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Avian ceca are required for hindgut enteric nervous system development by promoting enteric neural crest cell proliferation and inhibiting neuronal differentiation via non-canonical Wnt signaling

ABSTRACT: The enteric nervous system (ENS), which is derived from enteric neural crest cells (ENCCs) during gut development, represents the neuronal innervation of the gastrointestinal tract and is critical for regulating normal intestinal function. Compromised ENCC migration can lead to Hirschsprung Disease, which is characterized by an aganglionic distal bowel. We find that removal of the ceca, a paired structure present at the midgut-hindgut junction in avian intestine, leads to severe hindgut aganglionosis, suggesting that the ceca are required for ENS development. To test this, we replaced the ceca of embryonic day 6 (E6) wild-type chicks with ceca from transgenic GFP chicks. Interestingly, the entire hindgut ENS arises from the GFP+ ceca-derived ENCC population. Comparative transcriptome profiling of the cecal buds compared to the interceca region shows that the non-canonical Wnt signaling pathway is preferentially expressed within the ceca. Specifically, Wnt11 is highly expressed in the ceca, as confirmed by RNA in situ hybridization, leading us to hypothesize that cecal expression of Wnt11 is important for ENCC colonization of the hindgut. Organ cultures were prepared using E6 avian intestine, when ENCCs are migrating through the ceca, and showed that Wnt11 inhibits enteric neuronal differentiation. These results reveal an essential role for the ceca during hindgut ENS formation and highlight an important function for non-canonical Wnt signaling in regulating ENCC differentiation and thereby promoting their migration into the colon.

ORGANISM(S): Gallus gallus

PROVIDER: GSE182783 | GEO | 2021/11/01

REPOSITORIES: GEO

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Project description:Besides symptoms caused by central nervous system (CNS) lesions, the majority of patients with multiple sclerosis (MS) also exhibit gastrointestinal dysfunction that has frequently been noted, but was not directly linked to the autoimmune etiology of the disease.We studied the enteric nervous system (ENS) in a murine model of MS by histology and electron microscopy. Serum IgG against enteric neurons and enteroglia was measured by ELISA and binding to the ENS was confirmed by immunohistochemistry. Target antigens were identified by mass spectrometry. Gastrointestinal dysfunction was determined by measuring dye transit time. RNA expression profiling was conducted with small intestines of MP4-immunized and control-immunized mice. Data from the mouse model were confirmed in MS patients by immunohistochemistry of the ENS in bowel resectates. In addition, ELISA was performed on plasma samples to detect antibodies against four specific target antigens as identified in the mouse model. ENS degeneration was evident already before the onset of clinical disease in the mouse model. Pathology was predominantly antibody-mediated and caused a significant decrease in gastrointestinal transit, which was associated with severe gliosis of the ENS. Unlike the dense infiltrates that developed in the perivascular compartments of the CNS of MP4-immunized mice, the infiltrates in the ENS consisted of single cells scattered throughout the tissue. RNA expression profiling could support these results, as the expression of inflammatory markers in the small intestine was similar between MP4-immunized and HEL-immunized mice. We identified four specific target antigens derived from enteric neurons and/or enteroglia. Antibodies against all four target antigens were present in MS patients. MS patients also showed gliosis and signs of ENS degeneration in the small intestine. For the first time, this study establishes a pathomechanistic link between the well-established autoimmune attack on the CNS and the ENS in MS. The presence of ENS pathology prior to CNS degeneration introduces entirely novel ways to explain MS etiology and immunopathogenesis.

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Avian ceca are required for hindgut enteric nervous system development by promoting enteric neural crest cell proliferation and inhibiting neuronal differentiation via non-canonical Wnt signaling

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