Gastrointestinal tract disorder in natriuretic peptide receptor B gene mutant mice.
Natriuretic peptide receptor B (NPR-B), which has high affinity for C-type natriuretic peptide (CNP) and synthesizes intracellular cGMP, may be involved in gastrointestinal tract (GIT) regulation. A mutant allele of the NPR-B-encoding gene (Npr2) is responsible for the phenotype of the short-limb dwarfism (SLW) mouse. Homozygosity for this autosomal-recessive gene (slw/slw) leads to dwarfism and death before weaning because of milk retention in the stomach and intestinal distention. To elucidate the relationship between CNP/NPR-B signaling and GIT function, we investigated the association between Npr2 mutation and the GIT phenotype in slw/slw mice. The pylorus and large intestine of the mutants did not respond to CNP stimulation; further, they showed pyloric lumen narrowing with randomly aligned circular muscle cells. Comparison of the cGMP and neuronal marker distribution in GIT tissues confirmed cGMP expression in neuronal tissues. An Auerbach's plexus and submucosal tissues of the mutants didn't express cGMP and expressed Ca(2+). In contrast, those of normal mice (controls) expressed both cGMP and Ca(2+). Sequencing revealed that the causative Npr2 mutation was a 7-base deletion in exon 8, resulting in a frameshift and premature termination codon appearance. Therefore, the GIT phenotype of slw/slw mice is because of a CNP/NPR-B-signaling defect caused by an Npr2 mutation. These results facilitate better understanding of the role of CNP/NPR-B signaling in GIT motility.
Sogawa
Chizuru
C
Department of Animal Genetics, Graduate School of Natural Science and Technology, Okayama University, Okayama, Japan. c-sogawa@nirs.go.jp
Abe
Asaki
A
Tsuji
Takehito
T
Koizumi
Mitsuru
M
Saga
Tsuneo
T
Kunieda
Tetsuo
T
D000818:Animals; D002118:Calcium / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004252:DNA Mutational Analysis; D005260:Female; D005767:Gastrointestinal Diseases / Q000235:genetics*; D041981:Gastrointestinal Tract / Q000033:anatomy & histology / Q000502:physiology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D009130:Muscle, Smooth / Q000502:physiology; D009154:Mutation; D020098:Natriuretic Peptide, C-Type / Q000378:metabolism; D017461:Receptors, Atrial Natriuretic Factor / Q000235:genetics* / Q000378:metabolism; D000099242:Atrial Natriuretic Factor Receptor B
D002118:Calcium; D006152:Cyclic GMP; D020098:Natriuretic Peptide, C-Type; D017461:Receptors, Atrial Natriuretic Factor; D000099242:Atrial Natriuretic Factor Receptor B