Mechanically sensitive HSF1 is a key regulator of left-right symmetry breaking in zebrafish embryos

Jing Du; Shu-Kai Li; Liu-Yuan Guan; Zheng Guo; Jiang-Fan Yin; Li Gao; Toru Kawanishi; Atsuko Shimada; Qiu-Ping Zhang; Li-Sha Zheng; Yi-Yao Liu; Xi-Qiao Feng; Lin Zhao; Dong-Yan Chen; Hiroyuki Takeda; Yu-Bo Fan

doi:10.1016/j.isci.2023.107864

Mechanically sensitive HSF1 is a key regulator of left-right symmetry breaking in zebrafish embryos

iScience. 2023 Sep 9;26(10):107864. doi: 10.1016/j.isci.2023.107864. eCollection 2023 Oct 20.

Authors

Jing Du^{1

2

3}, Shu-Kai Li¹, Liu-Yuan Guan², Zheng Guo¹, Jiang-Fan Yin⁴, Li Gao⁴, Toru Kawanishi³, Atsuko Shimada³, Qiu-Ping Zhang⁵, Li-Sha Zheng¹, Yi-Yao Liu⁶, Xi-Qiao Feng², Lin Zhao⁵, Dong-Yan Chen⁵, Hiroyuki Takeda³, Yu-Bo Fan¹

Affiliations

¹ Key Laboratory for Biomechanics and Mechanobiology of Ministry of Education, Beijing Advanced Innovation Center for Biomedical Engineering, School of Biological Science and Medical Engineering, Beihang University, Beijing 100083, China.
² Institute of Biomechanics and Medical Engineering, Department of Mechanical Engineering, School of Aerospace, Tsinghua University, Beijing 100084, China.
³ Department of Biological Sciences, Graduate School of Science, University of Tokyo, Tokyo 113-0033, Japan.
⁴ College of life science, Hebei Normal University, Shijiazhuang 050024, China.
⁵ Tianjin Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, Department of Histology and Embryology, School of Medicine, Nankai University, Tianjin 300071, China.
⁶ Department of Biophysics, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu 610054, China.

Abstract

The left-right symmetry breaking of vertebrate embryos requires nodal flow. However, the molecular mechanisms that mediate the asymmetric gene expression regulation under nodal flow remain elusive. Here, we report that heat shock factor 1 (HSF1) is asymmetrically activated in the Kupffer's vesicle of zebrafish embryos in the presence of nodal flow. Deficiency in HSF1 expression caused a significant situs inversus and disrupted gene expression asymmetry of nodal signaling proteins in zebrafish embryos. Further studies demonstrated that HSF1 is a mechanosensitive protein. The mechanical sensation ability of HSF1 is conserved in a variety of mechanical stimuli in different cell types. Moreover, cilia and Ca²⁺-Akt signaling axis are essential for the activation of HSF1 under mechanical stress in vitro and in vivo. Considering the conserved expression of HSF1 in organisms, these findings unveil a fundamental mechanism of gene expression regulation by mechanical clues during embryonic development and other physiological and pathological transformations.

Keywords: Cell biology; Developmental biology; Embryology; Molecular biology.