Moreno-Irusta Ayelen, Dominguez Esteban M, Iqbal Khursheed, Zhang Xiaoyu, Wang Ning, Soares Michael J
Institute for Reproductive and Developmental Sciences, University of Kansas Medical Center, Kansas City, Kansas, USA.
Department of Pathology & Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA.
FASEB J. 2024 Jan;38(1):e23376. doi: 10.1096/fj.202301716RR.
Male germ cell development is dependent on the orchestrated regulation of gene networks. TATA-box binding protein associated factors (TAFs) facilitate interactions of TATA-binding protein with the TATA element, which is known to coordinate gene transcription during organogenesis. TAF7 like (Taf7l) is situated on the X chromosome and has been implicated in testis development. We examined the biology of TAF7L in testis development using the rat. Taf7l was prominently expressed in preleptotene to leptotene spermatocytes. To study the impact of TAF7L on the testis we generated a global loss-of-function rat model using CRISPR/Cas9 genome editing. Exon 3 of the Taf7l gene was targeted. A founder was generated possessing a 110 bp deletion within the Taf7l locus, which resulted in a frameshift and the premature appearance of a stop codon. The mutation was effectively transmitted through the germline. Deficits in TAF7L did not adversely affect pregnancy or postnatal survival. However, the Taf7l disruption resulted in male infertility due to compromised testis development and failed sperm production. Mutant germ cells suffer meiotic arrest at late zygotene/early pachynema stages, with defects in sex body formation. This testis phenotype was more pronounced than previously described for the subfertile Taf7l null mouse. We conclude that TAF7L is essential for male germ cell development in the rat.
雄性生殖细胞的发育依赖于基因网络的协调调控。TATA框结合蛋白相关因子（TAFs）促进TATA结合蛋白与TATA元件的相互作用，已知TATA元件在器官发生过程中协调基因转录。类TAF7（Taf7l）位于X染色体上，与睾丸发育有关。我们利用大鼠研究了TAF7L在睾丸发育中的生物学特性。Taf7l在细线前期到细线期精母细胞中显著表达。为了研究TAF7L对睾丸的影响，我们使用CRISPR/Cas9基因组编辑技术构建了一个全身性功能缺失大鼠模型。靶向Taf7l基因的外显子3。产生了一个奠基者，其Taf7l基因座内有110 bp的缺失，导致移码并提前出现终止密码子。该突变通过种系有效传递。TAF7L的缺陷对妊娠或出生后存活没有不利影响。然而，Taf7l基因的破坏导致雄性不育，原因是睾丸发育受损和精子生成失败。突变的生殖细胞在合线期晚期/粗线期早期减数分裂停滞，性体形成存在缺陷。这种睾丸表型比之前描述的生育力低下的Taf7l基因敲除小鼠更为明显。我们得出结论，TAF7L对大鼠雄性生殖细胞的发育至关重要。
