PUBLICATION

Augmentation of progestin signaling rescues testis organization and spermatogenesis in zebrafish with the depletion of androgen signaling

Authors
Zhai, G., Shu, T., Yu, G., Tang, H., Shi, C., Jia, J., Lou, Q., Dai, X., Jin, X., He, J., Xiao, W., Liu, X., Yin, Z.
ID
ZDB-PUB-220302-20
Date
2022
Source
eLIFE   11: (Journal)
Registered Authors
He, Jiangyan, Liu, Xiaochun, Xiao, Wuhan, Yin, Zhan, Yu, Guangqing, Zhai, Gang
Keywords
developmental biology, genetics, genomics, zebrafish
MeSH Terms
  • Androgens/metabolism
  • Male
  • Receptors, Progesterone/metabolism
  • Animals
  • Receptors, Androgen/metabolism
  • Zebrafish/genetics
  • Spermatogenesis/genetics
  • Progestins*/metabolism
  • Progestins*/pharmacology
  • Testis*/metabolism
(all 10)
PubMed
35225789 Full text @ Elife
Abstract
Disruption of androgen signaling is known to cause testicular malformation and defective spermatogenesis in zebrafish. However, knockout of cyp17a1, a key enzyme responsible for the androgen synthesis, in ar-/- male zebrafish paradoxically causes testicular hypertrophy and enhanced spermatogenesis. Because Cyp17a1 plays key roles in hydroxylation of pregnenolone and progesterone (P4), and convert of 17α-hydroxypregnenolone to dehydroepiandrosterone and 17α-hydroxyprogesterone to androstenedione, we hypothesize that the unexpected phenotype in cyp17a1-/-;androgen receptor (ar)-/- zebrafish may be mediated through an augmentation of progestin/nuclear progestin receptor (nPgr) signaling. In support of this hypothesis, we show that knockout of cyp17a1 leads to accumulation of 17α,20β-dihydroxy-4-pregnen-3-one (DHP) and P4. Further, administration of progestin, a synthetic DHP mimetic, is sufficient to rescue testicular development and spermatogenesis in ar-/- zebrafish, whereas knockout of npgr abolishes the rescue effect of cyp17a1-/- in the cyp17a1-/-;ar-/- double mutant. Analyses of the transcriptomes among the mutants with defective testicular organization and spermatogenesis (ar-/-, ar-/-;npgr-/- and cyp17a-/-;ar-/-;npgr-/-), those with normal phenotype (Control and cyp17a1-/-), and rescued phenotype (cyp17a1-/-;ar-/-) reveal a common link between a down-regulated expression of insl3 and its related downstream genes in cyp17a-/-;ar-/-;npgr-/- zebrafish. Taken together, our data suggest that genetic or pharmacological augmentation of the progestin/nPgr pathway is sufficient to restore testis organization and spermatogenesis in zebrafish with the depletion of androgen signaling.
Genes / Markers
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Expression
No data available
Phenotype
No data available
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
ihb144
    		Small Deletion
    ihb351
      		Indel
      ihb1226
        		Small Deletion
        zf723
          		Small Deletion
          1 - 4 of 4
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          Human Disease / Model
          No data available
          Sequence Targeting Reagents
          No data available
          Fish
          No data available
          Antibodies
          Name Type Antigen Genes Isotypes Host Organism
          Ab4-ddx4polyclonalIgGRabbit
          1 - 1 of 1
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          Orthology
          No data available
          Engineered Foreign Genes
          No data available
          Mapping
          No data available
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          Citation
          Zhai, G., Shu, T., Yu, G., Tang, H., Shi, C., Jia, J., Lou, Q., Dai, X., Jin, X., He, J., Xiao, W., Liu, X., Yin, Z. (2022) Augmentation of progestin signaling rescues testis organization and spermatogenesis in zebrafish with the depletion of androgen signaling. eLIFE. 11:.