AUTHOR=Song Yanlong , Chen Weiting , Zhu Bo , Ge Wei 

TITLE=Disruption of Epidermal Growth Factor Receptor but Not EGF Blocks Follicle Activation in Zebrafish Ovary

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=9

YEAR=2022

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2021.750888

DOI=10.3389/fcell.2021.750888

ISSN=2296-634X

ABSTRACT=<p>Folliculogenesis is controlled by intimate communications between oocytes and surrounding follicle cells. Epidermal growth factor (EGF/Egf) is an important paracrine/autocrine factor in vertebrate ovary, and it is well known for its stimulation of oocyte maturation. However, the role of EGF signaling through its receptor (EGFR/Egfr) in ovarian folliculogenesis is poorly understood, especially at early stages of follicle development. In this study, we created zebrafish mutants for Egf (<italic>egf</italic><sup><italic>−/−</italic></sup>) and Egfr (<italic>egfra</italic><sup><italic>−/−</italic></sup> and <italic>egfrb</italic><sup><italic>−/−</italic></sup>) by CRISPR/Cas9 technique. Surprisingly, these mutants all survived well with little abnormality in growth and development. Spermatogenesis and folliculogenesis were both normal in <italic>egf</italic><sup><italic>−/−</italic></sup> males and females. Their fecundity was comparable to that of the wildtype fish at 4 months post-fertilization (mpf); however, the fertilization rate of mutant eggs (<italic>egf</italic><sup><italic>−/−</italic></sup>) decreased significantly at 7 mpf. Interestingly, disruption of <italic>egfra</italic> (<italic>egfra</italic><sup><italic>−/−</italic></sup>) led to failed follicle activation with folliculogenesis being blocked at primary–secondary growth transition (PG-SG transition), leading to female infertility, whereas the mutant males remained fertile. The mutant ovary (<italic>egfra</italic><sup><italic>−/−</italic></sup>) showed abnormal expression of a substantial number of genes involved in oxidative metabolism, gene transcription, cytomembrane transport, steroid hormone biosynthesis, and immune response. The stunted PG oocytes in <italic>egfra</italic><sup><italic>−/−</italic></sup> ovary eventually underwent degeneration after 6 months followed by sex reversal to males with functional testes. No abnormal phenotypes were found in the mutant of truncated form of EGFR (<italic>egfrb</italic>). In summary, our data revealed critical roles for EGFR signaling in early folliculogenesis, especially at the PG-SG transition or follicle activation.</p>