Loss of Lsc/p115 protein leads to neuronal hypoplasia in the esophagus and an achalasia-like phenotype in mice

• Published in: Gastroenterology (New York, N.Y. 1943) Vol. 139; no. 4; p. 1344
• Main Authors: Zizer, Eugen, Beilke, Sven, Bäuerle, Tobias, Schilling, Kerstin, Möhnle, Ursula, Adler, Guido, Fischer, Klaus-Dieter, Wagner, Martin
• Format: Journal Article
• Language: English
• Published: United States 01.10.2010
• Subjects: Animals; Esophageal Achalasia - etiology; Esophageal Sphincter, Lower - pathology; Esophageal Sphincter, Lower - physiology; Esophagus - innervation; Esophagus - pathology; Glial Fibrillary Acidic Protein; Guanine Nucleotide Exchange Factors - deficiency; Guanine Nucleotide Exchange Factors - genetics; Guanine Nucleotide Exchange Factors - physiology; Mice; Mice, Knockout; Nerve Growth Factor - analysis; Nerve Tissue Proteins - analysis; Neurites - pathology; Neurons - pathology; Phenotype; Proto-Oncogene Proteins - deficiency; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - physiology; Rho Guanine Nucleotide Exchange Factors
• ISSN: 1528-0012
• DOI: 10.1053/j.gastro.2010.06.041

Lsc/p115 originally was described as hematopoietic Ras homologous protein guanine exchange factor (Rho-GEF) regulating leukocyte migration, adhesion, and marginal zone B-cell homeostasis. Here we investigate the expression pattern of lsc/p115 in the gastrointestinal tract and the consequences of lsc/p115 deficiency in lsc/p115-knockout mice. The phenotype of lsc/p115-deficient mice was analyzed in vivo with small-animal computed tomography scans and esophageal manometry. The morphology and myenteric plexus were evaluated with immunohistochemistry, morphometry, Western blot analyses, and quantitative reverse-transcription polymerase chain reaction. lsc/p115 is expressed in the gastrointestinal tract, sparing the segment of the small intestine. Immunohistochemical staining detects lsc/p115 in the muscle layer and the glial fibrillary acidic protein-positive glia in the esophagus. Esophageal manometry uncovers a severe motor dysfunction in lsc/p115-deficient mice. This achalasia-like phenotype is characterized by disturbed peristalsis, hypertension of the lower esophageal sphincter, and impaired relaxation of the lower esophageal sphincter. Lsc/p115-deficient mice develop a progressive dilatation of the esophagus and decrease of the muscle layer. The muscle cell differentiation is not altered in lsc/p115-deficient mice. However, the density of inhibitory and excitatory neurons and glia cells in the myenteric plexus and the muscle layer are reduced in morphometric analyses. This reduced number of glia cells is accompanied by reduced expression of the neurotrophic nerve growth factor. lsc/p115 deficiency results in impaired neuronal innervation and in motor dysfunction recapitulating several aspects of esophageal achalasia. Reduced expression of nerve growth factor and a reduced number of glia cells most likely contribute to this phenotype.