Abstract
The N6-methyladenosine (m6A) modification is the most prevalent internal RNA modification in eukaryotes. The majority of m6A sites are found in the last exon and 3' UTRs. Here we show that the nuclear m6A reader YTHDC1 is essential for embryo viability and germline development in mouse. Specifically, YTHDC1 is required for spermatogonial development in males and for oocyte growth and maturation in females; Ythdc1-deficient oocytes are blocked at the primary follicle stage. Strikingly, loss of YTHDC1 leads to extensive alternative polyadenylation in oocytes, altering 3' UTR length. Furthermore, YTHDC1 deficiency causes massive alternative splicing defects in oocytes. The majority of splicing defects in mutant oocytes are rescued by introducing wild-type, but not m6A-binding-deficient, YTHDC1. YTHDC1 is associated with the pre-mRNA 3' end processing factors CPSF6, SRSF3, and SRSF7. Thus, YTHDC1 plays a critical role in processing of pre-mRNA transcripts in the oocyte nucleus and may have similar non-redundant roles throughout fetal development.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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3' Untranslated Regions / genetics
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Adenosine / analogs & derivatives
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Adenosine / metabolism
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Alternative Splicing / genetics*
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Animals
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Cell Nucleus / metabolism
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Cleavage And Polyadenylation Specificity Factor / metabolism
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Embryonic Development / genetics
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Exons / genetics
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Female
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Male
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Mice / genetics
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Mice / growth & development*
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Mice, Transgenic
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Mutation
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Nerve Tissue Proteins / deficiency
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Nerve Tissue Proteins / genetics*
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Nerve Tissue Proteins / metabolism
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Oocytes / growth & development*
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Oocytes / metabolism
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Polyadenylation / genetics*
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RNA Precursors / genetics
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RNA Splicing Factors / deficiency
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RNA Splicing Factors / genetics*
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RNA Splicing Factors / metabolism
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RNA, Messenger / genetics
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Serine-Arginine Splicing Factors / metabolism
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Spermatogonia / growth & development
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Spermatogonia / metabolism
Substances
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3' Untranslated Regions
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CPSF6 protein, mouse
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Cleavage And Polyadenylation Specificity Factor
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Nerve Tissue Proteins
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RNA Precursors
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RNA Splicing Factors
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RNA, Messenger
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Srsf3 protein, mouse
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Serine-Arginine Splicing Factors
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N-methyladenosine
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Adenosine