Coevolution of the ileum with Brk/Ptk6 family kinases confers robustness to ileal homeostasis

Ippei Kikuchi; Yusuke Iwashita; Atsushi Takahashi-Kanemitsu; Michinori Koebis; Atsu Aiba; Masanori Hatakeyama

doi:10.1016/j.bbrc.2023.07.051

Coevolution of the ileum with Brk/Ptk6 family kinases confers robustness to ileal homeostasis

Biochem Biophys Res Commun. 2023 Oct 8:676:190-197. doi: 10.1016/j.bbrc.2023.07.051. Epub 2023 Jul 26.

Authors

Ippei Kikuchi¹, Yusuke Iwashita², Atsushi Takahashi-Kanemitsu³, Michinori Koebis⁴, Atsu Aiba⁴, Masanori Hatakeyama⁵

Affiliations

¹ Laboratory of Microbial Carcinogenesis, Institute of Microbial Chemistry, Microbial Chemistry Research Foundation, Tokyo, 141-0021, Japan; Division of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan.
² Division of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan.
³ Division of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan; Department of Biochemistry and Systems Biomedicine, Juntendo University Graduate School of Medicine, Tokyo, 113-8421, Japan.
⁴ Laboratory of Animal Resources, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan.
⁵ Laboratory of Microbial Carcinogenesis, Institute of Microbial Chemistry, Microbial Chemistry Research Foundation, Tokyo, 141-0021, Japan; Division of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan; Center of Infection-associated Cancer, Institute for Genetic Medicine, Hokkaido University, Sapporo, 060-0815, Japan. Electronic address: mhata@m.u-tokyo.ac.jp.

PMID: 37523817
DOI: 10.1016/j.bbrc.2023.07.051

Abstract

Brk/Ptk6, Srms, and Frk constitute a Src-related but distinct family of tyrosine kinases called Brk family kinases (BFKs) in higher vertebrates. To date, however, their biological roles have remained largely unknown. In this study, we generated BFK triple-knockout (BFK/TKO) mice lacking all BFK members using CRISPR/Cas9-mediated genome editing. BFK/TKO mice exhibited impaired intestinal homeostasis, represented by a reduced stem/progenitor cell population and defective recovery from radiation-induced severe mucosal damage, specifically in the ileum, which is the most distal segment of the small intestine. RNA-seq analysis revealed that BFK/TKO ileal epithelium showed markedly elevated IL-22/STAT3 signaling, resulting in the aberrant activation of mucosal immune response and altered composition of the ileal microbiota. Since single- or double-knockout of BFK genes did not elicit such abnormalities, BFKs may redundantly confer robust homeostasis to the ileum, the most recently added intestinal segment that plays crucial roles in nutrient absorption and mucosal immunity. Given that BFK diversification preceded the appearance of the ileum in vertebrate phylogeny, the present study highlights the coevolution of genes and organs, the former of which shapes up the latter in higher vertebrates.

Keywords: Brk/Ptk6 family kinases; IL-22; Ileum; Intestinal stem cell; Mucosal immunity; Tyrosine kinase.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Homeostasis
Ileum*
Intestine, Small
Mice
Signal Transduction*