SOX10is abnormally expressed in aganglionic bowel of Hirschsprung's disease infants

Abstract

Background-The primary pathology of Hirschsprung's disease (HD) is a congenital absence of ganglion cells in the caudal most gut. The spastic aganglionic bowel is often innervated by a network of hypertrophied nerve fibres. Recently, mutations of SOX10 have been identified in patients with HD but only in those with Waardenburg-Shah syndrome. Aims-To understand the molecular basis for the pathogenesis of HD we intended to determine the specific cell lineages in the enteric nervous system which normally express SOX10 but are aVected in disease conditions. Methods-We studied colon biopsies from 10 non-syndromic HD patients, aged three months to four years, and 10 age matched patients without HD as normal controls. The absence of mutation in the SOX10 gene of HD patients was confirmed by DNA sequencing. Expression and cellular distribution of SOX10 in bowel segments of normal and HD infants were examined by reverse transcriptionpolymerase chain reaction and in situ hybridisation. Results-We found that in normal infants and normoganglionic bowel segments of HD patients, SOX10 was expressed in both neurones and glia of the enteric plexuses and in the nerves among the musculature in normal colon. In the aganglionic bowel segments of patients, SOX10 expression was consistently lower and was found to be associated with the hypertrophic nerve trunks in the muscle and extrinsic nerves in the serosa. Conclusion-We conclude that SOX10 is normally required postnatally in the functional maintenance of the entire enteric nervous system, including neurones and glia. In non-syndromic HD patients who do not have the SOX10 mutation, the SOX10 gene expressed in the sacral region may be involved in the pathogenesis of the abnormal nerve trunks through interaction with other factors. (Gut 2001;49:220-226)

Genome-wide association study identifies NRG1 as a susceptibility locus for Hirschsprung's disease

“…It is tempting to speculate that miss-expression of NRG1 could affect the Sox10-mediated maintenance of ENS progenitors and contribute to aganglionosis. In addition, similarly to NRG1, Sox10 is important for defining and maintaining the identity of glial cells in later development stages (43), including the mature human ENS, and abnormal Sox10 expression has been observed in the aganglionic bowel of HSCR patients (44). Whether the latter could be linked to the role proposed above for NRG1 in adult gut and whether they altogether could account for the abnormalities of the extra-cellular matrix characteristic of the aganglionic bowel needs further investigation.…”

Expression of Intermediate Filament Proteins and Neuronal Markers in the Human Fetal Gut

“…Due to the fact that PGP9.5 is also a pan-neuronal marker, strong efforts have to be undertaken to identify other stemcell markers that will be able to selectively identify neuronal stem cells, ideally at all ages. Interesting candidates such as p75, Phox2b (Young et al 1999), and SOX10 (Bondurand et al 1998;Kapur 1999;Sham et al 2001) were found in various animal models and will be tested in our human samples. …”

The importance of having your SOX on: role of SOX10† in the development of neural crest-derived melanocytes and glia

“…They encompass expression in emerging NCCs and neural crest derivatives (Figure 3; Bondurand et al, 1998;Herbarth et al, 1998;Kuhlbrodt et al, 1998a;Pusch et al, 1998;Southard-Smith et al, 1998;Kapur, 1999), including the enteric ganglia of HSCR patients (Sham et al, 2001b) and mouse embryos (Figure 3), and expression in the and Site inner ear during mouse development (Watanabe et al, 2000). The Sox10 Dom heterozygous mice show enteric aganglionosis (megacolon) and hypopigmentation phenotypes characteristic of WS-IV.…”