Zfx mutation results in small animal size and reduced germ cell number in male and female mice

Development ◽  
1997 ◽  
Vol 124 (11) ◽  
pp. 2275-2284
Author(s):  
S.W. Luoh ◽  
P.A. Bain ◽  
R.D. Polakiewicz ◽  
M.L. Goodheart ◽  
H. Gardner ◽  
...  

The zinc-finger proteins ZFX and ZFY, encoded by genes on the mammalian X and Y chromosomes, have been speculated to function in sex differentiation, spermatogenesis, and Turner syndrome. We derived Zfx mutant mice by targeted mutagenesis. Mutant mice (both males and females) were smaller, less viable, and had fewer germ cells than wild-type mice, features also found in human females with an XO karyotype (Turner syndrome). Mutant XY animals were fully masculinized, with testes and male genitalia, and were fertile, but sperm counts were reduced by one half. Homozygous mutant XX animals were fully feminized, with ovaries and female genitalia, but showed a shortage of oocytes resulting in diminished fertility and shortened reproductive lifespan, as in premature ovarian failure in humans. The number of primordial germ cells was reduced in both XX and XY mutant animals at embryonic day 11.5, prior to gonadal sex differentiation. Zfx mutant animals exhibited a growth deficit evident at embryonic day 12.5, which persisted throughout postnatal life and was not complemented by the Zfy genes. These phenotypes provide the first direct evidence for a role of Zfx in growth and reproductive development.

Endocrinology ◽  
2007 ◽  
Vol 149 (4) ◽  
pp. 1813-1819 ◽  
Author(s):  
Eri Shiraishi ◽  
Norifumi Yoshinaga ◽  
Takeshi Miura ◽  
Hayato Yokoi ◽  
Yuko Wakamatsu ◽  
...  

Müllerian inhibiting substance (MIS) is a glycoprotein belonging to the TGF-β superfamily. In mammals, MIS is responsible for the regression of Müllerian ducts in the male fetus. However, the role of MIS in gonadal sex differentiation of teleost fish, which have no Müllerian ducts, has yet to be clarified. In the present study, we examined the expression pattern of mis and mis type 2 receptor (misr2) mRNAs and the function of MIS signaling in early gonadal differentiation in medaka (teleost, Oryzias latipes). In situ hybridization showed that both mis and misr2 mRNAs were expressed in the somatic cells surrounding the germ cells of both sexes during early sex differentiation. Loss-of-function of either MIS or MIS type II receptor (MISRII) in medaka resulted in suppression of germ cell proliferation during sex differentiation. These results were supported by cell proliferation assay using 5-bromo-2′-deoxyuridine labeling analysis. Treatment of tissue fragments containing germ cells with recombinant eel MIS significantly induced germ cell proliferation in both sexes compared with the untreated control. On the other hand, culture of tissue fragments from the MIS- or MISRII-defective embryos inhibited proliferation of germ cells in both sexes. Moreover, treatment with recombinant eel MIS in the MIS-defective embryos dose-dependently increased germ cell number in both sexes, whereas in the MISRII-defective embryos, it did not permit proliferation of germ cells. These results suggest that in medaka, MIS indirectly stimulates germ cell proliferation through MISRII, expressed in the somatic cells immediately after they reach the gonadal primordium.


Development ◽  
1972 ◽  
Vol 28 (2) ◽  
pp. 385-395
Author(s):  
Noriyuki Satoh ◽  
Nobuo Egami

Mitotic and meiotic activities of germ cells during early development in the medaka, Oryzias latipes, are dealt with in this report. Primordial germ cells were obviously distinguishable from somatic cells 3 days after fertilization and began to proliferate about 7 days after fertilization. The mean number of primordial germ cells increased during a period of 7–10 days after fertilization, reaching about 90 immediately before hatching. Newly hatched fry could be classified into two types according to the number and the nucleic activity of germ cells in the gonadal rudiment. One type consisted of fry containing about 100 germ cells and no cells in the meiotic prophase. In the other type of fry the number of germ cells increased by mitotic divisions and some of the cells began to enter into the meiotic prophase. During the course of further development the fry of the former type differentiated into males and the latter into females. Therefore it can be concluded that the morphological sex differentiation of germ cells occurs at the time of hatching. However, no sexual differences in the histological structure of somatic elements in the gonad are observable at that time.


2018 ◽  
Vol 100 (3) ◽  
pp. 697-710 ◽  
Author(s):  
Akihiko Sakashita ◽  
Takuya Wakai ◽  
Yukiko Kawabata ◽  
Chiaki Nishimura ◽  
Yusuke Sotomaru ◽  
...  

Abstract The fertility of sex-reversed XY female mice is severely impaired by a massive loss of oocytes and failure of meiotic progression. This phenomenon remains an outstanding mystery. We sought to determine the molecular etiology of XY oocyte dysfunction by generating sex-reversed females that bear genetic ablation of Sry, a vital sex determination gene, on an inbred C57BL/6 background. These mutant mice, termed XYsry− mutants, showed severe attrition of germ cells during fetal development, resulting in the depletion of ovarian germ cells prior to sexual maturation. Comprehensive transcriptome analyses of primordial germ cells (PGCs) and postnatal oocytes demonstrated that XYsry− females had deviated significantly from normal developmental processes during the stages of mitotic proliferation. The impaired proliferation of XYsry− PGCs was associated with aberrant β-catenin signaling and the excessive expression of transposable elements. Upon entry to the meiotic stage, XYsry− oocytes demonstrated extensive defects, including the impairment of crossover formation, the failure of primordial follicle maintenance, and no capacity for embryo development. Together, these results suggest potential molecular causes for germ cell disruption in sex-reversed female mice, thereby providing insights into disorders of sex differentiation in humans, such as “Swyer syndrome,” in which patients with an XY karyotype present as typical females and are infertile.


2008 ◽  
Vol 52 (4) ◽  
pp. 333-344 ◽  
Author(s):  
Christopher Runyan ◽  
Ying Gu ◽  
Amanda Shoemaker ◽  
Leendert Looijenga ◽  
Christopher Wylie

1953 ◽  
Vol 31 (2) ◽  
pp. 73-79 ◽  
Author(s):  
J. G. Robertson

The differentiation of the gonad is described in chum salmon embryos and alevins. Contrary to classical findings in teleosts, sex differentiation in the chum salmon proceeds in the male or female direction without an intermediate female phase. From an initially indifferent gonad there is a progressive development of one sex or the other. The organ forms as a fold from the splanchnic mesoderm and, at the time of first appearance, contains primordial germ cells. These enlarge to form the definitive germ cells which, after a series of divisions, form smaller oogonia or spermatogonia. Oogonia are followed by primary and secondary (growing) oocytes, the appearance of which is the criterion of sex distinction. Spermatogonia continue to multiply but do not undergo growth in the alevin. The ovary develops an open endovarial canal and is supported by a prominent mesovarium. The testis remains small and, in the alevin, develops no ducts. It is suspended by a mesorchium.


Endocrinology ◽  
2019 ◽  
Vol 161 (1) ◽  
Author(s):  
Ke Feng ◽  
Xuefan Cui ◽  
Yanlong Song ◽  
Binbin Tao ◽  
Ji Chen ◽  
...  

Abstract Gonadotropin-releasing hormone (Gnrh) plays important roles in reproduction by stimulating luteinizing hormone release, and subsequently ovulation and sperm release, ultimately controlling reproduction in many species. Here we report on a new role for this decapeptide. Surprisingly, Gnrh3-null zebrafish generated by CRISPR/Cas9 exhibited a male-biased sex ratio. After the dome stage, the number of primordial germ cells (PGCs) in gnrh3-/- fish was lower than that in wild-type, an effect that was partially rescued by gnrh3 overexpression. A terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) analysis revealed no detectable apoptosis of PGCs in gnrh3-/- embryos. Proliferating PGCs could be detected in wild-type embryos, while there was no detectable signal in gnrh3-/- embryos. Compared with wild type, the phosphorylation of AKT was not significantly different in gnrh3-/- embryos, but the phosphorylation of ERK1/2 decreased significantly. Treatment with a Gnrh analog (Alarelin) induced ERK1/2 phosphorylation and increased PGC numbers in both wild-type and gnrh3-/- embryos, and this was blocked by the MEK inhibitor PD0325901. The relative expression of sox9a, amh, and cyp11b were significantly upregulated, while cyp19a1a was significantly downregulated at 18 days post-fertilization in gnrh3-/- zebrafish. Taken together, these results indicate that Gnrh3 plays an important role in early sex differentiation by regulating the proliferation of PGCs through a MAPK-dependent path.


1975 ◽  
Vol 31 (5) ◽  
pp. 589-590 ◽  
Author(s):  
J. A. McCoshen ◽  
D. J. McCallion

2019 ◽  
Vol 242 (1) ◽  
pp. T51-T68 ◽  
Author(s):  
Patrycja A Jazwiec ◽  
Deborah M Sloboda

It is well established that early life environmental signals, including nutrition, set the stage for long-term health and disease risk – effects that span multiple generations. This relationship begins early, in the periconceptional period and extends into embryonic, fetal and early infant phases of life. Now known as the Developmental Origins of Health and Disease (DOHaD), this concept describes the adaptations that a developing organism makes in response to early life cues, resulting in adjustments in homeostatic systems that may prove maladaptive in postnatal life, leading to an increased risk of chronic disease and/or the inheritance of risk factors across generations. Reproductive maturation and function is similarly influenced by early life events. This should not be surprising, since primordial germ cells are established early in life and thus vulnerable to early life adversity. A multitude of ‘modifying’ cues inducing developmental adaptations have been identified that result in changes in reproductive development and impairments in reproductive function. Many types of nutritional challenges including caloric restriction, macronutrient excess and micronutrient insufficiencies have been shown to induce early life adaptations that produce long-term reproductive dysfunction. Many pathways have been suggested to underpin these associations, including epigenetic reprogramming of germ cells. While the mechanisms still remain to be fully investigated, it is clear that a lifecourse approach to understanding lifetime reproductive function is necessary. Furthermore, investigations of the impacts of early life adversity must be extended to include the paternal environment, especially in epidemiological and clinical studies of offspring reproductive function.


Development ◽  
1991 ◽  
Vol 113 (2) ◽  
pp. 689-699 ◽  
Author(s):  
K. Yoshinaga ◽  
S. Nishikawa ◽  
M. Ogawa ◽  
S. Hayashi ◽  
T. Kunisada ◽  
...  

Recent studies have shown that the dominant white spotting (W) locus encodes the proto-oncogene c-kit, a member of the tyrosine kinase receptor family. One symptom of mice bearing mutation within this gene is sterility due to developmental failure of the primordial germ cells during early embryogenesis. To elucidate the role of the c-kit in gametogenesis, we used an anti-c-kit monoclonal antibody, ACK2, as an antagonistic blocker for c-kit function to interfere with the development of male and female germ cells during postnatal life. ACK2 enabled us to detect the expression of c-kit in the gonadal tissue and also to determine the functional status of c-kit, which is expressed on the surface of a particular cell lineage. Consistent with our immunohistochemical findings, the intravenous injection of ACK2 into adult mice caused a depletion in the differentiating type A spermatogonia from the testis during 24–36 h, while the undifferentiated type A spermatogonia were basically unaffected. Intraperitoneal injections of ACK2 into prepuberal mice could completely block the mitosis of mature (differentiating) type A spermatogonia, but not the mitosis of the gonocytes and primitive type A spermatogonia, or the meiosis of spermatocytes. Our results indicate that the survival and/or proliferation of the differentiating type A spermatogonia requires c-kit, but the primitive (undifferentiated) type A spermatogonia or spermatogenic stem cells are independent from c-kit. Moreover, the antibody administration had no significant effect on oocyte maturation despite its intense expression of c-kit.


2007 ◽  
Vol 77 (Suppl_1) ◽  
pp. 207-208
Author(s):  
Yukiko Yamazaki ◽  
Hirotaka Yoshioka ◽  
Eleanor Low ◽  
Ryuzo Yanagimachi ◽  
Kazuhiro Iwahashi

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