Immature enteric neurons in Ncx/Hox11L.1 deficient intestinal neuronal dysplasia model mice

Abstract

The Ncx/Hox11L.1 gene is required for adequate development of enteric neurons in mice and Ncx/Hox11L.1 deficient (Ncx-/-) mice are used as a model for human intestinal neuronal dysplasia (IND) because of similar histopathology (hyperganglionosis), however, some 50% of Ncx-/- mice develop megacolon with a caliber change in the proximal colon, and die when 21-35 days old. We used polysialylated neural cell adhesion molecule (PSA-NCAM) to examine the maturity of enteric neurons in Ncx-/- mice to further understand the etiology of IND. PSA-NCAM immunoreactivity was measured in specimens taken 1 cm proximal to the ileocecal valve (ileum), 1 cm distal to the ileocecal valve (proximal colon), and 1 cm proximal to the anus (distal colon) from 63 mice (Ncx-/-: n = 14, Ncx+/-: n = 30, and Ncx+/+: n = 19) on days 14 (D14), 21 (D21), and 27 or later (>D27). PSA-NCAM was positive (indicating immaturity) in proximal colon (submucosal and myenteric plexuses) from 8/14 (57%) Ncx-/- mice (2/4 on D14, 4/6 on D21, and 2/4 on >D27) and from 5/30 (17%) Ncx+/- mice (0/2 in D14, 2/13 in D21, and 3/15 in >D27). PSA-NCAM was negative (indicating maturity) in all other specimens. The incidence of PSA-NCAM positive neurons in Ncx-/- appeared to be correlated with the mortality rate seen in IND mice. Our data suggest that colonic dysmotility and pathology seen in Ncx-/- mice may be due to persistence of immature neurons in the proximal colon, which could also be the case in human IND and warrants further investigation.