New developments in goblet cell mucus secretion and function

Birchenough, George; Johansson, Malin; Gustafsson, Jenny; Bergström, Joakim H.; Hansson, Gunnar C.

doi:10.1038/mi.2015.32

Cited by 624 publications

(508 citation statements)

References 81 publications

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“…In the case of lacrimal glands, it would be expected that the [K + ] in the tears of LRRC26 KO mice would be reduced. Furthermore, in intestine and colon, given the importance of goblet and Paneth cells in maintaining the normal mucus layer and protection against bacterial infection (45,46), it might be expected that LRRC26 KO mice may manifest gastrointestinal and colon dysfunctions with appropriate triggers. We anticipate that the LRRC26 KO mice will be useful in assessing important physiological roles of secretory epithelial cells in a variety of cells.…”

Section: Discussionmentioning

confidence: 99%

Knockout of the LRRC26 subunit reveals a primary role of LRRC26-containing BK channels in secretory epithelial cells

Yang

González-Pérez

Mukaibo

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Leucine-rich-repeat-containing protein 26 (LRRC26) is the regulatory γ1 subunit of Ca 2+ -and voltage-dependent BK-type K + channels. BK channels that contain LRRC26 subunits are active near normal resting potentials even without Ca 2+ , suggesting they play unique physiological roles, likely limited to very specific cell types and cellular functions. By using Lrrc26 KO mice with a β-gal reporter, Lrrc26 promoter activity is found in secretory epithelial cells, especially acinar epithelial cells in lacrimal and salivary glands, and also goblet and Paneth cells in intestine and colon, although absent from neurons. We establish the presence of LRRC26 protein in eight secretory tissues or tissues with significant secretory epithelium and show that LRRC26 protein coassembles with the pore-forming BK α-subunit in at least three tissues: lacrimal gland, parotid gland, and colon. In lacrimal, parotid, and submandibular gland acinar cells, LRRC26 KO shifts BK gating to be like α-subunit-only BK channels. Finally, LRRC26 KO mimics the effect of SLO1/BK KO in reducing [K + ] in saliva. LRRC26-containing BK channels are competent to contribute to resting K + efflux at normal cell membrane potentials with resting cytosolic Ca 2+ concentrations and likely play a critical physiological role in supporting normal secretory function in all secretory epithelial cells.L arge-conductance, voltage-and Ca 2+ -regulated BK-type channels are widely expressed proteins, found not only in excitable cells, such as neurons, muscle, and endocrine cells, but also nonexcitable cells, including salivary (1) and lacrimal gland (2) acinar cells, and colonic crypt cells (3). Given the almost ubiquitous expression of BK channels among cells that play quite distinct physiological roles, it is particularly important to define the specific properties of BK channels in a given cell type and determine what the specific physiological role played by BK channels in a given cell may be. A hallmark of BK channels is their dual regulation by both membrane voltage and cytosolic Ca 2+ (4), both properties embedded within the tetramer of pore-forming α-subunits of each BK channel (5). However, the specific range of voltages over which a BK channel is active at a given Ca 2+ concentration is markedly dependent on the identity of regulatory subunits that can coassemble with the α-subunit in the mature channel complex. Of the two families of known BK regulatory subunits, β (6-11) and γ (12-14), an important feature of many of these subunits is the ability to shift the range of activation voltages at a given Ca 2+ . Although there is growing information about the loci of expression and functional roles of BK channels containing specific β-subunits (15), much less is known about those BK channels containing the γ1 (LRRC26, leucine-rich-repeat-containing subunit 26) subunit. However, LRRC26 is particularly fascinating because it causes the largest shift in BK gating (approximately −120 mV) of any known non-pore-forming regulatory subunit, resulting in BK channels that...

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Section: Discussionmentioning

confidence: 99%

Knockout of the LRRC26 subunit reveals a primary role of LRRC26-containing BK channels in secretory epithelial cells

Yang

González-Pérez

Mukaibo

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…In this regard, mice null for Muc2 exhibit changes in goblet cell morphology (53), and MUC2 is a CDX2 target (54). It is therefore tempting to speculate that Muc2 may be co-regulated by Cdx and SWI-SNF.…”

Section: Journal Of Biological Chemistry 3393mentioning

confidence: 99%

Cdx2 Regulates Gene Expression through Recruitment of Brg1-associated Switch-Sucrose Non-fermentable (SWI-SNF) Chromatin Remodeling Activity

Nguyen

Savory

Brooke-Bisschop

et al. 2017

Journal of Biological Chemistry

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Edited by John M. DenuThe packaging of genomic DNA into nucleosomes creates a barrier to transcription that can be relieved through ATP-dependent chromatin remodeling via complexes such as the switch-sucrose non-fermentable (SWI-SNF) chromatin remodeling complex. The SWI-SNF complex remodels chromatin via conformational or positional changes of nucleosomes, thereby altering the access of transcriptional machinery to target genes. The SWI-SNF complex has limited ability to bind to sequencespecific elements, and, therefore, its recruitment to target loci is believed to require interaction with DNA-associated transcription factors. The Cdx family of homeodomain transcript ion factors (Cdx1, Cdx2, and Cdx4) are essential for a number of developmental programs in the mouse. Cdx1 and Cdx2 also regulate intestinal homeostasis throughout life. Although a number of Cdx target genes have been identified, the basis by which Cdx members impact their transcription is poorly understood. We have found that Cdx members interact with the SWI-SNF complex and make direct contact with Brg1, a catalytic member of SWI-SNF. Both Cdx2 and Brg1 co-occupy a number of Cdx target genes, and both factors are necessary for transcriptional regulation of such targets. Finally, Cdx2 and Brg1 occupancy occurs coincident with chromatin remodeling at some of these loci. Taken together, our findings suggest that Cdx transcription factors regulate target gene expression, in part, through recruitment of Brg1-associated SWI-SNF chromatin remodeling activity.The Cdx genes are vertebrate orthologs of Drosophila caudal and encode homeodomain transcriptional factors. In the mouse, the three members of this family (Cdx1, Cdx2, and Cdx4) are co-expressed in the caudal embryo in all three germ layers commencing at mid-gastrulation and play overlapping roles in a number of developmental programs, including axial elongation, endoderm specification, and anterior-posterior vertebral patterning (1-6). Both Cdx1 and Cdx2 are also expressed in the intestinal epithelium throughout life, where they play critical roles in intestinal homeostasis (7-11) and can function as tumor suppressors (12-15). Although Cdx members play critical roles in governing gene expression during development and in the adult intestine, little is known about the mechanisms by which Cdx members regulate target gene transcription.The packaging of DNA into nucleosomes creates a barrier to transcription by obstructing access of the basal transcription machinery as well as modulating access of other transcriptional regulators to their DNA binding motifs (16 -19). Alteration of the chromatin structure by ATP-dependent remodeling complexes can alleviate these constraints, and such complexes play important roles in the transcriptional regulation of many eukaryotic genes. Such complexes include the switch-sucrose non-fermentable (SWI-SNF) 2 chromatin-remodeling complex (16, 20 -22), which remodels the chromatin structure via conformational or positional changes of nucleosomes (23,24). Because the SWI-...

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“…Goblet cells produce and secrete mucin (Fig. 2), and thereby protect the mucosa from invasion of the pathogenic bacteria [41]. However, ''depletion of goblet cells'' is a common pathologic finding in IBD [42].…”

Section: Role Of Iecs In the Pathogenesis Of Ibdmentioning

confidence: 99%

Role of epithelial cells in the pathogenesis and treatment of inflammatory bowel disease

2015

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In the past decades, continuous effort has been paid to deeply understanding the pathophysiology of inflammatory bowel diseases (IBD), such as ulcerative colitis or Crohn's disease. As the disease typically arises as chronic inflammation of the gastrointestinal mucosa, research has been focused on how such an uncontrolled, deleterious immune response may arise and persist in a certain cohort of patients. Based on those immunologic analyses, the establishment of anti-TNF-a therapy, and the following series of biologic agents achieved great success and dramatically changed the therapeutic strategy of IBD patients. However, to guarantee long-term remission of the disease, the therapeutic standard has been raised to achieve ''mucosal healing'', which requires complete repair of the gastrointestinal mucosa. Recent studies have revealed the unexpected importance of epithelial cells in the pathophysiology of IBD. The general barrier function as well as the cell lineage-specific functions have been deeply attributed to the development of chronic intestinal inflammation. Also, the groundbreaking establishment of the in vitro intestinal stem cell culture system has opened up a way of developing stem cell transplantation therapy to treat otherwise refractory ulcers that may persist in IBD patients. In this review, we would like to focus on the role of epithelial cells in the pathophysiology of IBD, and also give a perspective to the upcoming development of regenerative therapies that may become one of the therapeutic choices to achieve mucosal healing in refractory patients of IBD.

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New developments in goblet cell mucus secretion and function

Cited by 624 publications

References 81 publications

Knockout of the LRRC26 subunit reveals a primary role of LRRC26-containing BK channels in secretory epithelial cells

Knockout of the LRRC26 subunit reveals a primary role of LRRC26-containing BK channels in secretory epithelial cells

Cdx2 Regulates Gene Expression through Recruitment of Brg1-associated Switch-Sucrose Non-fermentable (SWI-SNF) Chromatin Remodeling Activity

Role of epithelial cells in the pathogenesis and treatment of inflammatory bowel disease

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