Sox10 haploinsufficiency affects maintenance of progenitor cells in a mouse model of Hirschsprung disease

Abstract

Hirschsprung disease, or congenital megacolon, is characterized by aganglionosis of the terminal bowel, which leads to intestinal obstruction and chronic constipation. Several genes involved in the disease have been identified. In particular, haploinsufficiency of SOX10, which encodes a transcription factor, results in megacolon, often in combination with other disorders. Although Hirschsprung disease has been recognized as a neurocristopathy, the cellular mechanisms that lead to aganglionosis in affected individuals are unclear. Failure of mutant enteric progenitor cells to migrate into the gut, to survive, or to differentiate into appropriate cell types at the appropriate time and in correct numbers might contribute to the disease phenotype. In the present study, we use mice with a targeted deletion of Sox10 to study the etiology of Hirschsprung disease. We demonstrate that neural crest-derived enteric progenitors that are heterozygous for the Sox10 mutation colonize the proximal intestine and are unaffected in their survival capacity. However, unlike their wild-type counterparts, mutant enteric neural crest-derived cells are unable to maintain their progenitor state and acquire preneuronal traits, which results in a reduction of the progenitor pool size. Thus, the cells that normally colonize the hindgut are depleted in the Sox10 mutant, causing the distal bowel to become aganglionic.

Distant regulatory elements in a Sox10‐βGEO BAC transgene are required for expression of Sox10 in the enteric nervous system and other neural crest‐derived tissues

“…LacZ-KO/ϩ line is haploinsufficient for Sox10 and, thus, exhibits multiple deficiencies of neural crest migration and differentiation (Britsch et al, 2001;SonnenbergRiethmacher et al, 2001;Paratore et al, 2002). This finding is clearly evident in Sox10…”

Transforming Growth Factor β-Mediated Sox10 Suppression Controls Mesenchymal Progenitor Generation in Neural Crest Stem Cells

“…Hence, loss of Sox10 might represent the cardinal event in the generation of a NC-derived mesenchymal progenitor cells. To test this postulate, we prepared trunk NC explants from control embryos and from embryos carrying a targeted deletion of Sox10 (Sox10 À/À embryos) [14,32]. The cells were cultured in CM without prior TGFb1 priming and immunostained for collagen II.…”

“…6A, 6B). As Sox10 þ/À NC cells display haploinsufficiency [14,32], we quantified the number of Collagen II- positive colonies in control, Sox10 þ/À and Sox10 À/À explants cultured in CM without prior TGFb1 priming. The graph (Fig.…”

XenopusId3 is required downstream of Myc for the formation of multipotent neural crest progenitor cells

“…Indeed, a closely related and at least partially redundant factor, Snail, continues to be expressed by neural crest precursors throughout their migration. In order to further explore the significance of the observed Id3-mediated failure to downregulate Slug, we examined the effects of Id3 activity on the expression of Sox10, a factor implicated in the regulation neural crest stem cell maintenance (Paratore et al, 2002;Kim et al, 2003). This HMG-family transcription factor is initially expressed in all multipotent neural crest stem cells (Fig.…”