Sox10 and Itgb1 interaction in enteric neural crest cell migration

Abstract

SOX10 involvement in syndromic form of Hirschsprung disease (intestinal aganglionosis, HSCR) in humans as well as developmental defects in animal models highlight the importance of this transcription factor in control of the pool of enteric progenitors and their differentiation. Here, we characterized the role of SOX10 in cell migration and its interactions with β1-integrins. To this end, we crossed the Sox10(lacZ/+) mice with the conditional Ht-PA::Cre; beta1(neo/+) and beta1(fl/fl) mice and compared the phenotype of embryos of different genotypes during enteric nervous system (ENS) development. The Sox10(lacZ/+); Ht-PA::Cre; beta1(neo/fl) double mutant embryos presented with increased intestinal aganglionosis length and more severe neuronal network disorganization compared to single mutants. These defects, detected by E11.5, are not compensated after birth, showing that a coordinated and balanced interaction between these two genes is required for normal ENS development. Use of video-microscopy revealed that defects observed result from reduced migration speed and altered directionality of enteric neural crest cells. Expression of β1-integrins upon SOX10 overexpression or in Sox10(lacZ/+) mice was also analyzed. The modulation of SOX10 expression altered β1-integrins, suggesting that SOX10 levels are critical for proper expression and function of this adhesion molecule. Together with previous studies, our results strongly indicate that SOX10 mediates ENCC adhesion and migration, and contribute to the understanding of the molecular and cellular basis of ENS defects observed both in mutant mouse models and in patients carrying SOX10 mutations.

Endothelin-3 stimulates cell adhesion and cooperates with β1-integrins during enteric nervous system ontogenesis

“…We thus observed that the β1 het guts were fully colonized whereas the β1 null guts exhibited delayed colonization (absence of TUJ1 + cells from the caecum, Fig. 5a), consistent with previous findings242838. All the β1 het ;Edn3 het guts were fully colonized and were similar to β1 neo ;Edn3 het (Fig.…”

“…We also observed disorganisation of the neuronal network with abnormal aggregates surrounded by enlarged TUJ1-free spaces along the β1 null guts, as previously described242838. This network disorganisation was greater in β1 null ;Edn3 null guts that exhibited larger TUJ1-free regions, but not in other genotypes (Fig.…”

Colonizing while migrating: how do individual enteric neural crest cells behave?

“…The molecular bases of the adhesive interactions between ENCCs are not completely understood but L1CAM and β1 integrins play roles [55-59]. Despite the strong adhesive interactions, ENCCs that are transiently solitary are frequently observed at the migratory wavefront [22].…”

Mouse models of Hirschsprung disease and other developmental disorders of the enteric nervous system: Old and new players

“…Suppression of Sox10 expression is required for neuronal differentiation to occur and complete absence of ENCCs within the digestive tract of homozygous mutants is due to early cell death of vagal crest cells before they reach the gut (Kapur, 1999; Southard-Smith et al, 1998), illustrating the critical requirement of this transcription factor for ENCC survival and differentiation. More recently, Sox10 was also shown to control cell migration (Corpening et al, 2011) by modulating cell adherence properties (Watanabe et al, 2013). In vitro studies indicate that Sox10 in concert with Pax3 regulates expression of Ret , and additional molecular studies in vitro suggest that Sox10 is capable of binding regulatory regions for Ednrb and Sox10 itself (Lang et al, 2000; Wahlbuhl et al, 2012; Zhu et al, 2004).…”