Reelin expression is up-regulated in mice colon in response to acute colitis and provides resistance against colitis

Abstract

Reelin is an extracellular matrix protein first known for its key role in neuronal migration. Studies in rodent small intestine suggested that reelin protects the organism from intestinal pathology. Here we determined in mice colon, by real time-PCR and immunological assays, the expression of the reelin signalling system; its response to dextran sulphate sodium (DSS) and the response of wild-type and reeler mice to DSS-treatment. DNA methylation was determined by bisulfite modification and sequencing of genomic DNA. In the colon mucosa reelin expression is restricted to the myofibroblasts, whereas both epithelial cells and myofibroblasts express reelin receptors (ApoER2 and VLDLR) and its effector protein Dab1. The muscle layer also expresses reelin. DSS-treatment reduces reelin expression in the muscle but it is activated in the mucosa. Activation of mucosal reelin is greater in magnitude and is delayed until after the activation of the myofibroblasts marker, α-SMA. This indicates that the DSS-induced reelin up-regulation results from changes in the reelin gene expression rather than from myofibroblasts proliferation. DSS-treatment does not modify Sp1 or Tbr1 mRNA abundance, but increases that of TGF-β1 and ApoER2, decreases that of CASK and DNMT1 and it also decreases the reelin promoter methylation. Finally, the reeler mice exhibit higher inflammatory scores than wild-type mice, indicating that the mutation increases the susceptibility to DSS-colitis. In summary, this data are the first to demonstrate that mouse distal colon increases reelin production in response to DSS-colitis via a DNMT1-dependent hypo-methylation of the gene promoter region and that reelin provides protection against colitis.

Decreased generation of C‐terminal fragments of ApoER2 and increased reelin expression in Alzheimer's disease

“…Nevertheless, a relation between high expression of reelin and hypomethylation of the RELN promoter region in myeloma cell lines as well as in patients with cancer has been reported (60). Similarly, up-regulation of reelin expression in mouse colon in response to acute colitis has been associated with a decrease in DNMT1 and in RELN promoter methylation (61).…”

Calcium/Calmodulin-dependent Serine Protein Kinase-associated Neuro-gastrointestinal Disorder: First Report of a Patient With Hirschsprung‘s Disease

“…7,8 A few studies have reported dysfunction of CASK with esophageal carcinoma and colitis. 2,3 This patient presented with refractory constipation with abdominal distension at onset, followed by neurological manifestations and displayed HD and PCH with CASK mutation. The CASK loss-of-function mutation led to the decreased expression of protein 4.1, which affected microfilament contraction and cell differentiation, leading to cytoskeletal abnormalities in the axons of the ganglion cells in the distal bowel and central nervous system; smooth muscle dysfunction, further contributed to these presentations.…”

“…Although Hirschsprung’s disease (HD) is the most common congenital malformation of the enteric nervous system in children, its genetic etiology remains unclear. 1 Calcium/calmodulin-dependent serine protein kinase (CASK) is associated with digestive diseases, including cancer and proctitis; 2 , 3 however, CASK mutations have not been shown to cause HD. We report a case involving a male child with CASK mutation and HD, demonstrating the disease’s typical neurological manifestations.…”

Proper E‐cadherin membrane location in colon requires Dab2 and it modifies by inflammation and cancer

“…Following sacrifice, the colon was removed, washed with ice‐cold saline solution and fixed by overnight incubation with phosphate buffer saline (PBS; in mM, 137 NaCl, 2.7 KCl, 10 Na 2 HPO 4 , and 1.8 KH 2 PO 4 ; pH7.4) containing 4% paraformaldehyde for histological analysis. The progression of the colon inflammation was assessed by determining disease activity index (DAI), histological score and by the messenger RNA levels of the proinflammatory cytokines IL‐1β and TNF‐α, as described (Carvajal et al, 2017). For DAI evaluation, daily, throughout the DSS‐treatment, animals were monitored for weight loss, stool consistency and blood in the feces (scale of 0–3).…”