Gas1 is a receptor for sonic hedgehog to repel enteric axons

Jin, Shiying; Martinelli, David C.; Zheng, Xiaobin; Tessier‐Lavigne, Marc; Fan, Chen‐Ming

doi:10.1073/pnas.1418629112

Cited by 42 publications

(45 citation statements)

References 47 publications

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“…In Shh −/− mice, the intestine contains increased numbers of neurons that differentiate ectopically under the epithelium and project abnormal extensions into the villi (Ramalho-Santos et al, 2000; Jin et al, 2015). Deletion of Gas1, a Hh cell-surface receptor, or Gnaz, an intracellular effector for Gas1, leads to similar phenotypes, with mislocalized enteric ganglia and increased enteric neuronal numbers (Biau et al, 2013;Jin et al, 2015). Conversely, overexpression of Gli1 leads to a patchy absence of enteric ganglia in the gut (Yang et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

Sonic hedgehog controls enteric nervous system development by patterning the extracellular matrix

Nagy¹,

Barad²,

Graham³

et al. 2016

Journal of Cell Science

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The enteric nervous system (ENS) develops from neural crest cells that migrate along the intestine, differentiate into neurons and glia, and pattern into two plexuses within the gut wall. Inductive interactions between epithelium and mesenchyme regulate gut development, but the influence of these interactions on ENS development is unknown. Epithelial-mesenchymal recombinations were constructed using avian hindgut mesenchyme and nonintestinal epithelium from the bursa of Fabricius. These recombinations led to abnormally large and ectopically positioned ganglia. We hypothesized that sonic hedgehog (Shh), a secreted intestinal epithelial protein not expressed in the bursa, mediates this effect. Inhibition of Shh signaling, by addition of cyclopamine or a function-blocking antibody, resulted in large, ectopic ganglia adjacent to the epithelium. Shh overexpression, achieved in ovo using Shhencoding retrovirus and in organ culture using recombinant protein, led to intestinal aganglionosis. Shh strongly induced the expression of versican and collagen type IX, whereas cyclopamine reduced expression of these chondroitin sulfate proteoglycans that are known to be inhibitory to neural crest cell migration. Shh also inhibited enteric neural crest-derived cell (ENCC) proliferation, promoted neuronal differentiation, and reduced expression of Gdnf, a key regulator of ENS formation. Ptc1 and Ptc2 were not expressed by ENCCs, and migration of isolated ENCCs was not inhibited by Shh protein. These results suggest that epithelial-derived Shh acts indirectly on the developing ENS by regulating the composition of the intestinal microenvironment.

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Section: Discussionmentioning

confidence: 99%

Sonic hedgehog controls enteric nervous system development by patterning the extracellular matrix

Nagy¹,

Barad²,

Graham³

et al. 2016

Journal of Cell Science

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“…Recent sequencing of DNA and genome-wide association studies identified mutations in Ptc1 and Gli genes in human HSCR [170,171]. In Shh -deficient mice, ENCCs colonize the gut but develop ectopic ganglia in the subepithelial mesenchyme, increased neuronal cell numbers, and abnormal neurite projections [172,173]. Inhibiting SHH signaling using cyclopamine or function-blocking antibody resulted in similar large, ectopic ganglia adjacent to the epithelium, while SHH overexpression led to intestinal aganglionosis [148].…”

Section: Molecular and Cellular Control Of Ens Developmentmentioning

confidence: 99%

Enteric nervous system development: A crest cell’s journey from neural tube to colon

Nagy

Goldstein

2017

Seminars in Cell & Developmental Biology

178

134

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The enteric nervous system (ENS) is comprised of a network of neurons and glial cells that are responsible for coordinating many aspects of gastrointestinal (GI) function. These cells arise from the neural crest, migrate to the gut, and then continue their journey to colonize the entire length of the GI tract. Our understanding of the molecular and cellular events that regulate these processes has advanced significantly over the past several decades, in large part facilitated by the use of rodents, avians, and zebrafish as model systems to dissect the signals and pathways involved. These studies have highlighted the highly dynamic nature of ENS development and the importance of carefully balancing migration, proliferation, and differentiation of enteric neural crest-derived cells (ENCCs). Proliferation, in particular, is critically important as it drives cell density and speed of migration, both of which are important for ensuring complete colonization of the gut. However, proliferation must be tempered by differentiation among cells that have reached their final destination and are ready to send axonal extensions, connect to effector cells, and begin to produce neurotransmitters or other signals. Abnormalities in the normal processes guiding ENCC development can lead to failure of ENS formation, as occurs in Hirschsprung disease, in which the distal intestine remains aganglionic. This review summarizes our current understanding of the factors involved in early development of the ENS and discusses areas in need of further investigation.

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“…In addition, components of the Shh signaling pathway can also regulate transcription-independent cellular processes. This nontranscriptional branch of the pathway regulates axon guidance (Charron et al ., 2003; Sánchez-Camacho and Bovolenta, 2008; Jin et al ., 2015) and fibroblast migration (Bijlsma et al ., 2007, 2012). Of note, Shh-dependent chemotaxis in fibroblasts occurs even in cells completely lacking cilia, suggesting that nontranscriptional Shh signaling is cilia-independent (Bijlsma et al ., 2012).…”

Section: Introductionmentioning

confidence: 99%