expression

ABSTRACT: Rho GTPases integrate control of cell structure and adhesion with downstream signaling events. In keratinocytes, RhoA is activated at early times of differentiation and plays an essential function in establishment of cell-cell adhesion. We report here that, surprisingly, Rho signaling suppresses downstream gene expression events associated with differentiation. Similar inhibitory effects are exerted by a specific Rho effector, CRIK (Citron kinase), which is selectively down-modulated with differentiation, thereby allowing the normal process to occur. The suppressing function of Rho/CRIK on differentiation is associated with induction of KyoT1/2, a LIM domain protein gene implicated in integrin-mediated processes and/or Notch signaling. Like activated Rho and CRIK, elevated KyoT1/2 expression suppresses differentiation. Thus, Rho signaling exerts an unexpectedly complex role in keratinocyte differentiation, which is coupled with induction of KyoT1/2, a LIM domain protein gene with a potentially important role in control of cell self renewal. Keywords: epithelial cell differentiation | gene expression | Rho signaling | stem cell

ORGANISM(S): Mus musculus

PROVIDER: GSE3162 | GEO | 2005/08/18

SECONDARY ACCESSION(S): PRJNA92999

REPOSITORIES: GEO

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Transcription profiling of mouse primary keratinocytes expressing Rho/CRIK to study the impact of Rho signaling pathway on gene expression.

Project description:Rho GTPases integrate control of cell structure and adhesion with downstream signaling events. In keratinocytes, RhoA is activated at early times of differentiation and plays an essential function in establishment of cellcell adhesion. We report here that, surprisingly, Rho signaling suppresses downstream gene expression events associated with differentiation. Similar inhibitory effects are exerted by a specific Rho effector, CRIK (Citron kinase), which is selectively down-modulated with differentiation, thereby allowing the normal process to occur. The suppressing function of Rho/CRIK on differentiation is associated with induction of KyoT1/2, a LIM domain protein gene implicated in integrin-mediated processes and/or Notch signaling. Like activated Rho and CRIK, elevated KyoT1/2 expression suppresses differentiation. Thus, Rho signaling exerts an unexpectedly complex role in keratinocyte differentiation, which is coupled with induction of KyoT1/2, a LIM domain protein gene with a potentially important role in control of cell self renewal. Experiment Overall Design: Total RNA from primary mouse keratinocytes infected with adeno-GFP, adeno-RhoV14, or adeno-CRIK-SK for 48 h was used for biotin-labeled cRNA probe preparation and hybridization to Affymetrix U74A gene chips. cRNA probes from each condition were tested in duplicate.

2007-09-07 | E-GEOD-3162 | biostudies-arrayexpress

Isl1-Lhx3 fusion specifies motor neuron fate by inducing motor neuron genes and concomitantly suppressing the interneuron programs

Project description:Combinatorial transcription codes generate the myriad of cell types during development, and thus likely provide crucial insights into directed differentiation of stem cells to a specific cell type. The LIM-complex composed of Isl1 and Lhx3 directs the specification of spinal motor neurons (MNs) in embryos. Here, we report that Isl1-Lhx3, a LIMcomplex-mimicking fusion, induces a signature of MN transcriptome and concomitantly suppresses interneuron differentiation programs, thereby serving as a potent and specific inducer of MNs in stem cells. We show that an equimolar ratio of Isl1 and Lhx3 and the LIM-domain of Lhx3 are crucial for generating MNs without upregulating interneuron genes. These led us to design Isl1-Lhx3, which maintains the desirable 1:1 ratio of Isl1 and Lhx3 and the LIM-domain of Lhx3. Isl1-Lhx3 drives MN differentiation with high specificity and efficiency in the spinal cord and embryonic stem cells, bypassing the need for sonic hedgehog. RNA-seq analysis revealed that Isl1-Lhx3 induces the expression of a battery of MN genes that control various functional aspects of MNs, while suppressing key interneuron genes. Our studies uncover a highly efficient method for directed MN generation and MN gene networks. Our results also demonstrate a general strategy of utilizing embryonic transcription complexes for producing specific cell types from stem cells. Examine the RNA expression profiles of inducible motor neurons-embryonic stem cells (iMN-ESCs) with or without Dox treatment, with biological duplicates.

2012-02-03 | E-GEOD-35510 | biostudies-arrayexpress

Investigation of breast cancer-associated mutations in RND1 gene

Project description:We identified the Rho family GTPase Rnd1 as a candidate breast tumor suppressor by using bioinformatics analysis in conjunction with iRNA silencing. Upon silencing of Rnd1, normal mammary epithelial cells underwent a complete EMT but eventually became senescent, suggesting that they had experienced an oncogenic insult. Expression of c-Myc rescued the Rnd1-depleted cells from senescence by suppressing p27Kip and it enabled their neoplastic conversion. The resulting cells were able to grow in soft agar and to form invasive, multi-acinar structures in 3D Matrigel. Silencing of Rnd1 promoted disruption of epithelial adhesion and polarity in xenograft models. In contrast, expression of Rnd1 inhibited tumor development. Mechanistic studies revealed that Rnd1 suppresses Ras signaling and prevents the EMT by activating the Ras-GAP domain of Plexin B1. Finally, analysis of clinical samples and cancer cell lines provided evidence that gene deletion, epigenetic silencing, and missense mutations contribute to inactivate RND1 in a subset of human breast cancers. These results indicate that Rnd1 promotes epithelial adhesion and polarity and suppresses oncogenesis by restraining unscheduled activation of Ras. genomic DNA from 96 breast cancer tissues and 8 normal mammary tissues were extracted and subjected to SOLID deep sequencing for exons of the RND1 gene to identify tumor-associated mutations with the amino acid exchanges There were two separate SOLID runs (0136 and 0270), on the same 96 tumors. The pools are indicated by "A1", "A2", "B1", etc.

2014-01-01 | E-GEOD-43828 | biostudies-arrayexpress

Investigation of breast cancer-associated mutations in RND1 gene

2014-01-01 | GSE43828 | GEO

Isl1-Lhx3 fusion specifies motor neuron fate by inducing motor neuron genes and concomitantly suppressing the interneuron programs

2012-02-03 | GSE35510 | GEO

Next Generation Sequencing Facilitates Quantitative Analysis of Negative control/si-PDLIM3/si-PDLIM5/si-LMO7 Transcriptomes

Project description:The PDZ-LIM superfamily member is present in the nucleus of many cells and consists of one PDZ domain at the N-terminus and one or more LIM domains at the C-terminus. The family includes 10 genes, of which PDLIM3, PDLIM5 and LMO7 genes have been shown to promote mouse myoblast differentiation and participate in the regulation of skeletal muscle growth and development. To explore whether chicken PDLIM3, PDLIM5 and LMO7 genes have the same function, this study explored the expression of these genes in the before and after birth of chicken, and after the chicken skeletal muscle satellite cells cultured in vitro interfered with the expression of these genes. The proliferation and differentiation of satellite cells were finally analyzed by transcriptome sequencing. The molecular pathways involved in the regulation of cell proliferation and differentiation were analyzed. The main results are as follows: Transcriptome sequencing revealed that the differentially expressed genes of chicken skeletal muscle satellite cells interfering with PDLIM3 gene expression were mainly enriched in cGMP-PKG, Oxytocin, MAPK, Tight junction and other signaling pathways, and involved in cytoskeletal protein binding, actin binding, muscle tissue regeneration and development, adhesion and other functions. Transcriptome sequencing revealed that compared with the control group, the differentially expressed genes of chicken skeletal muscle satellite cells that interfered with PDLIM5 gene expression were mainly enriched in signaling pathways such as Tight junction, Oxytocin, p53, MAPK, and involved in myocyte production and muscle contraction. Muscle cell differentiation, and participate in cytoskeletal protein binding, actin cytoskeleton formation, actin and actin binding.

2020-05-30 | GSE151450 | GEO

Gene expression profiles of Lgr5-GFP high and Lgr5-GFP low cells in small intestines of Itgb7+/+ Lgr5-GFP mice and Itgb7-/- Lgr5-GFP mice

Project description:Intestinal stem cell (ISC) differentiation is regulated precisely by a niche in the crypt, where lymphocytes may interact with stem and transient amplifying (TA) cells. However, whether and how lymphocyte-stem/TA cell contact affects ISC differentiation is largely unknown. Here, we uncover a novel role of T cell-stem/TA cell contact in ISC fate decisions. We show that intestinal lymphocyte depletion results in skewed ISC differentiation in mice, which can be rescued by T cell transfer. Mechanistically, integrin αEβ7 expressed on T cells binds to E-cadherin on ISCs and TA cells, triggering E-cadherin endocytosis and the consequent Wnt and Notch signaling alterations. Blocking αEβ7—E-cadherin adhesion suppresses Wnt signaling and promotes Notch signaling in ISCs and TA cells, leading to defective ISC differentiation. Thus, αEβ7+ T cells regulate ISC differentiation at single-cell level through cell-cell contact-mediated αEβ7—E-cadherin adhesion signaling, highlighting a critical role of the T cell-stem/TA cell contact in maintaining intestinal homeostasis.

2021-09-14 | GSE133691 | GEO

mTORC1 Loss Impairs Epidermal Adhesion via Rho Kinase Activation

Project description:In this study, we use the epidermis as a model system to elucidate the cellular effects and signaling feedback sequelae of mTORC1 loss-of-function in epithelial tissue. In mice with conditional epidermal loss of mTORC1 components Rheb or Rptor, we find that mTORC1 loss-of-function unexpectedly results in a profound skin barrier defect with epidermal abrasions, blistering and early postnatal lethality, due to a thinned epidermis with decreased desmosome expression and incomplete biochemical differentiation. Impaired cell-cell adhesion in the context of mTORC1 loss-of-function is caused by constitutive activation of Rho kinase (ROCK) signaling with increased cytoskeletal tension, and inhibition or silencing of ROCK1 is sufficient to rescue keratinocyte adhesion and biochemical differentiation. mTORC1 loss-of-function results in marked feedback up-regulation of upstream TGF-β signaling, triggering ROCK activity and its downstream effects on desmosomal gene expression. These findings elucidate a novel role for mTORC1 in the regulation of epithelial barrier formation, cytoskeletal tension and cell adhesion and underscore the complexity of signaling feedback after mTORC1 inhibition

2020-04-14 | GSE102026 | GEO

CIT functions as an oncogene in ESCC

Project description:High expression of citron kinase contributes to the development of esophageal squamous cell carcinoma This study aimed to investigate the role and potential regulatory mechanism of citron kinase (CIT) in esophageal squamous cell carcinoma (ESCC).

2020-11-20 | GSE161804 | GEO

Cofactors of LIM domain (CLIM) proteins modulate Wnt signaling and regulate corneal epithelial stem cell maintenance

Project description:Cofactors of LIM domain proteins (CLIM1 and CLIM2) are widely expressed transcriptional cofactors that are recruited to gene regulatory regions by DNA-binding proteins, including LIM domain transcription factors. In the cornea, epithelial specific expression of a dominant negative (DN) CLIM under the Keratin 14 (K14) promoter causes blistering, inflammation, epithelial hyperplasia and neovascularization, followed by epithelial thinning and subsequent epidermal-like differentiation of the cornea epithelium. This phenotype resembles aspects of limbal stem cell deficiency, suggesting that CLIM proteins may be involved in regulating cornea stem cell maintenance. Consistent with this notion, the K14-DN-Clim cornea epithelium has fewer progenitor cells, and altered proliferation dynamics during epithelial development. Differentially regulated genes in DN-CLIM corneas include those in pathways crucial for stem cell maintenance and regulation of proliferation. In vivo ChIP-Seq experiments in the cornea epithelium show that CLIM associates with DNA regulatory elements containing binding sites for HLH and other non-LIM homeodomain factors, and that many genes that are highly expressed in the limbal epithelium, as well as genes with known roles in stem cell maintenance, are directly regulated by CLIM cofactors. DN-CLIM decreases the expression of Wnt inhibitors, including the direct target Wnt5a, causing increased Wnt signaling in the limbal region of DN-CLIM corneas. Together our results indicate that CLIMs regulate cornea stem cell maintenance by controlling Wnt activity and suggest the possibility that this pathway may be altered in limbal stem cell deficiency.

2016-04-28 | GSE59205 | GEO

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