Heat shock 70-kDa protein 5 (Hspa5) is essential for pronephros formation by mediating retinoic acid signaling.
Heat shock 70-kDa protein 5 (Hspa5), also known as binding immunoglobulin protein (Bip) or glucose-regulated protein 78 (Grp78), belongs to the heat shock protein 70 kDa family. As a multifunctional protein, it participates in protein folding and calcium homeostasis and serves as an essential regulator of the endoplasmic reticulum (ER) stress response. It has also been implicated in signal transduction by acting as a receptor or co-receptor residing at the plasma membrane. Its function during embryonic development, however, remains largely elusive. In this study, we used morpholino antisense oligonucleotides (MOs) to knock down Hspa5 activity in Xenopus embryos. In Hspa5 morphants, pronephros formation was strongly inhibited with the reduction of pronephric marker genes Lim homeobox protein 1 (lhx1), pax2, and β1 subunit of Na/K-ATPase (atp1b1). Pronephros tissue was induced in vitro by treating animal caps with all-trans-retinoic acid and activin. Depletion of Hspa5 in animal caps, however, blocked the induction of pronephros as well as reduced the expression of retinoic acid (RA)-responsive genes, suggesting that knockdown of Hspa5 attenuated RA signaling. Knockdown of Hspa5 in animal caps resulted in decreased expression of lhx1, a transcription factor directly regulated by RA signaling and essential for pronephros specification. Co-injection of Hspa5MO with lhx1 mRNA partially rescued the phenotype induced by Hspa5MO. These results suggest that the RA-Lhx1 signaling cascade is involved in Hspa5MO-induced pronephros malformation. This study shows that Hspa5, a key regulator of the unfolded protein response, plays an essential role in pronephros formation, which is mediated in part through RA signaling during early embryonic development.
From the Key Laboratory for Regenerative Medicine, Ministry of Education, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region (SAR), China.
Weili
W
Shi
School of Chinese Medicine, Hong Kong Baptist University, 7 Baptist University Road, Kowloon Tong, Hong Kong SAR, China.
Gang
G
Xu
From the Key Laboratory for Regenerative Medicine, Ministry of Education, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region (SAR), China, Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen 518057, China.
Chengdong
C
Wang
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029-6574.
Steven M
SM
Sperber
Key Laboratory of Regenerative Biology, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China, and.
Yonglong
Y
Chen
Division of Molecular Nephrology and Creative Training Center for Undergraduates, Ministry of Education Key Laboratory of Laboratory Medicine Diagnostics, College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, China.
Qin
Q
Zhou
Department of Biology, South University of Science and Technology of China, Shenzhen 518055, China, deng.y@sustc.edu.cn.
Yi
Y
Deng
From the Key Laboratory for Regenerative Medicine, Ministry of Education, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong Special Administrative Region (SAR), China, Shenzhen Research Institute, The Chinese University of Hong Kong, Shenzhen 518057, China, zhaohui@cuhk.edu.hk.
Hui
H
Zhao
D000818:Animals; D004625:Embryo, Nonmammalian; D000091342:Endoplasmic Reticulum Chaperone BiP; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006360:Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D038081:Organogenesis / Q000235:genetics; D060910:Pronephros / Q000254:growth & development / Q000378:metabolism*; D015398:Signal Transduction; D014212:Tretinoin / Q000378:metabolism*; D029867:Xenopus Proteins / Q000235:genetics* / Q000378:metabolism; D014982:Xenopus laevis / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism
D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D029867:Xenopus Proteins; D014212:Tretinoin
Development; Embryo; Endoplasmic Reticulum Stress (ER Stress); Kidney; Retinoic Acid; Xenopus