Accelerated Ovarian Aging in the Absence of the Transcription Regulator TAF4B in Mice1

Abstract

The mammalian ovary is unique in that its reproductive life span is limited by oocyte quantity and quality. Oocytes are recruited from a finite pool of primordial follicles that are usually exhausted from the ovary during midadult life. If regulation of this pool is perturbed, the reproductive capacity of the ovary is compromised. TAF4B is a gonad-enriched subunit of the TFIID complex required for female fertility in mice. Previous characterization of TAF4B-deficient ovaries revealed several reproductive deficits that collectively result in infertility. However, the etiology of such fertility defects remains unknown. By assaying estrous cycle, ovarian pathology, and gene expression changes in young Taf4b-null female mice, we show that TAF4B-deficient female mice exhibit premature reproductive senescence. The rapid decline of ovarian function in Taf4b-null mice begins in early postnatal life, and follicle depletion is completed by 16 wk of age. To uncover differences in gene expression that may underlie accelerated ovarian aging, we compared genome-wide expression profiles of 3-wk-old, prepubescent Taf4b-null and wild-type ovaries. At 3 wk of age, decreased gene expression in Taf4b-null ovaries is similar to that seen in aged ovaries, revealing several molecular signatures of premature reproductive senescence, including reduced Smc1b. One significantly reduced transcript in the young TAF4B-null ovary codes for MOV10L1, a putative germline-specific RNA helicase that is related to the Drosophila RNA interference protein, armitage. We show here that Mov10l1 is expressed in mouse oocytes and that its expression is sensitive to TAF4B level, linking TAF4B to the posttranscriptional control of ovarian gene expression.

The developmental origins of the mammalian ovarian reserve

“…One of the best-characterized selective subunits of the general transcriptional complex TFIID is TBP-associated factor 4b (TAF4b), a paralog of TAF4, originally identified in a human B-cell line and found to be primarily enriched in the mouse ovary and testis (Freiman et al, 2001). Taf4b-deficient female mice are viable but infertile and suffer from many hallmarks of premature ovarian failure, including follicle depletion, persistent estrous and high serum levels of the gonadotropin follicle stimulating hormone (FSH) (Falender et al, 2005;Freiman et al, 2001;Lovasco et al, 2010;Voronina et al, 2007). Recent work has demonstrated that Taf4b-deficient ovaries experience dramatic germ cell loss by apoptosis immediately after birth, the time at which the ovarian reserve is established (Grive et al, 2014).…”

“…Impaired cyst breakdown; loss of primordial follicles (Lechowska et al, 2011;Rajkovic et al, 2004;Suzumori et al, 2002) TBP-associated Factor 4b (Taf4b) Impaired cyst breakdown; loss of primordial follicles (Falender et al, 2005;Freiman et al, 2001;Grive et al, 2014;Lovasco et al, 2010;Voronina et al, 2007) …”

MOV10L1 in piRNA processing and gene silencing of retrotransposons during spermatogenesis

“…In brief, they evaluated the levels of gene expression in these mice in comparison with WT controls. Interestingly, Mov10l1 was found to be expressed in mouse oocytes, and their expression levels were significantly reduced in the Taf4b-null mouse (Lovasco et al 2010). Although the Mov10l1 K/K ; mutants contained the reduced transcription levels of the MILI protein, they also lacked piRNAs binding to this protein.…”

MOV10L1 is necessary for protection of spermatocytes against retrotransposons by Piwi-interacting RNAs

“…It was recently suggested that reduced Mov10l1 levels were at least partially responsible for accelerated ovarian aging and follicle depletion in mice that lack the transcriptional regulator TAF4B (16). However, in contrast to this proposal, female Mov10l1 −/− mice appeared to have normal and sustained fertility (9 ± 1.1 pups per litter; n = 10 litters), and we assume therefore that reduced Mov10l1 expression in TAF4B −/− mice is a marker rather than a cause for accelerated ovarian aging.…”

“…We discovered a putative DExD-box helicase (called CHAMP; cardiac helicase activated by MEF2C protein), encoded by differently sized transcripts in heart (exons [15][16][17][18][19][20][21][22][23][24][25][26] and testis (exons 1-26) (9). The testis-specific isoform has also been referred to as MOV10-like-1 (MOV10L1), on the basis of its extensive homology to Moloney leukemia virus 10 (MOV10), which was shown to interact with argonaute 1 and 2 in HeLa cells (10).…”