1. Kapur RP, Ambartsumyan L, Smith C. Are we underdiagnosing Hirschsprung disease? Pediatr Devel Pathol
2020;23:60–71.
HSCR Mouse Model With a RET Missense Mutation
2023
2. Airaksinen MS, Saarma M. The GDNF family: signalling,
biological functions and therapeutic value. Nat Rev
Neurosci 2002;3:383–394.
3. Schuchardt A, D’Agati V, Larsson-Blomberg L, et al.
Defects in the kidney and enteric nervous system of mice
lacking the tyrosine kinase receptor Ret. Nature 1994;
367:380–383.
4. Amiel J, Sproat-Emison E, Garcia-Barcelo M, et al.
Hirschsprung disease, associated syndromes and genetics: a review. J Med Genet 2008;45:1–14.
5. Romeo G, Ronchetto P, Luo Y, et al. Point mutations
affecting the tyrosine kinase domain of the RET protooncogene in Hirschsprung’s disease. Nature 1994;
367:377–378.
6. Edery P, Lyonnet S, Mulligan LM, et al. Mutations of the
RET proto-oncogene in Hirschsprung’s disease. Nature
1994;367:378–380.
7. Pasini B, Borrello MG, Greco A, et al. Loss of function
effect of RET mutations causing Hirschsprung disease.
Nat Genet 1995;10:35–40.
8. Iwashita T, Kurokawa K, Qiao S, et al. Functional analysis
of RET with Hirschsprung mutations affecting its kinase
domain. Gastroenterology 2001;121:24–33.
9. Amiel J, Lyonnet S. Hirschsprung disease, associated
syndromes, and genetics: a review. J Med Genet 2001;
38:729–739.
10. Heanue TA, Pachnis V. Enteric nervous system development and Hirschsprung’s disease: advances in genetic and stem cell studies. Nat Rev Neurosci 2007;
8:466–479.
11. Nakatani T, Iwasaki M, Yamamichi A, et al. Point mutagenesis in mouse reveals contrasting pathogenetic effects between MEN2B- and Hirschsprung diseaseassociated missense mutations of the RET gene.
Development,
Growth
Differentiation
2020;
62:214–222.
12. Bolk S, Pelet A, Hofstra RM, et al. A human model for
multigenic inheritance: phenotypic expression in
Hirschsprung disease requires both the RET gene and a
new 9q31 locus. Proc Natl Acad Sci U S A 2000;
97:268–273.
13. Seri M, Yin L, Barone V, et al. Frequency of RET mutations in long- and short-segment Hirschsprung disease.
Hum Mutat 1997;9:243–249.
14. Sugimoto K, Miyazawa T, Nishi H, et al. Heterozygous
p.S811F RET gene mutation associated with renal
agenesis, oligomeganephronia and total colonic
aganglionosis: a case report. BMC Nephrol 2016;
17:146.
15. Gould TW, Yonemura S, Oppenheim RW, et al. The
neurotrophic effects of glial cell line-derived neurotrophic
factor on spinal motoneurons are restricted to fusimotor
subtypes. J Neurosci 2008;28:2131–2146.
16. Sunardi M, Ito K, Enomoto H. Live visualization of a
functional RET-EGFP chimeric receptor in homozygous
knock-in mice. Development, Growth & Differentiation
2021;63:285–294.
17. Heanue TA, Pachnis V. Ret isoform function and marker
gene expression in the enteric nervous system is
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
1523
conserved across diverse vertebrate species. Mech Dev
2008;125:687–699.
Jijiwa M, Fukuda T, Kawai K, et al. A targeting mutation
of tyrosine 1062 in Ret causes a marked decrease of
enteric neurons and renal hypoplasia. Mol Cell Biol 2004;
24:8026–8036.
Nishiyama C, Uesaka T, Manabe T, et al. Trans-mesenteric neural crest cells are the principal source of the
colonic enteric nervous system. Nat Neurosci 2012;
15:1211–1218.
Uesaka T, Nagashimada M, Yonemura S, et al. Diminished Ret expression compromises neuronal survival in
the colon and causes intestinal aganglionosis in mice.
J Clin Invest 2008;118:1890–1898.
Carrasquillo MM, McCallion AS, Puffenberger EG, et al.
Genome-wide association study and mouse model
identify interaction between RET and EDNRB pathways
in Hirschsprung disease. Nat Genet 2002;32:237–244.
Badner JA, Sieber WK, Garver KL, et al. A genetic study
of Hirschsprung disease. Am J Hum Genet 1990;
46:568–580.
Pini Prato A, Rossi V, Mosconi M, et al. A prospective
observational study of associated anomalies in Hirschsprung’s disease. Orphanet J Rare Dis 2013;8:184.
Chatterjee S, Chakravarti A. A gene regulatory network
explains RET-EDNRB epistasis in Hirschsprung disease.
Hum Mol Genet 2019;28:3137–3147.
Kapur RP. Early death of neural crest cells is responsible
for total enteric aganglionosis in Sox10(Dom)/
Sox10(Dom) mouse embryos. Pediatr Dev Pathol 1999;
2:559–569.
Shen L, Pichel JG, Mayeli T, et al. Gdnf haploinsufficiency causes Hirschsprung-like intestinal
obstruction and early-onset lethality in mice. Am J Hum
Genet 2002;70:435–447.
Bergeron KF, Cardinal T, Toure AM, et al. Male-biased
aganglionic megacolon in the TashT mouse line due to
perturbation of silencer elements in a large gene desert
of chromosome 10. PLoS Genetics 2015;11:e1005093.
Li HB, Jin XQ, Jin X, et al. BMP4 knockdown of NCSCs
leads to aganglionosis in the middle embryonic stage.
Mol Med Rep 2018;17:5423–5427.
Okamoto M, Uesaka T, Ito K, et al. Increased RET activity
coupled with a reduction in the RET gene dosage causes
intestinal aganglionosis in mice. eNeuro 2021;8.
Enomoto H, Crawford PA, Gorodinsky A, et al. RET
signaling is essential for migration, axonal growth and
axon guidance of developing sympathetic neurons.
Development 2001;128:3963–3974.
de Graaff E, Srinivas S, Kilkenny C, et al. Differential
activities of the RET tyrosine kinase receptor isoforms
during mammalian embryogenesis. Genes Dev 2001;
15:2433–2444.
Carniti C, Belluco S, Riccardi E, et al. The Ret(C620R)
mutation affects renal and enteric development in a
mouse model of Hirschsprung’s disease. Am J Pathol
2006;168:1262–1275.
Asai N, Fukuda T, Wu Z, et al. Targeted mutation of
serine 697 in the Ret tyrosine kinase causes migration
1524
34.
35.
36.
37.
38.
39.
40.
41.
42.
Sunardi et al
Cellular and Molecular Gastroenterology and Hepatology Vol. 15, Iss. 6
defect of enteric neural crest cells. Development 2006;
133:4507–4516.
Jain S, Knoten A, Hoshi M, et al. Organotypic specificity
of key RET adaptor-docking sites in the pathogenesis of
neurocristopathies and renal malformations in mice.
J Clin Invest 2010;120:778–790.
Jain S, Naughton CK, Yang M, et al. Mice expressing a
dominant-negative Ret mutation phenocopy human
Hirschsprung disease and delineate a direct role of
Ret in spermatogenesis. Development 2004;131:
5503–5513.
Soret R, Schneider S, Bernas G, et al. Glial cell-derived
neurotrophic factor induces enteric neurogenesis and
improves colon structure and function in mouse models
of Hirschsprung disease. Gastroenterology 2020;
159:1824–1838 e17.
Cosma MP, Cardone M, Carlomagno F, et al. Mutations
in the extracellular domain cause RET loss of function by
a dominant negative mechanism. Mol Cell Biol 1998;
18:3321–3329.
Amaya E, Musci TJ, Kirschner MW. Expression of a
dominant negative mutant of the FGF receptor disrupts
mesoderm formation in Xenopus embryos. Cell 1991;
66:257–270.
Dumont DJ, Gradwohl G, Fong GH, et al. Dominantnegative and targeted null mutations in the endothelial
receptor tyrosine kinase, tek, reveal a critical role in
vasculogenesis of the embryo. Genes Dev 1994;
8:1897–1909.
Vajkoczy P, Knyazev P, Kunkel A, et al. Dominantnegative inhibition of the Axl receptor tyrosine kinase
suppresses brain tumor cell growth and invasion and
prolongs survival. Proc Natl Acad Sci U S A 2006;
103:5799–5804.
Hashimoto M, Takemoto T. Electroporation enables the
efficient mRNA delivery into the mouse zygotes and facilitates CRISPR/Cas9-based genome editing. Sci Rep
2015;5:11315.
Enomoto H, Araki T, Jackman A, et al. GFR alpha1deficient mice have deficits in the enteric nervous system and kidneys. Neuron 1998;21:317–324.
43. Enomoto H, Araki T, Jackman A, et al. GFR a1-deficient
mice have deficits in the enteric nervous system and
kidneys. Neuron 1998;21:317–324.
44. Enomoto H, Hughes I, Golden J, et al. GFRalpha1
expression in cells lacking RET is dispensable for
organogenesis and nerve regeneration. Neuron 2004;
44:623–636.
45. Kimball ES, Palmer JM, D’Andrea MR, et al. Acute colitis
induction by oil of mustard results in later development of an
IBS-like accelerated upper GI transit in mice. Am J Physiol
Gastrointest Liver Physiol 2005;288:G1266–G1273.
46. Greene JG, Noorian AR, Srinivasan S. Delayed gastric
emptying and enteric nervous system dysfunction in the
rotenone model of Parkinson’s disease. Exp Neurol
2009;218:154–161.
Received January 12, 2022. Accepted December 5, 2022.
Correspondence
Address correspondence to: Hideki Enomoto, MD, PhD, Division of Neural
Differentiation and Regeneration, Department of Physiology and Cell Biology,
Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuoku, Hyogo 650-0017, Japan. e-mail: enomotoh@med.kobe-u.ac.jp.
Acknowledgments
The authors thank all members of the Enomoto laboratory for their assistance
and discussion. They also thank their collaborators in T-CiRA for fruitful
discussion.
CRediT Authorship Contributions
Mukhamad Sunardi (Conceptualization: Equal; Data curation: Lead; Formal
analysis: Lead; Funding acquisition: Supporting; Investigation: Lead;
Methodology: Lead; Visualization: Lead; Writing – original draft: Lead)
Keisuke Ito (Investigation: Supporting)
Yuya Sato (Investigation: Supporting)
Toshihiro Uesaka (Investigation: Supporting)
Mitsuhiro Iwasaki (Methodology: Supporting)
Hideki Enomoto (Conceptualization: Lead; Data curation: Lead; Formal
analysis: Lead; Funding acquisition: Lead; Methodology: Lead; Project
administration: Lead; Resources: Equal; Supervision: Lead; Validation: Lead;
Writing – review & editing: Lead)
Conflicts of interest
The authors disclose no conflicts.
Funding
Supported by Grant-in-Aid from MEXT, Japan Society for the Promotion of
Science, Japan, Grant 20K21526, Japan Intractable Diseases Research
Foundation, and The Ichiro Kanehara Foundation for the Promotion of
Medical Sciences and Medical Care.
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