Zrsr2 and functional U12-dependent spliceosome are necessary for follicular development
Isabel Gómez-Redondo,
Eva Pericuesta,
Paula Navarrete-Lopez,
Priscila Ramos-Ibeas,
Benjamín Planells,
Noelia Fonseca-Balvís,
Aida Vaquero-Rey,
Raúl Fernández-González,
Ricardo Laguna-Barraza,
Keiko Horiuchi,
Alfonso Gutiérrez-Adán
Affiliations
Isabel Gómez-Redondo
Departamento de Reproducción Animal, INIA-CSIC, Avda. Puerta de Hierro nº 12. Local 10, 28040 Madrid, Spain
Eva Pericuesta
Departamento de Reproducción Animal, INIA-CSIC, Avda. Puerta de Hierro nº 12. Local 10, 28040 Madrid, Spain
Paula Navarrete-Lopez
Departamento de Reproducción Animal, INIA-CSIC, Avda. Puerta de Hierro nº 12. Local 10, 28040 Madrid, Spain
Priscila Ramos-Ibeas
Departamento de Reproducción Animal, INIA-CSIC, Avda. Puerta de Hierro nº 12. Local 10, 28040 Madrid, Spain
Benjamín Planells
Departamento de Reproducción Animal, INIA-CSIC, Avda. Puerta de Hierro nº 12. Local 10, 28040 Madrid, Spain
Noelia Fonseca-Balvís
Departamento de Reproducción Animal, INIA-CSIC, Avda. Puerta de Hierro nº 12. Local 10, 28040 Madrid, Spain
Aida Vaquero-Rey
Departamento de Reproducción Animal, INIA-CSIC, Avda. Puerta de Hierro nº 12. Local 10, 28040 Madrid, Spain
Raúl Fernández-González
Departamento de Reproducción Animal, INIA-CSIC, Avda. Puerta de Hierro nº 12. Local 10, 28040 Madrid, Spain
Ricardo Laguna-Barraza
Departamento de Reproducción Animal, INIA-CSIC, Avda. Puerta de Hierro nº 12. Local 10, 28040 Madrid, Spain
Keiko Horiuchi
Department of Protein-Protein Interaction Research, Institute for Advanced Medical Sciences, Nippon Medical School, 1-396 Kosugi-cho, Nakahara-ku, Kawasaki, Kanagawa 211-8533, Japan
Alfonso Gutiérrez-Adán
Departamento de Reproducción Animal, INIA-CSIC, Avda. Puerta de Hierro nº 12. Local 10, 28040 Madrid, Spain; Corresponding author
Summary: ZRSR2 is a splicing factor involved in recognition of 3′-intron splice sites that is frequently mutated in myeloid malignancies and several tumors; however, the role of mutations of Zrsr2 in other tissues has not been analyzed. To explore the biological role of ZRSR2, we generated three Zrsr2 mutant mouse lines. All Zrsr2 mutant lines exhibited blood cell anomalies, and in two lines, oogenesis was blocked at the secondary follicle stage. RNA-seq of Zrsr2mu secondary follicles showed aberrations in gene expression and showed altered alternative splicing (AS) events involving enrichment of U12-type intron retention (IR), supporting the functional Zrsr2 action in minor spliceosomes. IR events were preferentially associated with centriole replication, protein phosphorylation, and DNA damage checkpoint. Notably, we found alterations in AS events of 50 meiotic genes. These results indicate that ZRSR2 mutations alter splicing mainly in U12-type introns, which may affect peripheral blood cells, and impede oogenesis and female fertility.
