Deletion of IP3R1 by Pdgfrb-Cre in mice results in intestinal pseudo-obstruction and lethality

Autor: Siting Zhu, Kunfu Ouyang, Xi Fang, Beili Zhao, Huayuan Tang, Ju Chen, Ran Jing, Christa Trexler, Yali Li, Jie Liu, Hong Wang, Zhixiang Pan
Rok vydání: 2018
Předmět:
Oral and gastrointestinal
Potassium Chloride
Mice
chemistry.chemical_compound
0302 clinical medicine
Smooth Muscle
2.1 Biological and endogenous factors
Inositol
Aetiology
Receptor
5-Trisphosphate Receptors
Neurons
Gastroenterology
Platelet-Derived Growth Factor beta
Cell biology
Survival Rate
030220 oncology & carcinogenesis
Muscle
030211 gastroenterology & hepatology
Smooth
Intracellular
Muscle Contraction
Biotechnology
Colon
Knockout
1.1 Normal biological development and functioning
Clinical Sciences
IP3 receptor
Motility
PDGFRB
Cholinergic Agonists
Biology
Gut motility
03 medical and health sciences
Underpinning research
Animals
Gastrointestinal Transit
Myocytes
Integrases
Gastroenterology & Hepatology
Animal
Endoplasmic reticulum
Intestinal Pseudo-Obstruction
Inositol trisphosphate receptor
Inositol 1
Interstitial Cells of Cajal
chemistry
Genetically Engineered Mouse
Disease Models
Carbachol
Ca2+ release channel
Digestive Diseases
Zdroj: Journal of gastroenterology, vol 54, iss 5
ISSN: 1435-5922
0944-1174
DOI: 10.1007/s00535-018-1522-7
Popis: BackgroundInositol 1,4,5-trisphosphate receptors (IP3Rs) are a family of intracellular Ca2+ release channels located on the membrane of endoplasmic reticulum, which have been shown to play critical roles in various cellular and physiological functions. However, their function in regulating gastrointestinal (GI) tract motility in vivo remains unknown. Here, we investigated the physiological function of IP3R1 in the GI tract using genetically engineered mouse models.MethodsPdgfrb-Cre mice were bred with homozygous Itpr1 floxed (Itpr1f/f) mice to generate conditional IP3R1 knockout (pcR1KO) mice. Cell lineage tracing was used to determine where Pdgfrb-Cre-mediated gene deletion occurred in the GI tract. Isometric tension recording was used to measure the effects of IP3R1 deletion on muscle contraction.ResultsIn the mouse GI tract, Itpr1 gene deletion by Pdgfrb-Cre occurred in smooth muscle cells, enteric neurons, and interstitial cells of Cajal. pcR1KO mice developed impaired GI motility, with prolonged whole-gut transit time and abdominal distention. pcR1KO mice also exhibited lethality as early as 8weeks of age and 50% of pcR1KO mice were dead by 40weeks after birth. The frequency of spontaneous contractions in colonic circular muscles was dramatically decreased and the amplitude of spontaneous contractions was increased in pcR1KO mice. Deletion of IP3R1 in the GI tract also reduced the contractile response to the muscarinic agonist, carbachol, as well as to electrical field stimulation. However, KCl-induced contraction and expression of smooth muscle-specific contractile genes were not significantly altered in pcR1KO mice.ConclusionsHere, we provided a novel mouse model for impaired GI motility and demonstrated that IP3R1 plays a critical role in regulating physiological function of GI tract in vivo.
Databáze: OpenAIRE
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