A Novel Approach to Identify Genes Related to FGID

Abstract

To investigate novel genes involved in functional gastrointestinal disorders, we disrupted a master regulator of mRNA splicing, the survival motor neuron (SMN) protein. SMN disruption leads to widespread changes in gene expression but has not been evaluated for effects in the gastrointestinal (GI) tract. Mice with a Nestin‐cre transgene were crossed to cre reporter mice to analyze expression in the enteric nervous system (ENS). Gene expression was detected in excitatory and sensory neurons, interneurons, and intraganglionic glia throughout the myenteric plexus but not muscle. Next, nestin‐cre mice were crossed to mice with a floxed Smn allele on a SMNΔ7 background (SMN2+/+;SMNΔ7+/+;SmnF7/‐) to produce Nestin‐F7 mice. In organ baths, SMN reduction disrupted colon longitudinal muscle contraction during high frequency electrical field stimulation (EFS). Muscle relaxation was consistently greater in control tissue. The addition of L‐NAME had no effect on differences between control and Nestin‐F7 responses. Tissues showed no morphological changes or cell loss. Gastric emptying and intestinal transit were significantly slower in Nestin‐F7 mice compared to controls. Nestin‐F7 mice had dry, infrequent stool that corresponded to reduced colonic motility in the bead latency test. Collectively, these data suggest that SMN reduction results in impaired GI function. Future studies will identify specific enteric cell types sensitive to SMN reduction and evaluate mRNA expression in those cells.