scholarly journals Gonadal Sex Differentiation: Supporting Versus Steroidogenic Cell Lineage Specification in Mammals and Birds

2020 ◽  
Vol 8 ◽  
Author(s):  
Martin A. Estermann ◽  
Andrew T. Major ◽  
Craig A. Smith
Keyword(s):  
Cell Biology ◽  
Sex Chromosome ◽  
Sex Differentiation ◽  
Cell Lineage ◽  
Cellular Mechanisms ◽  
Lineage Specification ◽  
Steroidogenic Cell ◽  
Vertebrate Embryos ◽  
Steroidogenic Cells ◽  
Chicken Model

The gonads of vertebrate embryos are unique among organs because they have a developmental choice; ovary or testis formation. Given the importance of proper gonad formation for sexual development and reproduction, considerable research has been conducted over the years to elucidate the genetic and cellular mechanisms of gonad formation and sexual differentiation. While the molecular trigger for gonadal sex differentiation into ovary of testis can vary among vertebrates, from egg temperature to sex-chromosome linked master genes, the downstream molecular pathways are largely conserved. The cell biology of gonadal formation and differentiation has long thought to also be conserved. However, recent discoveries point to divergent mechanisms of gonad formation, at least among birds and mammals. In this mini-review, we provide an overview of cell lineage allocation during gonadal sex differentiation in the mouse model, focusing on the key supporting and steroidogenic cells and drawing on recent insights provided by single cell RNA-sequencing. We compare this data with emerging information in the chicken model. We highlight surprising differences in cell lineage specification between species and identify gaps in our current understanding of the cell biology underlying gonadogenesis.

Inactivation of Wt1 causes pre-granulosa cell to steroidogenic cell transformation and defect of ovary development†

2020 ◽  
Vol 103 (1) ◽  
pp. 60-69
Author(s):  
Changhuo Cen ◽  
Min Chen ◽  
Jingjing Zhou ◽  
Lianjun Zhang ◽  
Shuguang Duo ◽  
...  
Keyword(s):  
Granulosa Cell ◽  
Granulosa Cells ◽  
Sertoli Cells ◽  
Cell Transformation ◽  
Ovary Development ◽  
Marker Genes ◽  
Cell Marker ◽  
Lineage Specification ◽  
Steroidogenic Cell ◽  
Steroidogenic Cells

Abstract Wt1 gene encodes a nuclear transcription factor which is specifically expressed in ovarian granulosa cells and testicular Sertoli cells. Our previous studies demonstrated that Wt1 is required for the lineage specification of supporting cells and inactivation of Wt1 results in Sertoli cells to Leydig-like cells transformation. To test whether Wt1 is also involved in lineage maintenance of granulosa cells during ovary development, Wt1 was specifically deleted in pre-granulosa cells using Foxl2-cre. We found that the female Wt1−/flox; Foxl2-cre mice were infertile with atrophic ovaries and no growing follicles with multiple layers of granulosa cells were observed. A large number of 3β-HSD-positive steroidogenic cells were detected in ovaries of Wt1−/flox; Foxl2-cre mice during embryonic stage and these cells were derived from Foxl2-expressing pre-granulosa cells. The quantitative results showed the expression of granulosa cell marker genes (Foxl2, Follistatin) was downregulated and steroidogenic cell marker genes (3β-HSD, Cyp11a1, Star and Sf1) was dramatically increased in Wt1−/flox; Foxl2-cre ovaries. We also found that the meiosis of germ cells in Wt1−/flox; Foxl2-cre ovaries was delayed but not arrested. This study demonstrates that Wt1 is required for lineage maintenance of granulosa cells and inactivation of Wt1 results in pre-granulosa cells to steroidogenic cells transformation which in turn causes the defect of ovary development.

scholarly journals Genetic Regulation of Avian Testis Development

Genes ◽  
2021 ◽  
Vol 12 (9) ◽  
pp. 1459
Author(s):  
Martin Andres Estermann ◽  
Andrew Thomas Major ◽  
Craig Allen Smith
Keyword(s):  
Cell Biology ◽  
Genetic Regulation ◽  
Cell Lineage ◽  
Future Research ◽  
Z Chromosome ◽  
Rna Seq ◽  
Lineage Specification ◽  
Testis Development ◽  
Chicken Testis ◽  
Male Factors

As in other vertebrates, avian testes are the site of spermatogenesis and androgen production. The paired testes of birds differentiate during embryogenesis, first marked by the development of pre-Sertoli cells in the gonadal primordium and their condensation into seminiferous cords. Germ cells become enclosed in these cords and enter mitotic arrest, while steroidogenic Leydig cells subsequently differentiate around the cords. This review describes our current understanding of avian testis development at the cell biology and genetic levels. Most of this knowledge has come from studies on the chicken embryo, though other species are increasingly being examined. In chicken, testis development is governed by the Z-chromosome-linked DMRT1 gene, which directly or indirectly activates the male factors, HEMGN, SOX9 and AMH. Recent single cell RNA-seq has defined cell lineage specification during chicken testis development, while comparative studies point to deep conservation of avian testis formation. Lastly, we identify areas of future research on the genetics of avian testis development.

scholarly journals Programming of the reproductive axis by hormonal and genetic manipulation in mice

Reproduction ◽  
2018 ◽  
Author(s):  
Susana B Rulli ◽  
María Julia Cambiasso ◽  
Laura D Ratner
Keyword(s):  
Sex Chromosome ◽  
Genetic Manipulation ◽  
Sex Differentiation ◽  
Reproductive Function ◽  
Gonadal Steroids ◽  
Critical Periods ◽  
Female Reproduction ◽  
Control Male ◽  
Male And Female ◽  
The Brain

In mammals, the reproductive function is controlled by the hypothalamic-pituitary-gonadal axis. During development, mechanisms mediated by gonadal steroids exert an imprinting at the hypothalamic-pituitary level, by establishing sexual differences in the circuits that control male and female reproduction. In rodents, the testicular production of androgens increases drastically during the fetal/neonatal stage. This process is essential for the masculinization of the reproductive tract, genitals and brain. The conversion of androgens to estrogens in the brain is crucial for the male sexual differentiation and behavior. Conversely, feminization of the brain occurs in the absence of high levels of gonadal steroids during the perinatal period in females. Potential genetic contribution to the differentiation of brain cells through direct effects of genes located on sex chromosomes is also relevant. In this review, we will focus on the phenotypic alterations that occur on the hypothalamic-pituitary-gonadal axis of transgenic mice with persistently elevated expression of the human chorionic gonadotropin hormone (hCG). Excess of endogenously synthesized gonadal steroids due to a constant hCG stimulation is able to disrupt the developmental programming of the hypothalamic-pituitary axis in both transgenic males and females. Locally produced estrogens by the hypothalamic aromatase might play a key role in the phenotype of these mice. The “four core genotypes” mouse model demonstrated a potential influence of sex chromosome genes in brain masculinization before critical periods of sex differentiation. Thus, hormonal and genetic factors interact to regulate the local production of the neurosteroids necessary for the programming of the male and female reproductive function.

scholarly journals ESCs injected into the 8-cell stage mouse embryo modify pattern of cleavage and cell lineage specification

2016 ◽  
Vol 141 ◽  
pp. 40-50 ◽  
Author(s):  
Monika Humięcka ◽  
Magdalena Krupa ◽  
Maria M. Guzewska ◽  
Marek Maleszewski ◽  
Aneta Suwińska
Keyword(s):  
Mouse Embryo ◽  
Cell Lineage ◽  
Lineage Specification ◽  
Cell Stage

scholarly journals Tet1 and Tet2 Regulate 5-Hydroxymethylcytosine Production and Cell Lineage Specification in Mouse Embryonic Stem Cells

2011 ◽  
Vol 8 (2) ◽  
pp. 200-213 ◽  
Author(s):  
Kian Peng Koh ◽  
Akiko Yabuuchi ◽  
Sridhar Rao ◽  
Yun Huang ◽  
Kerrianne Cunniff ◽  
...  
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Embryonic Stem ◽  
Cell Lineage ◽  
Mouse Embryonic Stem Cells ◽  
Lineage Specification

Abstract 3665: COL4A1 and COL4A2 Mutations cause Genetically Modifiable Cerebrovascular Diseases

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Marion Jeanne ◽  
Yi-Chinn Weng ◽  
Michelle de Leau ◽  
Cassandre Labelle-Dumais ◽  
Berkeley W Kauffman ◽  
...  
Keyword(s):  
Er Stress ◽  
Cell Biology ◽  
Phenotypic Variability ◽  
Cerebrovascular Diseases ◽  
Basement Membranes ◽  
Mutant Mice ◽  
Genetic Modifiers ◽  
Cellular Mechanisms ◽  
Cerebral Magnetic Resonance Imaging ◽  
Genetic Context

Mutations in the type IV collagen alpha 1 gene (COL4A1) cause Cerebrovascular Diseases (CVDs) in mice and human patients. Patients with COL4A1 mutations suffer from a broad range of CVDs, from infantile porencephaly to debilitating or fatal intracerebral hemorrhage (ICH), to subclinical cerebral microbleeds, suggesting that environmental and other genetic factors may influence their phenotypes. COL4A1 is one of the most abundant proteins in basement membranes and forms heterotrimers with COL4A2. Among possible pathogenic mechanisms are cellular stress due to the toxic intracellular aggregation of the COL4A1 and COL4A2 proteins and/or their absence in the basement membrane. Our first goal is to identify the relative contributions of COL4A1 and COL4A2 mutations to sporadic ICH and to understand the cellular mechanisms and genetic complexity underlying the disease. We identified novel COL4A1 mutations and for the first time, we discovered COL4A2 mutations in a cohort of 96 patients with sporadic ICH. Using a cell-based assay we determined that the mutations impair COL4A1 and COL4A2 secretion. We showed that mutant COL4A1 or COL4A2 proteins accumulate within the cell where they titrate normal COL4A1 and COL4A2 proteins. Interestingly, we found that some of the mutations can ultimately result in endoplasmic reticulum (ER) stress and activation of the Unfolded Protein Response. Our second goal was to test the hypothesis that differences in genetic context could contribute to phenotypic variability in human patients. Thus, we characterized CVD in Col4a1 mutant mice with two different genetic backgrounds. Using cerebral magnetic resonance imaging and histological analysis, we show that one or more genetic modifiers from the CAST/EiJ strain significantly reduce the size and frequency of ICHs detected in Col4a1 mutant mice on a C57BL/6J background. In conclusion, we found that both COL4A1 and COL4A2 mutations cause ICH in human patients, our results support that ER stress could be involved in the pathogenesis and we showed that genetic context is crucial for expressivity and severity of the CVD. We predict that ongoing experiments to better understand the cell biology of COL4A1 and COL4A2 mutations and the mechanisms of genetic modification could lead to targeted therapeutics to reduce the risk of CVD in patients with COL4A1 or COL4A2 mutations.

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