Institute of Fisheries Science, NTU

Function and Regulation of Steroid Hormone Synthesis

We have been studying the functions of steroid hormones and the regulation of their synthesis. A key enzyme in the steroid synthetic pathway, cytochrome P450scc, is encoded by CYP11A, which is expressed in the adrenal cortex and gonads. We have characterized the regulation of CYP11A1 by transcription factor SF-1 (NR5A1) in culture cells and in transgenic and knockout mice. We have also found that steroids play especially important roles during zebrafish early embryogenesis. Three different aspects of steroid regulation have been the current focus of our investigation.

I.　Functions of Steroids in Zebrafish Early Embryogenesis

We found that a neurosteroid pregnenolone controls zebrafish embryonic cell migration and consequently morphogenesis. Pregnenolone binds to a microtubule associated protein CLIP-170, changing its conformation, thus promoting microtubule polymerization and consequently increasing cell motility. This action is important for neuronal projection and neuronal functions.

We also found that a different steroid, progesterone, is involved in dorsal/ventral cell fate determination by controlling BMP expression. The detailed molecular mechanism is being investigated.

II.　Zebrafish Gonad Development

The sex ratio in a batch of zebrafish culture can be screwed by environmental changes, but the mechanism of zebrafish sex determination is not clear. Studying the early events triggering zebrafish gonad differentiation, we and others have found that the first sign of gonad differentiation is germ cell proliferation. We are characterizing the control of this early gonad differentiation, hoping to reveal the mystery of fish gonad differentiation.

III.　Steroid Function and Regulation in Mouse

We have established mouse models with targeted Cyp11a1 gene disruption resulting in defective steroid synthesis. This mouse model enables the study of steroid functions in inflammation and stress response. For example, slight changes in promoter activity of Cyp11a1 resulted in higher sensitivity towards colitis. We would also like to investigate the role of steroid synthesis in the brain.

近年重要著作 (2010- ):

Wang C-Y, Huang EY-H, Huang S-C, and Chung B-c, “DNA-PK/Chk2 induces centrosome amplification during prolonged replication stress” Oncogene, 34” 1263-1269 (2015).

Huang S-C, Lee C-t, Chung B-c, “Tumor Necrosis Factor Suppresses NR5A2 Activity and Intestinal Glucocorticoid Synthesis to Sustain Chronic Colitis” Sci. Signal., 7 (314), ra20, 1-11 [DOI: 10.1126/scisignal.2004786] (2014).

Weng J-H, Liang M-R, Chen C-H, Tong S-K, Huang T-C, Lee S-P, Chen Y-R, Chen C-T, and Chung B-c, “Pregnenolone activates CLIP-170 to promote microtubule growth and cell migration” Nature Chem Biol, 9, 636-642 (2013). (cover picture)

Yu C, Cheng W-C, Wu M-R, Jiang S-T, Shen C-KJ, Chung B-c, “Mis-regulated Progesterone Secretion and Impaired Pregnancy in Cyp11a1 Transgenic Mice” Biol Reprod, 89 (4) 91, 1-10 (2013). (Recommended by Faculty of 1000 Prime)

Wang C-Y, Kao Y-H, Lai P-Y, Chen W-Y, and Chung B-c, “Steroidogenic Factor-1 (NR5A1) Maintains Centrosome Homeostasis in Steroidogenic Cells by Restricting Centrosomal DNA-PK Activation” Mol Cell Biol, 33, 476-484 (2013).

Lan H-S, Wu C-F, Shih H-M, and Chung B-c, “Death-Associated Protein 6 (Daxx) Mediates cAMP-Dependent Stimulation of Cyp11a1 (P450scc) Transcription” J Biol Chem 287, 5910–5916 (2012).

Lai P-Y*, Wang C-Y*, Chen W-Y, Kao Y-H, Tsai H-M, Tachibana T, Chung B-c, “Steroidogenic Factor 1 (NR5A1) resides in centrosomes and maintains genomic stability by controlling centrosome homeostasis” Cell Death Diff 18, 1836-1844, (2011). (*equal contribution).

Tong S-K, Hsu H-J, Chung B-c, “Zebrafish monosex population reveals female dominance in sex determination and earliest events of gonad differentiation”, Dev Biol, 344 (2), 849-856 (2010).

Diotel N, Le Page Y, Mouriec K, Tong S-K, Pellegrini E, Vaillant C, Anglade I, Brion F, Pakdel F, Chung B-c, Kah O, “Aromatase in the brain of teleost fish”, Front Neuroendocrin, 31, 172-192 (2010).