Cyp17a1 is required for female sex determination and male fertility by regulating sex steroid biosynthesis in fish

Endocrinology ◽  
2021 ◽  
Author(s):  
Lanying Yang ◽  
Xuefeng Zhang ◽  
Shujun Liu ◽  
Chenhua Zhao ◽  
Yiyang Miao ◽  
...  
Keyword(s):  
Sex Determination ◽  
Sex Differentiation ◽  
Ectopic Expression ◽  
Sex Reversal ◽  
Mitochondrial Morphology ◽  
Critical Window ◽  
Female Sex ◽  
Estrogen Production ◽  
Endogenous Estrogen ◽  
Cytochrome P450 Family

Abstract In teleost fish, sex steroids are involved in sex determination, sex differentiation, and fertility. Particularly, Cyp17a1 (Cytochrome P450 family 17 subfamily A member 1) is thought to play essential roles in fish steroidogenesis. Therefore, to further understand its roles in steroidogenesis, sex determination, and fertility in fish, we constructed a cyp17a1 gene mutant in Nile tilapia (Oreochromis niloticus). In XX fish, mutation of cyp17a1 gene led to a female-to-male sex reversal with a significant decline in 17β-estradiol (E2) and testosterone (T) production, and ectopic expression of male-biased markers (Dmrt1 and Gsdf) in gonads from the critical window of sex determination. Sex reversal was successfully rescued via T or E2 administration, and ovarian characteristics were maintained after termination of E2 supplementation in the absence of endogenous estrogen production in cyp17a1  -/--XX fish. Likewise, deficiencies in T and 11-KT production in both cyp17a1  -/--XX sex reversed males and cyp17a1  -/--XY mutants resulted in meiotic initiation delays, vas deferens obstruction and sterility due to excessive apoptosis and abnormal mitochondrial morphology. However, 11-KT treatment successfully rescued the dysspermia to produce normal sperm in cyp17a1  -/- male fish. Significant increases in fshβ, lhβ, and gth receptors in cyp17a1  -/- mutants may excessively upregulate steroidogenic gene expression in Leydig cells through a feedback loop. Taken together, our findings demonstrate that Cyp17a1 is indispensable for E2 production, which is fundamental for female sex determination and differentiation in XX tilapia. Additionally, Cyp17a1 is essential for T and 11-KT production, which further promotes spermatogenesis and fertility in XY males.

scholarly journals Antagonistic Roles of Dmrt1 and Foxl2 in Sex Differentiation via Estrogen Production in Tilapia as Demonstrated by TALENs

Endocrinology ◽  
2013 ◽  
Vol 154 (12) ◽  
pp. 4814-4825 ◽  
Author(s):  
Ming-Hui Li ◽  
Hui-Hui Yang ◽  
Meng-Ru Li ◽  
Yun-Lv Sun ◽  
Xiao-Long Jiang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Nile Tilapia ◽  
High Efficiency ◽  
Sex Differentiation ◽  
Sex Reversal ◽  
Serum Estradiol ◽  
Transcription Activator ◽  
Important Species ◽  
Estrogen Production ◽  
Estradiol 17Β

Transcription activator-like effector nucleases (TALENs) are a powerful approach for targeted genome editing and have been proved to be effective in several organisms. In this study, we reported that TALENs can induce somatic mutations in Nile tilapia, an important species for worldwide aquaculture, with reliably high efficiency. Six pairs of TALENs were constructed to target genes related to sex differentiation, including dmrt1, foxl2, cyp19a1a, gsdf, igf3, and nrob1b, and all resulted in indel mutations with maximum efficiencies of up to 81% at the targeted loci. Effects of dmrt1 and foxl2 mutation on gonadal phenotype, sex differentiation, and related gene expression were analyzed by histology, immunohistochemistry, and real-time PCR. In Dmrt1-deficient testes, phenotypes of significant testicular regression, including deformed efferent ducts, degenerated spermatogonia or even a complete loss of germ cells, and proliferation of steroidogenic cells, were observed. In addition, disruption of Dmrt1 in XY fish resulted in increased foxl2 and cyp19a1a expression and serum estradiol-17β and 11-ketotestosterone levels. On the contrary, deficiency of Foxl2 in XX fish exhibited varying degrees of oocyte degeneration and significantly decreased aromatase gene expression and serum estradiol-17β levels. Some Foxl2-deficient fish even exhibited complete sex reversal with high expression of Dmrt1 and Cyp11b2. Furthermore, disruption of Cyp19a1a in XX fish led to partial sex reversal with Dmrt1 and Cyp11b2 expression. Taken together, our data demonstrated that TALENs are an effective tool for targeted gene editing in tilapia genome. Foxl2 and Dmrt1 play antagonistic roles in sex differentiation in Nile tilapia via regulating cyp19a1a expression and estrogen production.

scholarly journals Two transcriptionally distinct pathways drive female development in a reptile with both genetic and temperature dependent sex determination

PLoS Genetics ◽  
2021 ◽  
Vol 17 (4) ◽  
pp. e1009465
Author(s):  
Sarah L. Whiteley ◽  
Clare E. Holleley ◽  
Susan Wagner ◽  
James Blackburn ◽  
Ira W. Deveson ◽  
...  
Keyword(s):  
Sex Determination ◽  
Model Organism ◽  
Sex Reversal ◽  
Female Development ◽  
Cellular Mechanisms ◽  
Regulatory Pathways ◽  
Female Sex ◽  
Thermally Driven ◽  
Pogona Vitticeps ◽  
Male To Female

How temperature determines sex remains unknown. A recent hypothesis proposes that conserved cellular mechanisms (calcium and redox; ‘CaRe’ status) sense temperature and identify genes and regulatory pathways likely to be involved in driving sexual development. We take advantage of the unique sex determining system of the model organism, Pogona vitticeps, to assess predictions of this hypothesis. P. vitticeps has ZZ male: ZW female sex chromosomes whose influence can be overridden in genetic males by high temperatures, causing male-to-female sex reversal. We compare a developmental transcriptome series of ZWf females and temperature sex reversed ZZf females. We demonstrate that early developmental cascades differ dramatically between genetically driven and thermally driven females, later converging to produce a common outcome (ovaries). We show that genes proposed as regulators of thermosensitive sex determination play a role in temperature sex reversal. Our study greatly advances the search for the mechanisms by which temperature determines sex.

scholarly journals The Role of Anti-Müllerian Hormone in Testis Differentiation Reveals the Significance of the TGF-β Pathway in Reptilian Sex Determination

Genetics ◽  
2019 ◽  
Vol 213 (4) ◽  
pp. 1317-1327 ◽  
Author(s):  
Yingjie Zhou ◽  
Wei Sun ◽  
Han Cai ◽  
Haisheng Bao ◽  
Yu Zhang ◽  
...  
Keyword(s):  
Sex Determination ◽  
Messenger Rna ◽  
Sex Differentiation ◽  
Sex Reversal ◽  
Testicular Development ◽  
Loss Of Function ◽  
Specific Expression ◽  
Male Sex ◽  
Specific Expression Pattern ◽  
Reptilian Species

Anti-Müllerian hormone (Amh, or Müllerian-inhibiting substance, Mis), a member of TGF-β superfamily, has been well documented in some vertebrates as initiator or key regulator in sexual development, and particularly in fish. However, its functional role has not yet been identified in reptiles. Here, we characterized the Amh gene in the Chinese soft-shelled turtle Pelodiscus sinensis, a typical reptilian species exhibiting ZZ/ZW sex chromosomes. The messenger RNA of Amh was initially expressed in male embryonic gonads by stage 15, preceding gonadal sex differentiation, and exhibited a male-specific expression pattern throughout embryogenesis. Moreover, Amh was rapidly upregulated during female-to-male sex reversal induced by aromatase inhibitor letrozole. Most importantly, Amh loss of function by RNA interference led to complete feminization of genetic male (ZZ) gonads, suppression of the testicular marker Sox9, and upregulation of the ovarian regulator Cyp19a1. Conversely, overexpression of Amh in ZW embryos resulted in female-to-male sex reversal, characterized by the formation of a testis structure, ectopic activation of Sox9, and a remarkable decline in Cyp19a1. Collectively, these findings provide the first solid evidence that Amh is both necessary and sufficient to drive testicular development in a reptilian species, P. sinensis, highlighting the significance of the TGF-β pathway in reptilian sex determination.

scholarly journals The role of Cyp19a1 in female pathway of a freshwater turtle (Mauremys reevesii) with temperature-dependent sex determination

2021 ◽  
Author(s):  
Pengfei Wu ◽  
Xifeng Wang ◽  
Fei Gao ◽  
Weiguo Du
Keyword(s):  
Sex Determination ◽  
Sex Differentiation ◽  
Critical Role ◽  
Temperature Shift ◽  
Vital Role ◽  
Freshwater Turtle ◽  
Temperature Dependent ◽  
Female Sex ◽  
Determination Process ◽  
Sexually Dimorphic Expression

The molecular mechanism of temperature-dependent sex determination (TSD) in reptiles has been drawn great interest from biologists for several decades. However, which genetic factors are essential for TSD remain elusive, especially for the female sex determination process. Cyp19a1, encodes an enzyme of aromatase catalyzing the conversion of testosterone to estrogen, has been confirmed to modulate steroid hormones involved in the sexual differentiation of many species, but whether it has a critical role in determining the gonadal sexual fate in TSD is still to be elucidated. Here, we identified that Cyp19a1 expression exhibited a temperature-dependent, sexually dimorphic expression pattern, preceding gonadal sex differentiation in a TSD turtle Mauremys reevesii. Cyp19a1 expression in gonads increased dramatically when embryos developed at high female-producing temperatures (FPT), but were extremely low throughout embryogenesis at low male-producing temperatures (MPT). Cyp19a1 expression increased rapidly in response to the temperature shift from MPT to FPT in developing gonads. The sexual phenotype of turtles was successfully reversed by aromatase inhibitor treatment at FPT, and by estrogen treatment at MPT, accompanied with the rapid upregulation of Cyp19a1. These results demonstrate that Cyp19a1 is essential for the female sex determination process in M. reevesii, indicating its vital role in the female pathway of TSD.

scholarly journals Dmrt1 mutation causes a male-to-female sex reversal after the sex determination by Dmy in the medaka

2011 ◽  
Vol 20 (1) ◽  
pp. 163-176 ◽  
Author(s):  
Haruo Masuyama ◽  
Masato Yamada ◽  
Yasuhiro Kamei ◽  
Tomoko Fujiwara-Ishikawa ◽  
Takeshi Todo ◽  
...  
Keyword(s):  
Sex Determination ◽  
Sex Reversal ◽  
Female Sex ◽  
Male To Female

scholarly journals Metabolism and Sex Differentiation in Animals from a Starvation Perspective

2021 ◽  
pp. 1-11
Author(s):  
Yuta Sakae ◽  
Minoru Tanaka
Keyword(s):  
Sex Determination ◽  
Environmental Changes ◽  
Sex Differentiation ◽  
Green Light ◽  
Acid Synthesis ◽  
Sex Reversal ◽  
Environmental Sex Determination ◽  
Biological Factors ◽  
Signal Transducers ◽  
Male Sex

Animals determine their sex genetically (GSD: genetic sex determination) and/or environmentally (ESD: environmental sex determination). Medaka (<i>Oryzias latipes</i>) employ a XX/XY GSD system, however, they display female-to-male sex reversal in response to various environmental changes such as temperature, hypoxia, and green light. Interestingly, we found that 5 days of starvation during sex differentiation caused female-to-male sex reversal. In this situation, the metabolism of pantothenate and fatty acid synthesis plays an important role in sex reversal. Metabolism is associated with other biological factors such as germ cells, HPG axis, lipids, and epigenetics, and supplys substances and acts as signal transducers. In this review, we discuss the importance of metabolism during sex differentiation and how metabolism contributes to sex differentiation.

scholarly journals Gtsf1 is essential for proper female sex determination and transposon silencing in the silkworm, Bombyx mori

PLoS Genetics ◽  
2020 ◽  
Vol 16 (11) ◽  
pp. e1009194
Author(s):  
Kai Chen ◽  
Ye Yu ◽  
Dehong Yang ◽  
Xu Yang ◽  
Linmeng Tang ◽  
...  
Keyword(s):  
Sex Determination ◽  
Bombyx Mori ◽  
Critical Role ◽  
Sex Reversal ◽  
Female Sex ◽  
Silk Moth ◽  
Transposon Silencing ◽  
Pirna Pathway ◽  
Silkworm Bombyx Mori ◽  
Male Pattern

Sex determination pathways are astoundingly diverse in insects. For instance, the silk moth Bombyx mori uniquely use various components of the piRNA pathway to produce the Fem signal for specification of the female fate. In this study, we identified BmGTSF1 as a novel piRNA factor which participates in B. mori sex determination. We found that BmGtsf1 has a distinct expression pattern compared to Drosophila and mouse. CRISPR/Cas9 induced mutation in BmGtsf1 resulted in partial sex reversal in genotypically female animals by shifting expression of the downstream targets BmMasc and Bmdsx to the male pattern. As levels of Fem piRNAs were substantially reduced in female mutants, we concluded that BmGtsf1 plays a critical role in the biogenesis of the feminizing signal. We also demonstrated that BmGTSF1 physically interacted with BmSIWI, a protein previously reported to be involved in female sex determination, indicating BmGTSF1 function as the cofactor of BmSIWI. BmGtsf1 mutation resulted in piRNA pathway dysregulation, including piRNA biogenesis defects and transposon derepression, suggesting BmGtsf1 is also a piRNA factor in the silkworm. Furthermore, we found that BmGtsf1 mutation leads to gametogenesis defects in both male and female. Our data suggested that BmGtsf1 is a new component involved in the sex determination pathway in B. mori.

scholarly journals Two transcriptionally distinct pathways drive female development in a reptile with both genetic and temperature dependent sex determination

2021 ◽  
Author(s):  
Sarah L. Whiteley ◽  
Clare E. Holleley ◽  
Susan Wagner ◽  
James Blackburn ◽  
Ira W. Deveson ◽  
...  
Keyword(s):  
Sex Determination ◽  
Sex Chromosomes ◽  
Model Organism ◽  
Sex Reversal ◽  
Ovary Development ◽  
Cellular Mechanisms ◽  
Regulatory Pathways ◽  
Female Sex ◽  
Thermally Driven ◽  
Male To Female

AbstractHow temperature determines sex remains unknown. A recent hypothesis proposes that conserved cellular mechanisms (calcium and redox; ‘CaRe’ status) sense temperature and identify genes and regulatory pathways likely to be involved in driving sexual development. We take advantage of the unique sex determining system of the model organism, Pogona vitticeps, to assess predictions of this hypothesis. P. vitticeps has ZZ male: ZW female sex chromosomes whose influence can be overridden in genetic males by high temperatures, causing male-to-female sex reversal. We compare a developmental transcriptome series of ZWf females and temperature sex reversed ZZf females. We demonstrate that early developmental cascades differ dramatically between genetically driven and thermally driven females, later converging to produce a common outcome (ovaries). We show that genes proposed as regulators of thermosensitive sex determination play a role in temperature sex reversal. Our study greatly advances the search for the mechanisms by which temperature determines sex.Author SummaryIn many reptiles and fish, environment can determine, or influence, the sex of developing embryos. How this happens at a molecular level that has eluded resolution for half a century of intensive research. We studied the bearded dragon, a lizard that has sex chromosomes (ZZ male and ZW female), but in which that temperature can override ZZ sex chromosomes to cause male to female sex reversal. This provides an unparalleled opportunity to disentangle, in the same species, the biochemical pathways required to make a female by these two different routes. We sequenced the transcriptomes of gonads from developing ZZ reversed and normal ZW dragon embryos and discovered that different sets of genes are active in ovary development driven by genotype or temperature. Females whose sex was initiated by temperature showed a transcriptional profile consistent with the recently-proposed Calcium-Redox hypotheses of cellular temperature sensing. These findings are an important for understanding how the environment influences the development of sex, and more generally how the environment can epigenetically modify the action of genes.

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