研究人员发现了雌小鼠卵巢正常发育所需要的基因。在雌小鼠发育的早期，包含未成熟卵细胞的卵泡需要进入一个生长阶段。Aleksandar Rajkovic和同事发现，缺少Nobox基因的雌小鼠的卵泡不进入这个生长阶段，所以卵细胞自我破坏。在这种情况下，卵泡被纤维组织所取代，这和某些妇女的过早卵巢失败发生的情况一样。Nobox看起来控制几个与卵泡成熟有关的其它基因。文章作者提出，这些变异的小鼠也许能提供一个有用的模式，来研究妇女的无症状卵巢失败，以及控制培养成熟卵子的产生和繁殖力。
NOBOX Deficiency Disrupts Early Folliculogenesis and Oocyte-Specific Gene Expression
Primordial ovarian follicles in mice form when somatic cells surround individual oocytes. We show that lack of Nobox, an oocyte-specific homeobox gene, accelerates postnatal oocyte loss and abolishes the transition from primordial to growing follicles in mice. Follicles are replaced by fibrous tissue in female mice lacking Nobox in a manner similar to nonsyndromic ovarian failure in women. Genes preferentially expressed in oocytes, including Oct4 and Gdf9, are down-regulated in Nobox–/– mice, whereas ubiquitous genes such as Bmp4, Kit, and Bax remain unaffected. Therefore, Nobox is critical for specifying an oocyte-restricted gene expression pattern essential for postnatal follicle development.
Fig. 1. Histology of Nobox–/– and control ovaries. Left panels, Nobox+/– ovaries; right panels, Nobox–/– ovaries. (A and B) Newborn Nobox+/– and Nobox–/– ovaries stained with antibody to GCNA1. GCNA1 localizes (brown staining) to oocyte nuclei within germ cell cysts (GC) and primordial follicles (PF). (C and D) Three-day-old Nobox+/– and Nobox –/– ovaries stained with antibody to MSY2 (cytoplasmic staining). Primary follicles (PrF) are present in Nobox+/– and absent in Nobox–/– ovaries. (E and F) Seven-day-old Nobox+/– and Nobox–/– ovaries stained with antibody to GCNA1. Secondary follicles (SF) are absent in null but present in heterozygous ovaries. (G and H) Fourteen-day-old Nobox+/– ovaries show presence of secondary follicles; Nobox–/– ovaries contain only empty follicular nests (EF) and degenerating oocytes (arrowhead). Scale bars, 20 µm.
Fig. 2. Gene and protein expression analysis. (A) RNA expression of selected genes in Nobox+/– and Nobox–/– ovaries. (B) Nobox, Oct4, and Gdf9 RNA expression in embryonic ovaries; –/– lane corresponds to Nobox–/– newborn ovaries. (C and D) Wild-type (WT) and Nobox–/– (–/–) ovaries stained with antibodies to NOBOX. NOBOX antigen predominantly localizes to the nuclei of germ cell cysts (GC) and primordial follicles (PF) of wild-type ovaries. NOBOX is absent from Nobox–/– ovaries.
Fig. 3. In situ hybridizations. Newborn Nobox+/– ovaries (A to D) and Nobox–/– ovaries (E to H) were hybridized to antisense Nobox, Gdf9, Rfpl4, and AW554400 riboprobes. Dark-field views are shown; corresponding bright-field panels are shown in fig. S7. AW554400, an expressed sequence tag that is expressed in Nobox+/– and Nobox–/– ovaries, served as a control for hybridization. GC, germ cell cysts; PF, primordial follicle.
