Harris Devon E, Kim Jongmin J, Stern Sarah R, Vicars Hannah M, Matias Neuza R, Gallicchio Lorenzo, Baker Catherine C, Fuller Margaret T
Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA 94305.
Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305.
Proc Natl Acad Sci U S A. 2025 May 20;122(20):e2418279122. doi: 10.1073/pnas.2418279122. Epub 2025 May 16.
The switch from precursor cell proliferation to onset of differentiation in adult stem cell lineages must be carefully regulated to produce sufficient progeny to maintain and repair tissues, yet prevent overproliferation that may enable oncogenesis. In the male germ cell lineage, spermatogonia produced by germ line stem cells undergo a limited number of transit amplifying mitotic divisions before switching to the spermatocyte program that sets up meiosis and eventual spermatid differentiation. The number of transit amplifying divisions is set by accumulation of the (Bam) protein to a critical threshold. In mutants, spermatogonia proliferate through several extra rounds of mitosis and then die without becoming spermatocytes. Here, we show that a key role of Bam for the mitosis to differentiation switch is repressing expression of Held Out Wings (), homolog of mammalian Quaking. Knockdown of in germ cells was sufficient to allow spermatogonia mutant for or its partner to differentiate, while forced expression of nuclear-targeted How protein in spermatogonia wild-type for resulted in continued proliferation at the expense of differentiation. Our findings suggest that Bam targets RNA for degradation by acting as an adapter to recruit the CCR4-NOT deadenylation complex via binding its subunit, Caf40. As How is itself an RNA-binding protein with roles in RNA processing, our findings reveal that the switch from proliferation to meiosis and differentiation in the male germ line adult stem cell lineage is regulated by a cascade of RNA-binding proteins.
在成体干细胞谱系中，从前体细胞增殖到分化开始的转变必须受到严格调控，以产生足够的后代来维持和修复组织，同时防止可能导致肿瘤发生的过度增殖。在雄性生殖细胞谱系中，生殖系干细胞产生的精原细胞在切换到启动减数分裂和最终精子细胞分化的精母细胞程序之前，会经历有限次数的过渡性增殖有丝分裂。过渡性增殖分裂的次数由（Bam）蛋白积累到临界阈值来设定。在突变体中，精原细胞通过额外的几轮有丝分裂进行增殖，然后在未成为精母细胞的情况下死亡。在这里，我们表明Bam在有丝分裂到分化转变中的关键作用是抑制Held Out Wings（How）的表达，How是哺乳动物Quaking的同源物。在生殖细胞中敲低How足以使缺乏Bam或其伴侣αBam的精原细胞分化，而在野生型Bam的精原细胞中强制表达核靶向的How蛋白则导致以分化为代价的持续增殖。我们的研究结果表明，Bam通过作为适配器结合其亚基Caf40来招募CCR4-NOT去腺苷酸化复合体，从而靶向How RNA进行降解。由于How本身是一种在RNA加工中起作用的RNA结合蛋白，我们的研究结果揭示了雄性生殖系成体干细胞谱系中从增殖到减数分裂和分化的转变是由一系列RNA结合蛋白调控的。
