Paracrine Hedgehog Signaling in Stomach and Intestine: New Roles for Hedgehog in Gastrointestinal Patterning

Kolterud, Åsa; Grosse, Ann S.; Zacharias, William J.; Walton, Katherine D.; Kretovich, Katherine E.; Madison, Blair B.; Waghray, Meghna; Ferris, Jennifer; Hu, Chunbo; Merchant, Juanita L.; Dlugosz, Andrzej A.; Kottmann, Andreas H.; Gumucio, Deborah L.

doi:10.1053/j.gastro.2009.05.002

Cited by 148 publications

(206 citation statements)

References 57 publications

(68 reference statements)

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“…S7). Initially, mesenchymal clusters form beneath a highly proliferative pseudostratified epithelium that is uniformly expressing Shh, Ihh, and PdgfA (9,17,43). These initial clusters are regularly spaced, as shown by our pattern analysis, although the mechanisms that determine their initial positioning and even distribution have yet to be elucidated.…”

Section: Discussionmentioning

confidence: 92%

“…At E14.0, Hh-responsive cells are scattered throughout the mesenchyme, with a greater concentration closer to the epithelial Hh signal ( Fig. 1 A and E) (17). Half a day later, still before villus emergence, distinct mesenchymal clusters appear, all of which are Ptc1 + and Gli1 + ( Fig.…”

Section: Hh-responsive Mesenchymal Clusters Form Before Villus Emergencementioning

confidence: 99%

“…X-Gal staining of sectioned tissues was performed as described previously (17). Whole-mount tissues were fixed in 4% (wt/vol) PFA for 10 min, washed in PBS and X-Gal stained as previously described (17).…”

Section: Methodsmentioning

confidence: 99%

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Hedgehog-responsive mesenchymal clusters direct patterning and emergence of intestinal villi

Walton

Kolterud

Czerwinski

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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In the adult intestine, an organized array of finger-like projections, called villi, provide an enormous epithelial surface area for absorptive function. Villi first emerge at embryonic day (E) 14.5 from a previously flat luminal surface. Here, we analyze the cell biology of villus formation and examine the role of paracrine epithelial Hedgehog (Hh) signals in this process. We find that, before villus emergence, tight clusters of Hh-responsive mesenchymal cells form just beneath the epithelium. Cluster formation is dynamic; clusters first form dorsally and anteriorly and spread circumferentially and posteriorly. Statistical analysis of cluster distribution reveals a patterned array; with time, new clusters form in spaces between existing clusters, promoting approximately four rounds of villus emergence by E18.5. Cells within mesenchymal clusters express Patched1 and Gli1, as well as Pdgfrα, a receptor previously shown to participate in villus development. BrdU-labeling experiments show that clusters form by migration and aggregation of Hh-responsive cells. Inhibition of Hh signaling prevents cluster formation and villus development, but does not prevent emergence of villi in areas where clusters have already formed. Conversely, increasing Hh signaling increases the size of villus clusters and results in exceptionally wide villi. We conclude that Hh signals dictate the initial aspects of the formation of each villus by controlling mesenchymal cluster aggregation and regulating cluster size.epithelial-mesenchymal cross-talk | field pattern | villus morphogenesis

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Section: Discussionmentioning

confidence: 92%

Section: Hh-responsive Mesenchymal Clusters Form Before Villus Emergencementioning

confidence: 99%

See 1 more Smart Citation

Hedgehog-responsive mesenchymal clusters direct patterning and emergence of intestinal villi

Walton

Kolterud

Czerwinski

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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143

230

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“…This alone, however, cannot definitively exclude a contribution from Shh-induced transcription. Importantly, it has been shown that the inner circular muscle, but not the myenteric plexus and outer longitudinal muscle, displays an Hh transcriptional response, as assessed using a Gli1 LacZ reporter mouse (46). We therefore propose that as the gut mesenchyme and smooth muscles expand, the maturing myenteric plexus becomes organized just outside the limit (i.e., circular muscle) of sufficient Hh levels for Gli1 activation.…”

Section: Gas1-smo-gnaz Defines a Signaling Pathway For Shh-directed Ementioning

confidence: 99%

Gas1 is a receptor for sonic hedgehog to repel enteric axons

Jin

Martinelli

Zheng

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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The myenteric plexus of the enteric nervous system controls the movement of smooth muscles in the gastrointestinal system. They extend their axons between two peripheral smooth muscle layers to form a tubular meshwork arborizing the gut wall. How a tubular axonal meshwork becomes established without invading centrally toward the gut epithelium has not been addressed. We provide evidence here that sonic hedgehog (Shh) secreted from the gut epithelium prevents central projections of enteric axons, thereby forcing their peripheral tubular distribution. Exclusion of enteric central projections by Shh requires its binding partner growth arrest specific gene 1 (Gas1) and its signaling component smoothened (Smo) in enteric neurons. Using enteric neurons differentiated from neurospheres in vitro, we show that enteric axon growth is not inhibited by Shh. Rather, when Shh is presented as a point source, enteric axons turn away from it in a Gas1-dependent manner. Of the Gαi proteins that can couple with Smo, G protein α Z (Gnaz) is found in enteric axons. Knockdown and dominant negative inhibition of Gnaz dampen the axon-repulsive response to Shh, and Gnaz mutant intestines contain centrally projected enteric axons. Together, our data uncover a previously unsuspected mechanism underlying development of centrifugal tubular organization and identify a previously unidentified effector of Shh in axon guidance.enteric neuron | axon guidance | chemorepellent | Hedgehog | Gas1

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“…Shh and Ihh expression continues to be detected throughout the adult gastrointestinal tract of both humans and rodents where it signals to the Gli-expressing mesenchyme (Kolterud et al, 2009;van den Brink et al, 2002van den Brink et al, , 2001van Dop et al, 2010). In the adult murine stomach, HH signaling is thought to be responsible for inhibiting proliferation and stimulating the differentiation of the gastric epithelium (van den Brink et al, 2002(van den Brink et al, , 2001.…”

Section: Respiratory and Gastrointestinal Systemsmentioning

confidence: 99%

Roles for Hedgehog signaling in adult organ homeostasis and repair

2014

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The hedgehog (HH) pathway is well known for its mitogenic and morphogenic functions during development, and HH signaling continues in discrete populations of cells within many adult mammalian tissues. Growing evidence indicates that HH regulates diverse quiescent stem cell populations, but the exact roles that HH signaling plays in adult organ homeostasis and regeneration remain poorly understood. Here, we review recently identified functions of HH in modulating the behavior of tissue-specific adult stem and progenitor cells during homeostasis, regeneration and disease. We conclude that HH signaling is a key factor in the regulation of adult tissue homeostasis and repair, acting via multiple different routes to regulate distinct cellular outcomes, including maintenance of plasticity, in a context-dependent manner.

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Paracrine Hedgehog Signaling in Stomach and Intestine: New Roles for Hedgehog in Gastrointestinal Patterning

Cited by 148 publications

References 57 publications

Hedgehog-responsive mesenchymal clusters direct patterning and emergence of intestinal villi

Hedgehog-responsive mesenchymal clusters direct patterning and emergence of intestinal villi

Gas1 is a receptor for sonic hedgehog to repel enteric axons

Roles for Hedgehog signaling in adult organ homeostasis and repair

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