Genetic background-dependent abnormalities of the enteric nervous system and intestinal function in Kif26a-deficient mice

Yukiko Ohara,Youichi Teratake,Hideo Yoshida,Mitsuyuki Nakata,Keita Terui,Takeshi Saito,Tetsuya Mitsunaga,Masahiko Hatano,Haruhiko Koseki,Shuichi Hiraoka,Akemi Sakamoto,Lisa Fujimura

doi:10.1038/s41598-021-82785-1

Yukiko Ohara, Youichi Teratake + Show 10 more

Open Access

https://doi.org/10.1038/s41598-021-82785-1

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Abstract

The Kif26a protein-coding gene has been identified as a negative regulator of the GDNF-Ret signaling pathway in enteric neurons. The aim of this study was to investigate the influence of genetic background on the phenotype of Kif26a-deficient (KO, −/−) mice. KO mice with both C57BL/6 and BALB/c genetic backgrounds were established. Survival rates and megacolon development were compared between these two strains of KO mice. Functional bowel assessments and enteric neuron histopathology were performed in the deficient mice. KO mice with the BALB/c genetic background survived more than 400 days without evidence of megacolon, while all C57BL/6 KO mice developed megacolon and died within 30 days. Local enteric neuron hyperplasia in the colon and functional bowel abnormalities were observed in BALB/c KO mice. These results indicated that megacolon and enteric neuron hyperplasia in KO mice are influenced by the genetic background. BALB/c KO mice may represent a viable model for functional gastrointestinal diseases such as chronic constipation, facilitating studies on the underlying mechanisms and providing a foundation for the development of treatments.

Highlights

The Kif26a protein-coding gene has been identified as a negative regulator of the glial-line derived neurotrophic factor (GDNF)-Ret signaling pathway in enteric neurons
A previous study reported that KO mice developed megacolon with enteric neuron hyperplasia and subsequently died within 1 m onth[24]
Kif26a heterozygous (HT) mice were backcrossed with C57BL/6 or BALB/c mice for nine generations and HT mice were interbred to obtain KO mice

Summary

Introduction

The Kif26a protein-coding gene has been identified as a negative regulator of the GDNF-Ret signaling pathway in enteric neurons. Local enteric neuron hyperplasia in the colon and functional bowel abnormalities were observed in BALB/c KO mice. These results indicated that megacolon and enteric neuron hyperplasia in KO mice are influenced by the genetic background. In humans, signaling required for proper ENS development is derived from glial-line derived neurotrophic factor (GDNF) and its receptor RET3–7 and endothelin-3 and its receptor endothelin receptor type B8–12 as well as transcription factors such as S OX1013,14 and P HOX2B15,16 Mutations in these genes have been reported in Hirschsprung disease. Ncx ( known as Tlx[2] or Hox11L1)-deficient mice develop hyperganglionic megacolon and represent a murine genetic model of I ND19,20. This represents an important signal transduction pathway between Ret receptor tyrosine kinase and downstream molecules such as Akt and E RK24

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