Nuclear m6A reader YTHDC1 regulates alternative polyadenylation and splicing during mouse oocyte development

Area of Science:

• Molecular Biology
• Developmental Biology
• Genetics

Background:

• N6-methyladenosine (m6A) is the most common internal RNA modification in eukaryotes.
• m6A sites are predominantly located in the last exon and 3' untranslated regions (UTRs).

Purpose of the Study:

• To investigate the role of the nuclear m6A reader YTHDC1 in mouse embryo viability and germline development.
• To elucidate the molecular mechanisms underlying YTHDC1's function in oocytes.

Main Methods:

• Generation and analysis of Ythdc1-deficient mice.
• Assessment of oocyte growth, maturation, and follicle development.
• Analysis of alternative polyadenylation and alternative splicing in oocytes.
• Co-immunoprecipitation assays to identify interacting proteins.

Main Results:

• YTHDC1 is essential for spermatogonial development and oocyte growth/maturation; Ythdc1-deficient oocytes arrest at the primary follicle stage.
• Loss of YTHDC1 leads to widespread alternative polyadenylation and alternative splicing defects in oocytes.
• Defects in mutant oocytes are rescued by wild-type YTHDC1, but not by an m6A-binding-deficient mutant.
• YTHDC1 interacts with pre-mRNA 3' end processing factors CPSF6, SRSF3, and SRSF7.

Conclusions:

• YTHDC1 plays a critical, non-redundant role in pre-mRNA 3' end processing within the oocyte nucleus.
• YTHDC1's function in RNA processing is essential for germline development and embryo viability.
• YTHDC1 may have similar essential roles in other fetal developmental stages.