Abnormal Sperm in Mice Lacking the Taf7l Gene

Abstract

TFIID is a general transcription factor required for transcription of most protein-coding genes by RNA polymerase II. TAF7L is an X-linked germ cell-specific paralogue of TAF7, which is a generally expressed component of TFIID. Here, we report the generation of Taf7l mutant mice by homologous recombination in embryonic stem cells by using the Cre-loxP strategy. While spermatogenesis was completed in Taf7l ؊/Y mice, the weight of Taf7l ؊/Y testis decreased and the amount of sperm in the epididymides was sharply reduced. Mutant epididymal sperm exhibited abnormal morphology, including folded tails. Sperm motility was significantly reduced, and Taf7l ؊/Y males were fertile with reduced litter size. Microarray profiling revealed that the abundance of six gene transcripts (including Fscn1) in Taf7l ؊/Y testes decreased more than twofold. In particular, FSCN1 is an F-action-bundling protein and thus may be critical for normal sperm morphology and sperm motility. Although deficiency of Taf7l may be compensated in part by Taf7, Taf7l has apparently evolved new specialized functions in the gene-selective transcription in male germ cell differentiation. Our mouse studies suggest that mutations in the human TAF7L gene might be implicated in X-linked oligozoospermia in men.TFIID, a general transcription factor, plays a central role in transcription initiation of most protein-coding genes by RNA polymerase II. TFIID is a multiprotein complex consisting of TATA-binding protein (TBP) and 12 to 15 TBPassociated factors (TAFs) (20,35). The assembly of TFIID at the promoter region recruits other basal transcription factors and RNA polymerase II (2, 31). TAFs play important roles in transcriptional regulation. Some TAFs directly interact with transcriptional activators and thus serve as coactivators. In addition, interactions between TAFs are critical for promoter recognition and selectivity by RNA polymerase II (17,36).Strikingly, studies of a number of tissue-specific TAFs in Drosophila melanogaster and mouse have identified cell-typespecific transcription programs. In Drosophila melanogaster, five testis-specific homologues of widely expressed TAFs have been reported: Can (homologue of dTAF5), Nht (homologue of dTAF4), Mia (homologue of dTAF6), Sa (homologue of dTAF8), and Rye (homologue of dTAF12) (18,19). Null mutations in can, nht, mia, and sa result in the same male sterile phenotype, and all four genes are required for meiotic cell cycle progression and onset of spermatid differentiation (27). In addition, Rye interacts with Nht, suggesting that these five testis-specific TAFs in Drosophila function in the same transcription regulatory pathway (18). Mechanistically, these TAFs may counteract transcriptional repression by Polycomb group (PcG) proteins in spermatocytes (8). In mice, TAF4B (homologue of TAF4) is highly expressed in the testis and the granulosa cells of the ovary, where it is required for follicular development (14). Testes of TAF4B-deficient males are initially normal but undergo progressive germ cell loss, r...

A multi-faceted approach to understanding male infertility: gene mutations, molecular defects and assisted reproductive techniques (ART)

“…In humans, the TAF7L gene is an X-linked and singlecopy testis-specific gene that may be essential for maintenance of spermatogenesis and a possible contributor to male infertility [112]. Recently, a number of publications have reported the importance of various TAFs genes such as TAF7L and TAF4b in mouse spermatogenesis.…”

“…A study by Falender et al, [113] showed that TAF4b (a gonad-specific subunit of TFIID) is required for the maintenance of spermatogenesis in the mouse. In a knockout model study by Cheng et al, [112], they discovered that disruption of TAF7L gene in mice results in reduced sperm count and motility. They proposed that its counterpart, the human TAF7L gene may also play a similarly important role in spermatogenesis.…”

Core promoter recognition complex changes accompany liver development

“…Initially oogenesis and spermatogenesis were found to require an altered TFIID in which paralogous TAF4b replaces the canonical TAF4 (3,4). Later spermatocytes were found to also express paralogous TAF7L that may cooperate with TBP and TAF1 in the regulation of spermatogenesis genes (5,6). Although unique paralogs of other canonical TAFs have been identified, their tissue-specific expression and functional significance remain to be elucidated (7).…”

The role of spermatogonially expressed germ cell-specific genes in mammalian meiosis

“…The fact that no causative mutations in TAF7L and USP26 have been identified so far does not exclude a role for these genes in meiosis or spermatogenesis, since mutations in these genes might cause oligospermia (low sperm count) rather than azoospermia. Indeed, our recent study has shown that mice lacking the Taf 7l gene exhibit reduced sperm count (Cheng et al 2007). In addition, causative point mutations in a single gene are extremely rare in infertile men, given that hundreds if not thousands of genes are specifically involved in regulation of male fertility (Matzuk & Lamb 2002).…”

“…As a component of the basal transcription factor TFIID complex, TAF7L might specify a germ cell-specific transcription program. Disruption of Taf7l leads to reduced testis weight, decreased sperm production, and defects in sperm motility but no meiotic arrest (Cheng et al 2007). However, TAF7L might play a non-essential role in meiosis.…”