Original Research
Mesenteric Neural Crest Cells Are the Embryological Basis of Skip Segment Hirschsprung’s Disease

https://doi.org/10.1016/j.jcmgh.2020.12.010Get rights and content
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Background & Aims

Defective rostrocaudal colonization of the gut by vagal neural crest cells (vNCCs) results in Hirschsprung's disease (HSCR), which is characterized by aganglionosis in variable lengths of the distal bowel. Skip segment Hirschsprung’s disease (SSHD), referring to a ganglionated segment within an otherwise aganglionic intestine, contradicts HSCR pathogenesis and underscores a significant gap in our understanding of the development of the enteric nervous system. Here, we aimed to identify the embryonic origin of the ganglionic segments in SSHD.

Methods

Intestinal biopsy specimens from HSCR patients were prepared via the Swiss-roll technique to search for SSHD cases. NCC migration from the neural tube to the gut was spatiotemporally traced using targeted cell lineages and gene manipulation in mice.

Results

After invading the mesentery surrounding the foregut, vNCCs separated into 2 populations: mesenteric NCCs (mNCCs) proceeded to migrate along the mesentery, whereas enteric NCCs invaded the foregut to migrate along the gut. mNCCs not only produced neurons and glia within the gut mesentery, but also continuously complemented the enteric NCC pool. Two new cases of SSHD were identified from 183 HSCR patients, and Ednrb-mutant mice, but not Ret-/- mice, showed a high incidence rate of SSHD-like phenotypes.

Conclusions

mNCCs, a subset of vNCCs that migrate into the gut via the gut mesentery to give rise to enteric neurons, could provide an embryologic explanation for SSHD. These findings lead to novel insights into the development of the enteric nervous system and the etiology of HSCR.

Keywords

Gastrointestinal Tract
Enteric Nervous System
Aganglionosis
EDN3/EDNRB Signaling Pathway

Abbreviations used in this paper

B-FABP
brain fatty acid-binding protein
CreERT
cre recombinase-mutated estrogen receptor
E
embryonic day
EDNRB
endothelin receptor type B
EDN3
endothelin 3
eNCC
enteric neural crest cell
ENS
enteric nervous system
ERBB3
human epidermal growth factor receptor 3
FLP
flippase
GDNF
glial cell-derived neurotrophic factor
GFP
green fluorescent protein
GI
gastrointestinal
HSCR
Hirschsprung’s disease
mNCC
mesenteric neural crest cell
NCC
neural crest cell
P
postnatal day
PBS
phosphate-buffered saline
PHOX2B
paired-like homeobox 2b
RET
ret proto-oncogene
SCP
Schwann cell precursor
sNCC
sacral neural crest cell
SOX10
sex determining region Y-box 10
SSHD
skip segment Hirschsprung’s disease
TCA
total colonic aganglionosis
tdTom
tandem dimer tomato
TM
tamoxifen
tmNCC
trans-mesenteric neural crest cell
TUJ1
neuron-specific class III beta-tubulin
vNCC
vagal neural crest cell
Wnt1
wingless-type MMTV integration site family member 1

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Conflicts of interest The authors disclose no conflicts.

Funding This work was supported by grants from the National Natural Science Foundation of China (82070527), the National Key R&D Program of China (2017YFA0104200), Zhejiang Provincial Natural Science Foundation of China (LY19C090005), the Fundamental Research Funds for the Central Universities (2019FZA7009), and the Chinese Ministry of Education Project 111 Program (B13026).

Authors share co-first authorship.