scholarly journals A Role for the Primary Cilium in Notch Signaling and Epidermal Differentiation during Skin Development

Cell ◽  
2011 ◽  
Vol 145 (7) ◽  
pp. 1129-1141 ◽  
Author(s):  
Ellen J. Ezratty ◽  
Nicole Stokes ◽  
Sophia Chai ◽  
Alok S. Shah ◽  
Scott E. Williams ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Primary Cilium ◽  
Epidermal Differentiation ◽  
Skin Development

scholarly journals A Presenilin-2–ARF4 trafficking axis modulates Notch signaling during epidermal differentiation

2016 ◽  
Vol 214 (1) ◽  
pp. 89-101 ◽  
Author(s):  
Ellen J. Ezratty ◽  
H. Amalia Pasolli ◽  
Elaine Fuchs
Keyword(s):  
Notch Signaling ◽  
Basal Body ◽  
Primary Cilia ◽  
Small Gtpase ◽  
Epidermal Differentiation ◽  
Basal Bodies ◽  
Skin Development ◽  
Epidermal Growth ◽  
Presenilin 2 ◽  
Polarized Exocytosis

How primary cilia impact epidermal growth and differentiation during embryogenesis is poorly understood. Here, we show that during skin development, Notch signaling occurs within the ciliated, differentiating cells of the first few suprabasal epidermal layers. Moreover, both Notch signaling and cilia disappear in the upper layers, where key ciliary proteins distribute to cell–cell borders. Extending this correlation, we find that Presenilin-2 localizes to basal bodies/cilia through a conserved VxPx motif. When this motif is mutated, a GFP-tagged Presenilin-2 still localizes to intercellular borders, but basal body localization is lost. Notably, in contrast to wild type, this mutant fails to rescue epidermal differentiation defects seen upon Psen1 and 2 knockdown. Screening components implicated in ciliary targeting and polarized exocytosis, we provide evidence that the small GTPase ARF4 is required for Presenilin basal body localization, Notch signaling, and subsequent epidermal differentiation. Collectively, our findings raise the possibility that ARF4-dependent polarized exocytosis acts through the basal body–ciliary complex to spatially regulate Notch signaling during epidermal differentiation.

scholarly journals NFAT5 Controls the Integrity of Epidermis

2021 ◽  
Vol 12 ◽  
Author(s):  
Khalid Muhammad ◽  
Delicia Xavier ◽  
Stefan Klein-Hessling ◽  
Muhammad Azeem ◽  
Tabea Rauschenberger ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Osmotic Stress ◽  
External Environment ◽  
Epidermal Differentiation ◽  
Strong Increase ◽  
Skin Development ◽  
Adult Mice ◽  
Epidermal Differentiation Complex ◽  
The Poor

The skin protects the human body against dehydration and harmful challenges. Keratinocytes (KCs) are the most abundant epidermal cells, and it is anticipated that KC-mediated transport of Na+ ions creates a physiological barrier of high osmolality against the external environment. Here, we studied the role of NFAT5, a transcription factor whose activity is controlled by osmotic stress in KCs. Cultured KCs from adult mice were found to secrete more than 300 proteins, and upon NFAT5 ablation, the secretion of several matrix proteinases, including metalloproteinase-3 (Mmp3) and kallikrein-related peptidase 7 (Klk7), was markedly enhanced. An increase in Mmp3 and Klk7 RNA levels was also detected in transcriptomes of Nfat5-/- KCs, along with increases of numerous members of the ‘Epidermal Differentiation Complex’ (EDC), such as small proline-rich (Sprr) and S100 proteins. NFAT5 and Mmp3 as well as NFAT5 and Klk7 are co-expressed in the basal KCs of fetal and adult epidermis but not in basal KCs of newborn (NB) mice. The poor NFAT5 expression in NB KCs is correlated with a strong increase in Mmp3 and Klk7 expression in KCs of NB mice. These data suggests that, along with the fragile epidermis of adult Nfat5-/- mice, NFAT5 keeps in check the expression of matrix proteases in epidermis. The NFAT5-mediated control of matrix proteases in epidermis contributes to the manifold changes in skin development in embryos before and during birth, and to the integrity of epidermis in adults.

scholarly journals Transcription Factor CTIP1/ BCL11A Regulates Epidermal Differentiation and Lipid Metabolism During Skin Development

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Shan Li ◽  
Amy Teegarden ◽  
Emily M. Bauer ◽  
Jaewoo Choi ◽  
Nadia Messaddeq ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Lipid Metabolism ◽  
Epidermal Differentiation ◽  
Skin Development

scholarly journals Notch Signaling Regulates Late-Stage Epidermal Differentiation and Maintains Postnatal Hair Cycle Homeostasis

PLoS ONE ◽  
2011 ◽  
Vol 6 (1) ◽  
pp. e15842 ◽  
Author(s):  
Hsien-Yi Lin ◽  
Cheng-Heng Kao ◽  
Kurt Ming-Chao Lin ◽  
Vesa Kaartinen ◽  
Liang-Tung Yang
Keyword(s):  
Notch Signaling ◽  
Late Stage ◽  
Epidermal Differentiation ◽  
Hair Cycle

scholarly journals MODL-30. DISSECTING THE ROLE OF MULTI-CILIOGENESIS NETWORK IN CHOROID PLEXUS TUMOR

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii417-iii417
Author(s):  
Haotian Zhao ◽  
Tasneem Zahran
Keyword(s):  
Epithelial Cells ◽  
Notch Signaling ◽  
Choroid Plexus ◽  
Tumor Cells ◽  
Primary Cilium ◽  
Primary Cilia ◽  
Coiled Coil ◽  
Molecular Cytogenetics ◽  
Shh Pathway

Abstract The choroid plexus (CP) in brain ventricles consists of a fibro-vascular core encapsulated by epithelial cells that possess clusters of primary cilia on cell surface. CP tumors are rare primary brain neoplasms that most commonly occur in young children. Compared to the benign CP papilloma, choroid plexus carcinoma (CPC) is poorly understood and highly lethal with few treatments available. Molecular, cytogenetics and genomics studies uncovered complex alterations in CPC including frequent chromosomal loss and recurrent focal aberrations, whereas abnormal NOTCH signaling is observed in many CP tumors. We showed that activation of both NOTCH and Sonic Hedgehog (SHH) signaling in mice drives the formation of aggressive CP tumor. Molecular and histology analyses demonstrated that these murine CP tumors closely resemble their human counterparts, which also display aberrant SHH and NOTCH signaling, suggesting they may represent potential therapeutic avenues. Indeed, treatment with vismodegib, an FDA-approved SHH pathway inhibitor, suppresses CP tumor growth. Unlike multi-ciliated CP epithelial cells, tumor cells in these animal models are characterized by a solitary primary cilium. Though key genes of the multi-ciliogenesis circuit driven by Geminin coiled-coil domain-containing protein 1 (GEMC1) are expressed in CP epithelium, GEMC1-dependent transcriptional program is suppressed in NOTCH-driven CP tumors. Importantly, CPCs in humans consist of tumor cells with a solitary primary cilium and exhibit profound defects multi-ciliogenesis program. Together, these results indicate that a solitary primary cilium is crucial for CPC development, whereas multi-ciliogenesis circuit possesses tumor suppressive functions and may represent a novel therapeutic target in CPC.

scholarly journals A comprehensive analysis of coding and non-coding transcriptomic changes in cutaneous squamous cell carcinoma

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Kunal Das Mahapatra ◽  
Lorenzo Pasquali ◽  
Jonas Nørskov Søndergaard ◽  
Jan Lapins ◽  
István Balazs Nemeth ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Skin Lesions ◽  
Cutaneous Squamous Cell Carcinoma ◽  
Epidermal Differentiation ◽  
Differentially Expressed ◽  
Circular Rnas ◽  
Altered Level ◽  
Skin Development

AbstractCutaneous Squamous Cell Carcinoma (cSCC) is the most common and fastest-increasing cancer with metastatic potential. Long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) are novel regulators of gene expression. To identify mRNAs, lncRNAs and circRNAs, which can be involved in cSCC, RNA-seq was performed on nine cSCCs and seven healthy skin samples. Representative transcripts were validated by NanoString nCounter assays using an extended cohort, which also included samples from pre-cancerous skin lesions (actinic keratosis). 5,352 protein-coding genes, 908 lncRNAs and 55 circular RNAs were identified to be differentially expressed in cSCC. Targets of 519 transcription factors were enriched among differentially expressed genes, 105 of which displayed altered level in cSCCs, including fundamental regulators of skin development (MYC, RELA, ETS1, TP63). Pathways related to cell cycle, apoptosis, inflammation and epidermal differentiation were enriched. In addition to known oncogenic lncRNAs (PVT1, LUCAT1, CASC9), a set of skin-specific lncRNAs were were identified to be dysregulated. A global downregulation of circRNAs was observed in cSCC, and novel skin-enriched circRNAs, circ_IFFO2 and circ_POF1B, were identified and validated. In conclusion, a reference set of coding and non-coding transcripts were identified in cSCC, which may become potential therapeutic targets or biomarkers.

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