Poreless Eggshells

Poreless eggshells Haifan Lin, Martin M. Matzuk J Clin Invest. 2015;125(11):4005-4007. https://doi.org/10.1172/JCI84692. Commentary The oocyte is the sole source of the female genetic material that will be fertilized by sperm to form an embryo. Many extrinsic and intrinsic factors are critical for oocyte development and survival; however, these mediators are incompletely understood. In this issue of the JCI, Weinberg-Shukron et al. uncover a novel recessive missense mutation in the gene encoding nucleoporin-107 (NUP107) that results in abnormal ovarian development. Recapitulation of the human mutation in the Drosophila NUP107 ortholog resulted in poor follicular development and demonstrated an evolutionarily conserved and ovary-specific role of NUP107. While NUP107 is required for nuclear pore complex function in somatic cells of flies and women, this specific amino acid change appears only to be disruptive in the ovary. All together, these findings imply that missense mutations in other genes could be specifically disruptive of ovarian or testicular function, while leaving extragonadal function intact. Find the latest version: https://jci.me/84692/pdf The Journal of Clinical Investigation COMMENTARY Poreless eggshells Haifan Lin1 and Martin M. Matzuk2 1Yale Stem Cell Center and Department of Cell Biology, Yale University School of Medicine, Yale University, New Haven, Connecticut, USA. 2Departments of Pathology and Immunology; Molecular and Cellular Biology; Molecular and Human Genetics; and Pharmacology; and Center for Drug Discovery, Baylor College of Medicine, Houston, Texas, USA. with hypergonadotropic hypogonadism fail to have menstrual cycles or initiate puberty The oocyte is the sole source of the female genetic material that will be and have other defects in secondary sex fertilized by sperm to form an embryo. Many extrinsic and intrinsic factors characteristics (10, 11). Excitingly, Wein- are critical for oocyte development and survival; however, these mediators berg-Shukron et al. (9) identified a recessive are incompletely understood. In this issue of the JCI, Weinberg-Shukron mutation in nucleoporin-107 (NUP107) as et al. uncover a novel recessive missense mutation in the gene encoding the underling cause of XX gonadal dysgen- nucleoporin-107 (NUP107) that results in abnormal ovarian development. esis in all four of the female family mem- Recapitulation of the human mutation in the Drosophila NUP107 ortholog bers they described. This lone point muta- resulted in poor follicular development and demonstrated an evolutionarily tion (c.1339G>A) results in a single amino conserved and ovary-specific role of NUP107. While NUP107 is required acid change in an evolutionarily conserved for nuclear pore complex function in somatic cells of flies and women, this amino acid (p.D447N) of NUP107. Based on specific amino acid change appears only to be disruptive in the ovary. All structural models, this single mutation was together, these findings imply that missense mutations in other genes could predicted to be detrimental, and Weinberg- be specifically disruptive of ovarian or testicular function, while leaving Shukron et al. speculated that this D447N extragonadal function intact. change would impair NUP107 interactions in the nuclear pore only in the ovary. NUP107 conserved between fly and human oogenesis Oocyte development and involves bidirectional paracrine signal- Weinberg-Shukron et al. (9) used Drosoph- function ing pathways that control oocyte destiny ila as a model to predict the potential func- Although there are morphological differ- (3–6). These pathways include KIT ligand tion of NUP107 in human female gonadal ences between the ovaries of invertebrates signaling from the granulosa cells to the dysgenesis. RNAi-mediated knockdown and vertebrates, in all egg-producing ani- oocyte (7) and secretion of growth differ- of NUP107 in Drosophila somatic gonadal mals, the ovary is critical for propagation of entiation factor 9 (GDF9) and bone mor- cells led to female sterility due to defec- the species and is responsible for nourish- phogenetic protein 15 (BMP15) from the tive oogenesis, including decreased egg ing and maturing the female genetic mate- oocyte, which engage a receptor system production. While NUP107 knockdown rial contained within the egg (or oocyte). on the surrounding granulosa cells (8). The resulted in a dramatic female phenotype, In Drosophila, the oocyte shares the cyto- effects of disrupting these pathways have NUP107-deficient male flies continued plasm with 15 nurse cells due to incom- been explored in detail in mouse models to be fertile. Introduction of an RFP- plete cytokinesis (1). Together, these cells and flies; however, few mutations that NUP107 transgene in NUP107-null flies form an interconnected 16-cell cluster that cause intrinsic defects in the ovary have rescued the lethal phenotype and fertil- is surrounded by a layer of somatic follicle been uncovered in women with infertility. ity of female flies: however, introduction cells. Both nurse cells and follicle cells In this issue, Weinberg-Shukron and of an RFP-NUP107D364N transgene, which serve as supporting cells for the oocyte colleagues (9) identify and characterize recapitulates the mutation identified in the and produce key nutrients and factors for four related patients with XX female gonad- patients with XX female gonadal dysgene- oocyte development (Figure 1). In women, al dysgenesis. All of these women had the sis, rescued the developmental phenotype, cognate supporting cells, called granulosa normal complement of X chromosomes but but these flies had reduced female fertility, cells, provide the nutrient system for the displayed small or streak ovaries. This ovar- abnormal egg production, decreased egg mammalian gamete (Figure 1). Whereas ian phenotype resulted in reduced levels of quality, and increased apoptosis. Despite communication between the supporting estrogen and a consequential loss of nega- the vast evolutionary distance and mor- cells and the fly oocyte is mostly unidi- tive feedback on the synthesis of pituitary phological difference between Drosophila rectional (2), communication between the gonadotropins, such as follicle-stimulating and humans, some of the most fundamen- mammalian oocyte and granulosa cells hormone and luteinizing hormone. Women tal aspects of gonadogenesis and gametogenesis are well conserved between the two. For example, meiosis is conserved, Related Article: p. 4295 including arrest at prophase I during Conflict of interest: The authors have declared that no conflict of interest exists. oogenesis and resumption during oocyte Reference information: J Clin Invest. 2015;125(11):4005–4007. doi:10.1172/JCI84692. maturation. Moreover, the codevelopment jci.org Volume 125 Number 11 November 2015 4005 COMMENTARY The Journal of Clinical Investigation Figure 1. Schematic drawing of a Drosophila early egg chamber and a human primary follicle at equivalent stages of oogenesis. (A) A Drosophila early egg chamber. The inset illustrates that NUP107 plays a critical cell-autonomous role in regulating the Drosophila follicle cell development. (B) A human primary follicle. NUP107 might play a role in follicle-cell communication with the oocyte as well as a cell-autonomous role in oocyte development. Cell types are indicated in the figure. of the oocyte and the somatic follicle lin- ber as well as their derivative structure line-autonomous function of NUP107, eage that eventually form a multicellular in the mature egg, the eggshell, are both Weinberg-Shukron and colleagues did complex called an egg chamber in Dro- severely defective. In addition, the Dro- not make this comparison, likely due to sophila and the follicle in humans is also sophila experiments predict an additional the complex and variable defects of the preserved. This multicellular complex of possible function of NUP107 in human nup107EB mutant and the somatic nup107- supporting somatic cells, known as follicle granulosa cells in controlling oocyte devel- RNAi–treated flies, compounded with cells in Drosophila and granulosa cells in opment, as specific knockdown of NUP107 the incomplete knockout of the NUP107 humans, surrounds each oocyte and plays expression in Drosophila follicle cells protein in follicle cells. Despite the lack an important role in nourishing the oocyte causes defects in nurse cells and oocytes, of an analysis of germline autonomy, the and regulating its development. As expect- both of which are germline cells. conserved function of Drosophila and ed, the conservation of these oogenic pro- human NUP107 during oogenesis processes likely reflects common underlying Outstanding questions and vides an exciting opportunity for explor- molecular mechanisms that are shared future directions ing mechanisms that relate to the nuclear between Drosophila and humans. For While the work of Weinberg-Shukron et pore complexes and are responsible for example, the Drosophila diaphanous (dia) al. shows a remarkable phenotype when oogenesis in humans. In particular, the gene is involved in cytokinesis and other NUP107 is disrupted in the follicle cells, it specific defects in oogenesis associated morphogenetic processes that are medi- will be important for future experiments with NUP107 mutants in the female ated by actin during gametogenesis, and to assess whether NUP107 has cell-auton- reproductive system in both humans and mutations in a human homolog of dia cor- omous functions in the germline. Such Drosophila is quite surprising,

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