title: Smoothelin-a is essential for functional intestinal smooth muscle contractility in mice.
abstract: OBJECTIVE
  In patients with chronic intestinal pseudo-obstruction, intestinal motility is disturbed by either nervous or myogenic aberrations. The cause of the myogenic form is unknown, but it is likely to originate in the contractile apparatus of the smooth muscle cells. Smoothelins are actin-binding proteins that are expressed abundantly in visceral (smoothelin-A) and vascular (smoothelin-B) smooth muscle. Experimental data indicate a role for smoothelins in smooth muscle contraction. A smoothelin-deficient mouse model may help to establish the role of smoothelin-A in intestinal contraction and provide a model for myogenic chronic intestinal pseudo-obstruction.
  
  
  METHODS
  We used gene targeting to investigate the function of smoothelin-A in intestinal tissues. By deletion of exons 18, 19, and 20 from the smoothelin gene, the expression of both smoothelin isoforms was disrupted. The effects of the deficiency were evaluated by pathologic and physiologic analyses.
  
  
  RESULTS
  In smoothelin-A/B knockout mice, the intestine was fragile and less flexible compared with wild-type littermates. The circular and longitudinal muscle layers of the intestine were hypertrophic. Deficiency of smoothelin-A led to irregular slow wave patterns and impaired contraction of intestinal smooth muscle, leading to hampered transport in vivo. This caused obstructions that provoked intestinal diverticulosis and occasionally intestinal rupture.
  
  
  CONCLUSIONS
  Smoothelin-A is essential for functional contractility of intestinal smooth muscle. Hampered intestinal transit in smoothelin-A/B knockout mice causes obstruction, starvation, and, ultimately, premature death. The pathology of mice lacking smoothelin-A is reminiscent of that seen in patients with chronic intestinal pseudo-obstruction.
authors.affiliation: Department of Genetics and Cell Biology, Cardiovascular Institute Maastricht, University of Maastricht, Maastricht, The Netherlands.
authors.forename: Petra
authors.initials: P
authors.lastname: Niessen
authors.forename: Sander
authors.initials: S
authors.lastname: Rensen
authors.forename: Jan
authors.initials: J
authors.lastname: van Deursen
authors.forename: Joris
authors.initials: J
authors.lastname: De Man
authors.forename: Ann
authors.initials: A
authors.lastname: De Laet
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Vanderwinden
authors.forename: Thilo
authors.initials: T
authors.lastname: Wedel
authors.forename: Darren
authors.initials: D
authors.lastname: Baker
authors.forename: Pieter
authors.initials: P
authors.lastname: Doevendans
authors.forename: Marten
authors.initials: M
authors.lastname: Hofker
authors.forename: Marion
authors.initials: M
authors.lastname: Gijbels
authors.forename: Guillaume
authors.initials: G
authors.lastname: van Eys
mesh_terms: D000818:Animals; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004195:Disease Models, Animal; D004240:Diverticulum / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D005260:Female; D015870:Gene Expression; D007150:Immunohistochemistry; D007418:Intestinal Pseudo-Obstruction / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D007422:Intestines / Q000473:pathology / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009119:Muscle Contraction / Q000502:physiology*; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D009130:Muscle, Smooth / Q000473:pathology / Q000502:physiology*; D010641:Phenotype; D011247:Pregnancy
chemical_list: D003598:Cytoskeletal Proteins; D009124:Muscle Proteins; C491050:Smtn protein, mouse