Claudin-1 regulates intestinal epithelial homeostasis through the modulation of Notch-signalling

Jillian L. Pope, Ajaz Ahmad Bhat, Ashok Sharma, Rizwan Ahmad, Moorthy Krishnan, Mary K. Washington, Robert D. Beauchamp, Amar B. Singh, Punita Dhawan

Research output: Contribution to journalArticle

65 Citations (Scopus)

Abstract

Objective Claudin-1 expression is increased and dysregulated in colorectal cancer and causally associates with the dedifferentiation of colonic epithelial cells, cancer progression and metastasis. Here, we have sought to determine the role claudin-1 plays in the regulation of intestinal epithelial homeostasis. Design We have used a novel villin-claudin-1 transgenic (Cl-1Tg) mouse as model (with intestinal claudin-1 overexpression). The effect of claudin-1 expression upon colonic epithelial differentiation, lineage commitment and Notch-signalling was determined using immunohistochemical, immunoblot and real-time PCR analysis. The frequently used mouse model of dextran sodium sulfate (DSS)-colitis was used to model inflammation, injury and repair. Results In Cl-1Tg mice, normal colonocyte differentiation programme was disrupted and goblet cell number and mucin-2 (muc-2) expressions were significantly downregulated while Notch- and ERK1/2-signalling were upregulated, compared with the wild type-littermates. Cl-1Tg mice were also susceptible to colonic inflammation and demonstrated impaired recovery and hyperproliferation following the DSS-colitis. Our data further show that claudin-1 regulates Notchsignalling through the regulation of matrix metalloproteinase-9 (MMP-9) and p-ERK signalling to regulate proliferation and differentiation. Conclusions Claudin-1 helps regulate intestinal epithelial homeostasis through the regulation of Notchsignalling. An upregulated claudin-1 expression induces MMP-9 and p-ERK signalling to activate Notchsignalling, which in turn inhibits the goblet cell differentiation. Decreased goblet cell number decreases muc-2 expression and thus enhances susceptibility to mucosal inflammation. Claudin-1 expression also induces colonic epithelial proliferation in a Notch-dependent manner. Our findings may help understand the role of claudin-1 in the regulation of inflammatory bowel diseases and CRC.

Original languageEnglish
Pages (from-to)622-634
Number of pages13
JournalGut
Volume63
Issue number4
DOIs
Publication statusPublished - 1 Jan 2014
Externally publishedYes

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Claudin-1
Homeostasis
Goblet Cells
Mucin-2
Transgenic Mice
Dextran Sulfate
Matrix Metalloproteinase 9
Colitis
Inflammation
Cell Count
Inflammatory Bowel Diseases

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Pope, J. L., Bhat, A. A., Sharma, A., Ahmad, R., Krishnan, M., Washington, M. K., ... Dhawan, P. (2014). Claudin-1 regulates intestinal epithelial homeostasis through the modulation of Notch-signalling. Gut, 63(4), 622-634. https://doi.org/10.1136/gutjnl-2012-304241

Claudin-1 regulates intestinal epithelial homeostasis through the modulation of Notch-signalling. / Pope, Jillian L.; Bhat, Ajaz Ahmad; Sharma, Ashok; Ahmad, Rizwan; Krishnan, Moorthy; Washington, Mary K.; Beauchamp, Robert D.; Singh, Amar B.; Dhawan, Punita.

In: Gut, Vol. 63, No. 4, 01.01.2014, p. 622-634.

Research output: Contribution to journalArticle

Pope, JL, Bhat, AA, Sharma, A, Ahmad, R, Krishnan, M, Washington, MK, Beauchamp, RD, Singh, AB & Dhawan, P 2014, 'Claudin-1 regulates intestinal epithelial homeostasis through the modulation of Notch-signalling', Gut, vol. 63, no. 4, pp. 622-634. https://doi.org/10.1136/gutjnl-2012-304241
Pope, Jillian L. ; Bhat, Ajaz Ahmad ; Sharma, Ashok ; Ahmad, Rizwan ; Krishnan, Moorthy ; Washington, Mary K. ; Beauchamp, Robert D. ; Singh, Amar B. ; Dhawan, Punita. / Claudin-1 regulates intestinal epithelial homeostasis through the modulation of Notch-signalling. In: Gut. 2014 ; Vol. 63, No. 4. pp. 622-634.
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abstract = "Objective Claudin-1 expression is increased and dysregulated in colorectal cancer and causally associates with the dedifferentiation of colonic epithelial cells, cancer progression and metastasis. Here, we have sought to determine the role claudin-1 plays in the regulation of intestinal epithelial homeostasis. Design We have used a novel villin-claudin-1 transgenic (Cl-1Tg) mouse as model (with intestinal claudin-1 overexpression). The effect of claudin-1 expression upon colonic epithelial differentiation, lineage commitment and Notch-signalling was determined using immunohistochemical, immunoblot and real-time PCR analysis. The frequently used mouse model of dextran sodium sulfate (DSS)-colitis was used to model inflammation, injury and repair. Results In Cl-1Tg mice, normal colonocyte differentiation programme was disrupted and goblet cell number and mucin-2 (muc-2) expressions were significantly downregulated while Notch- and ERK1/2-signalling were upregulated, compared with the wild type-littermates. Cl-1Tg mice were also susceptible to colonic inflammation and demonstrated impaired recovery and hyperproliferation following the DSS-colitis. Our data further show that claudin-1 regulates Notchsignalling through the regulation of matrix metalloproteinase-9 (MMP-9) and p-ERK signalling to regulate proliferation and differentiation. Conclusions Claudin-1 helps regulate intestinal epithelial homeostasis through the regulation of Notchsignalling. An upregulated claudin-1 expression induces MMP-9 and p-ERK signalling to activate Notchsignalling, which in turn inhibits the goblet cell differentiation. Decreased goblet cell number decreases muc-2 expression and thus enhances susceptibility to mucosal inflammation. Claudin-1 expression also induces colonic epithelial proliferation in a Notch-dependent manner. Our findings may help understand the role of claudin-1 in the regulation of inflammatory bowel diseases and CRC.",
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N2 - Objective Claudin-1 expression is increased and dysregulated in colorectal cancer and causally associates with the dedifferentiation of colonic epithelial cells, cancer progression and metastasis. Here, we have sought to determine the role claudin-1 plays in the regulation of intestinal epithelial homeostasis. Design We have used a novel villin-claudin-1 transgenic (Cl-1Tg) mouse as model (with intestinal claudin-1 overexpression). The effect of claudin-1 expression upon colonic epithelial differentiation, lineage commitment and Notch-signalling was determined using immunohistochemical, immunoblot and real-time PCR analysis. The frequently used mouse model of dextran sodium sulfate (DSS)-colitis was used to model inflammation, injury and repair. Results In Cl-1Tg mice, normal colonocyte differentiation programme was disrupted and goblet cell number and mucin-2 (muc-2) expressions were significantly downregulated while Notch- and ERK1/2-signalling were upregulated, compared with the wild type-littermates. Cl-1Tg mice were also susceptible to colonic inflammation and demonstrated impaired recovery and hyperproliferation following the DSS-colitis. Our data further show that claudin-1 regulates Notchsignalling through the regulation of matrix metalloproteinase-9 (MMP-9) and p-ERK signalling to regulate proliferation and differentiation. Conclusions Claudin-1 helps regulate intestinal epithelial homeostasis through the regulation of Notchsignalling. An upregulated claudin-1 expression induces MMP-9 and p-ERK signalling to activate Notchsignalling, which in turn inhibits the goblet cell differentiation. Decreased goblet cell number decreases muc-2 expression and thus enhances susceptibility to mucosal inflammation. Claudin-1 expression also induces colonic epithelial proliferation in a Notch-dependent manner. Our findings may help understand the role of claudin-1 in the regulation of inflammatory bowel diseases and CRC.

AB - Objective Claudin-1 expression is increased and dysregulated in colorectal cancer and causally associates with the dedifferentiation of colonic epithelial cells, cancer progression and metastasis. Here, we have sought to determine the role claudin-1 plays in the regulation of intestinal epithelial homeostasis. Design We have used a novel villin-claudin-1 transgenic (Cl-1Tg) mouse as model (with intestinal claudin-1 overexpression). The effect of claudin-1 expression upon colonic epithelial differentiation, lineage commitment and Notch-signalling was determined using immunohistochemical, immunoblot and real-time PCR analysis. The frequently used mouse model of dextran sodium sulfate (DSS)-colitis was used to model inflammation, injury and repair. Results In Cl-1Tg mice, normal colonocyte differentiation programme was disrupted and goblet cell number and mucin-2 (muc-2) expressions were significantly downregulated while Notch- and ERK1/2-signalling were upregulated, compared with the wild type-littermates. Cl-1Tg mice were also susceptible to colonic inflammation and demonstrated impaired recovery and hyperproliferation following the DSS-colitis. Our data further show that claudin-1 regulates Notchsignalling through the regulation of matrix metalloproteinase-9 (MMP-9) and p-ERK signalling to regulate proliferation and differentiation. Conclusions Claudin-1 helps regulate intestinal epithelial homeostasis through the regulation of Notchsignalling. An upregulated claudin-1 expression induces MMP-9 and p-ERK signalling to activate Notchsignalling, which in turn inhibits the goblet cell differentiation. Decreased goblet cell number decreases muc-2 expression and thus enhances susceptibility to mucosal inflammation. Claudin-1 expression also induces colonic epithelial proliferation in a Notch-dependent manner. Our findings may help understand the role of claudin-1 in the regulation of inflammatory bowel diseases and CRC.

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