GRHL2 coordinates regeneration of a polarized mucociliary epithelium from basal stem cells

Gao, Xia; Bali, Aman; Randell, Scott H.; Hogan, Brigid L.M.

doi:10.1083/jcb.201506014

Cited by 93 publications

(72 citation statements)

References 51 publications

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“…26,27 In addition to the adult kidney, Grhl2 is expressed in embryonic epithelia, such as the surface ectoderm, gut tube, nephric ducts, and ureteric buds of the developing kidneys [25][26][27][28] ; adult lung epithelia 29,30 ; and placental trophoblast epithelia. 31 The widespread expression of Grhl2 in barrier-forming epithelia and its function as a transcriptional activator of barrier-associated signature genes 24,26,27,[29][30][31][32][33][34][35][36][37] make Grhl2 one key candidate regulator of epithelial barrier function.…”

mentioning

confidence: 99%

GRHL2 Is Required for Collecting Duct Epithelial Barrier Function and Renal Osmoregulation

Hinze

Ruffert

Walentin

et al. 2017

JASN

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Collecting ducts make up the distal-most tubular segments of the kidney, extending from the cortex, where they connect to the nephron proper, into the medulla, where they release urine into the renal pelvis. During water deprivation, body water preservation is ensured by the selective transepithelial reabsorption of water into the hypertonic medullary interstitium mediated by collecting ducts. The collecting duct epithelium forms tight junctions composed of barrier-enforcing claudins and exhibits a higher transepithelial resistance than other segments of the renal tubule exhibit. However, the functional relevance of this strong collecting duct epithelial barrier is unresolved. Here, we report that collecting duct-specific deletion of an epithelial transcription factor, grainyhead-like 2 (GRHL2), in mice led to reduced expression of tight junction-associated barrier components, reduced collecting duct transepithelial resistance, and defective renal medullary accumulation of sodium and other osmolytes. ,-deficient collecting duct cells displayed increased paracellular flux of sodium, chloride, and urea. Consistent with these effects, -deficient mice had diabetes insipidus, produced dilute urine, and failed to adequately concentrate their urine after water restriction, resulting in susceptibility to prerenal azotemia. These data indicate a direct functional link between collecting duct epithelial barrier characteristics, which appear to prevent leakage of interstitial osmolytes into urine, and body water homeostasis.

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confidence: 99%

GRHL2 Is Required for Collecting Duct Epithelial Barrier Function and Renal Osmoregulation

Hinze

Ruffert

Walentin

et al. 2017

JASN

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“…CRISPR‐edited knockout cell lines and animals have so far helped to validate the role of genes involved in surfactant production, epithelial cell senescence in COPD and inflammation and fibrosis in nasal and lung epithelial cells . CRISPR deletions have helped to elucidate the process of primary human basal progenitor cell differentiation to organoids and mucociliary epithelium in vitro, which could assist efforts to generate these tissue types for research purposes or future cellular therapy. CRISPR‐mediated disruptions have also been influential in the study of CF.…”

Section: Preclinical Modelling Of Respiratory Disease With Crispr/casmentioning

confidence: 99%

Applications of CRISPR systems in respiratory health: Entering a new ‘red pen’ era in genome editing

Moses

Kaur

2019

Respirology

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Respiratory diseases, such as influenza infection, acute tracheal bronchitis, pneumonia, tuberculosis, chronic obstructive pulmonary disease, asthma, lung cancer and nasopharyngeal carcinoma, continue to significantly impact human health. Diseases of the lung and respiratory tract are influenced by environmental conditions and socio-economic factors; however, many of these serious respiratory disorders are also rooted in genetic or epigenetic causes. Clustered regularly interspaced palindromic repeats (CRISPR) and CRISPRassociated (Cas) proteins, isolated from the immune system of prokaryotes, provide a tool to manipulate gene sequences and gene expression with significant implications for respiratory research. CRISPR/Cas systems allow preclinical modelling of causal factors involved in many respiratory diseases, providing new insights into their underlying mechanisms. CRISPR can also be used to screen for genes involved in respiratory processes, development and pathology, identifying novel disease drivers or drug targets. Finally, CRISPR/-Cas systems can potentially correct genetic mutations and edit epigenetic marks that contribute to respiratory disorders, providing a form of personalized medicine that could be used in conjunction with other technologies such as stem cell reprogramming and transplantation. CRISPR gene editing is a young field of research, and concerns regarding its specificity, as well as the need for efficient and safe delivery methods, need to be addressed further. However, CRISPR/Cas systems represent a significant step forward for research and therapy in respiratory health, and it is likely we will see the breakthroughs generated from this technology continue.

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“…Expression of interleukin-8 protein was significantly dampened in MUC18 -knockout AECs when stimulated with Toll-like receptor 2, 3 and 4 agonists, suggesting that MUC18 has a proinflammatory function in AECs in bacterially and virally infected lungs. Gao et al also introduced CRISPR/Cas9 targeted to Grainyhead-like 2 ( Grhl2 ) into primary human bronchial epithelial (HBE) cells by using lentiviral transduction 77. They found that the loss of Grhl2 inhibited HBE cells to differentiate into multiciliated cells, and organoid morphogenesis and reduced the mRNA level of both Notch and ciliogenesis genes, indicating that the Grhl2 plays an important role in epithelial morphogenesis and differentiation of the airway epithelium.…”

Section: Introductionmentioning

confidence: 99%

Gene editing as a promising approach for respiratory diseases

Bai

Liu

Su³

et al. 2018

J Med Genet

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Respiratory diseases, which are leading causes of mortality and morbidity in the world, are dysfunctions of the nasopharynx, the trachea, the bronchus, the lung and the pleural cavity. Symptoms of chronic respiratory diseases, such as cough, sneezing and difficulty breathing, may seriously affect the productivity, sleep quality and physical and mental well-being of patients, and patients with acute respiratory diseases may have difficulty breathing, anoxia and even life-threatening respiratory failure. Respiratory diseases are generally heterogeneous, with multifaceted causes including smoking, ageing, air pollution, infection and gene mutations. Clinically, a single pulmonary disease can exhibit more than one phenotype or coexist with multiple organ disorders. To correct abnormal function or repair injured respiratory tissues, one of the most promising techniques is to correct mutated genes by gene editing, as some gene mutations have been clearly demonstrated to be associated with genetic or heterogeneous respiratory diseases. Zinc finger nucleases (ZFN), transcription activator-like effector nucleases (TALEN) and clustered regulatory interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9) systems are three innovative gene editing technologies developed recently. In this short review, we have summarised the structure and operating principles of the ZFNs, TALENs and CRISPR/Cas9 systems and their preclinical and clinical applications in respiratory diseases.

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GRHL2 coordinates regeneration of a polarized mucociliary epithelium from basal stem cells

Abstract: Crispr/Cas9-mediated mutation of the transcription factor GRHL2 or either of its predicted downstream targets ZNF750 and SMAGP in primary human bronchial epithelial basal cells leads to defects in ciliogenesis and/or barrier function.

Cited by 93 publications

References 51 publications

GRHL2 Is Required for Collecting Duct Epithelial Barrier Function and Renal Osmoregulation

GRHL2 Is Required for Collecting Duct Epithelial Barrier Function and Renal Osmoregulation

Applications of CRISPR systems in respiratory health: Entering a new ‘red pen’ era in genome editing

Gene editing as a promising approach for respiratory diseases

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