Abstract
ABSTRACTCAR-like membrane protein (CLMP), an immunoglobulin cell adhesion molecule (IgCAM), has been implicated in congenital short-bowel syndrome in humans, a condition with high mortality for which there is currently no cure. We therefore studied the function of CLMP in a Clmp-deficient mouse model. Although we found that the levels of mRNAs encoding Connexin43 or Connexin45 were not or were only marginally affected, respectively, by Clmp deficiency, the absence of CLMP caused a severe reduction of both proteins in smooth muscle cells of the intestine and of Connexin43 in the ureter. Analysis of calcium signaling revealed a disordered cell-cell communication between smooth muscle cells, which in turn induced an impaired and uncoordinated motility of the intestine and the ureter. Consequently, insufficient transport of chyme and urine caused a fatal delay to thrive, a high rate of mortality, and provoked a severe hydronephrosis in CLMP knockouts. Neurotransmission and the capability of smooth muscle cells to contract in ring preparations of the intestine were not altered. Physical obstructions were not detectable and an overall normal histology in the intestine as well as in the ureter was observed, except for a slight hypertrophy of smooth muscle layers. Deletion of Clmp did not lead to a reduced length of the intestine as shown for the human CLMP gene but resulted in gut malrotations. In sum, the absence of CLMP caused functional obstructions in the intestinal tract and ureter by impaired peristaltic contractions most likely due to a lack of gap-junctional communication between smooth muscle cells.
Highlights
CLMP (CAR-like membrane protein; termed ACAM – adipocyte adhesion molecule) is a cell adhesion protein of the Ig superfamily with a widespread tissue and organ distribution in mice with a maximal expression in the brain and heart based on Northern blot data (Raschperger et al, 2004;Eguchi et al, 2005)
Clmp mRNA revealed a 4172 fold higher expression in the smooth muscle layer in comparison to villi suggesting that CLMP might exert its function in the smooth muscle layer of the intestine and not in epithelial cells of the villi (Figure 1A; Supplemental Figure S2 shows the enrichment of these tissue preparations by using cell-type specific markers in Western blotting)
In cross sections of embryonic intestine and ureter CLMP was predominantly localized in the developing smooth muscle layer as revealed by affinity purified antibodies to the extracellular domain of CLMP (Figure S3)
Summary
CLMP (CAR-like membrane protein; termed ACAM – adipocyte adhesion molecule) is a cell adhesion protein of the Ig superfamily with a widespread tissue and organ distribution in mice with a maximal expression in the brain and heart based on Northern blot data (Raschperger et al, 2004;Eguchi et al, 2005). In human patients homozygous and compound heterozygous lossof-function mutations have been characterized in the CLMP gene that correlated with congenital short-bowel syndrome (CSBS) – a rare gastrointestinal disorder for which no cure is available (OMIM 615237). These patients have a very short small intestine with a length of approximately 50 cm at birth compared to 190-280 cm in healthy humans (Van Der Werf et al, 2012;Alves et al, 2016;Hamilton et al, 1969;Gonnaud et al, 2016). Functional obstruction including a disturbed peristalsis has been discussed as the main source for a shortened intestine (Van Der Werf et al, 2015;Schalamon et al, 1999)
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