scholarly journals Retinoic acid synthesis by ALDH1A proteins is dispensable for meiosis initiation in the mouse fetal ovary

2020 ◽  
Vol 6 (21) ◽  
pp. eaaz1261
Author(s):  
Anne-Amandine Chassot ◽  
Morgane Le Rolle ◽  
Geneviève Jolivet ◽  
Isabelle Stevant ◽  
Jean-Marie Guigonis ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Germ Cells ◽  
Gene Deletion ◽  
Ex Vivo ◽  
Acid Synthesis ◽  
Distinct Gene ◽  
Fetal Ovary ◽  
Present View

In mammals, the timing of meiosis entry is regulated by signals from the gonadal environment. All-trans retinoic acid (ATRA) signaling is considered the key pathway that promotes Stra8 (stimulated by retinoic acid 8) expression and, in turn, meiosis entry. This model, however, is debated because it is based on analyzing the effects of exogenous ATRA on ex vivo gonadal cultures, which not accurately reflects the role of endogenous ATRA. Aldh1a1 and Aldh1a2, two retinaldehyde dehydrogenases synthesizing ATRA, are expressed in the mouse ovaries when meiosis initiates. Contrary to the present view, here, we demonstrate that ATRA-responsive cells are scarce in the ovary. Using three distinct gene deletion models for Aldh1a1;Aldh1a2;Aldh1a3, we show that Stra8 expression is independent of ATRA production by ALDH1A proteins and that germ cells progress through meiosis. Together, these data demonstrate that ATRA signaling is dispensable for instructing meiosis initiation in female germ cells.

Citral, an inhibitor of retinoic acid synthesis, modifies pattern formation during limb regeneration in the axolotl Ambystoma mexicanum

1999 ◽  
Vol 77 (11) ◽  
pp. 1835-1837 ◽  
Author(s):  
Steven R Scadding
Keyword(s):  
Retinoic Acid ◽  
Pattern Formation ◽  
Limb Regeneration ◽  
Acid Synthesis ◽  
Ambystoma Mexicanum

While the effects of exogenous retinoids on amphibian limb regeneration have been studied extensively, the role of endogenous retinoids is not clear. Hence, I wished to investigate the role of endogenous retinoic acid during axolotl limb regeneration. Citral is a known inhibitor of retinoic acid synthesis. Thus, I treated regenerating limbs of the larval axolotl Ambystoma mexicanum with citral. The result of this inhibition of retinoic acid synthesis was that limb regeneration became extremely irregular and hypomorphic, with serious pattern defects, or was inhibited altogether. I conclude that endogenous retinoic acid plays an important role in pattern formation during limb regeneration.

Retinoic acid signaling is required during early chick limb development

Development ◽  
1996 ◽  
Vol 122 (5) ◽  
pp. 1385-1394 ◽  
Author(s):  
J.A. Helms ◽  
C.H. Kim ◽  
G. Eichele ◽  
C. Thaller
Keyword(s):  
Retinoic Acid ◽  
Limb Development ◽  
Acid Synthesis ◽  
Apical Ectodermal Ridge ◽  
Limb Bud ◽  
Retinoid Receptor ◽  
Limb Morphogenesis ◽  
Wing Bud ◽  
Zone Of Polarizing Activity

In the chick limb bud, the zone of polarizing activity controls limb patterning along the anteroposterior and proximodistal axes. Since retinoic acid can induce ectopic polarizing activity, we examined whether this molecule plays a role in the establishment of the endogenous zone of polarizing activity. Grafts of wing bud mesenchyme treated with physiologic doses of retinoic acid had weak polarizing activity but inclusion of a retinoic acid-exposed apical ectodermal ridge or of prospective wing bud ectoderm evoked strong polarizing activity. Likewise, polarizing activity of prospective wing mesenchyme was markedly enhanced by co-grafting either a retinoic acid-exposed apical ectodermal ridge or ectoderm from the wing region. This equivalence of ectoderm-mesenchyme interactions required for the establishment of polarizing activity in retinoic acid-treated wing buds and in prospective wing tissue, suggests a role of retinoic acid in the establishment of the zone of polarizing activity. We found that prospective wing bud tissue is a high-point of retinoic acid synthesis. Furthermore, retinoid receptor-specific antagonists blocked limb morphogenesis and down-regulated a polarizing signal, sonic hedgehog. Limb agenesis was reversed when antagonist-exposed wing buds were treated with retinoic acid. Our results demonstrate a role of retinoic acid in the establishment of the endogenous zone of polarizing activity.

RALDH2, the enzyme for retinoic acid synthesis, mediates meiosis initiation in germ cells of the female embryonic chickens

Amino Acids ◽  
2012 ◽  
Vol 44 (2) ◽  
pp. 405-412 ◽  
Author(s):  
Minli Yu ◽  
Ping Yu ◽  
Imdad H. Leghari ◽  
Chutian Ge ◽  
Yuling Mi ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Germ Cells ◽  
Acid Synthesis

scholarly journals Meiosis Initiates In The Fetal Ovary Of Mice Lacking All Retinoic Acid Receptor Isotypes

2019 ◽  
Author(s):  
Nadège Vernet ◽  
Manuel Mark ◽  
Diana Condrea ◽  
Betty Féret ◽  
Muriel Klopfenstein ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Germ Cells ◽  
Congenital Abnormalities ◽  
Retinoic Acid Receptor ◽  
Current Model ◽  
Fetal Life ◽  
Genetic Approach ◽  
Molecular Signal ◽  
Fetal Ovary ◽  
Multiple Congenital Abnormalities

AbstractGametes are generated through a specialized cell differentiation process, meiosis which, in most mammals, is initiated in ovaries during fetal life. It is widely admitted that all-trans retinoic acid (ATRA) is the molecular signal triggering meiosis initiation in mouse female germ cells, but a genetic approach in which ATRA synthesis is impaired disputes this proposal. In the present study, we investigated the contribution of endogenous ATRA to meiosis by analyzing fetuses lacking all RARs ubiquitously, obtained through a tamoxifen-inducible cre recombinase-mediated gene targeting approach. Efficient ablation of RAR-coding genes was assessed by the multiple congenital abnormalities displayed by the mutant fetuses. Unexpectedly, their germ cells robustly expressed STRA8, REC8, SYCP1 and SYCP3, showing that RAR are actually dispensable up to the zygotene stage of meiotic prophase I. Thus our study goes against the current model according to which meiosis is triggered by endogenous ATRA in the developing ovary and revives the identification of the meiosis-preventing substance synthesized by CYP26B1 in the fetal testis.

scholarly journals Identification of regulatory elements required for Stra8 expression, in fetal ovarian germ cells of the mouse

Development ◽  
2021 ◽  
pp. dev.194977
Author(s):  
Chun-Wei Feng ◽  
Guillaume Burnet ◽  
Cassy M. Spiller ◽  
Fiona Ka Man Cheung ◽  
Kallayanee Chawengsaksophak ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Germ Cells ◽  
Regulatory Element ◽  
Regulatory Elements ◽  
Egfp Expression ◽  
Spatiotemporal Regulation ◽  
Targeted Mutation ◽  
Fetal Ovary

In mice, the entry of germ cells into meiosis critically depends on the expression of stimulated by retinoic acid gene 8 (Stra8). Stra8 is expressed specifically in pre-meiotic germ cells of females and males, at fetal and postnatal stages respectively, but the mechanistic details of its spatiotemporal regulation are yet to be defined. In particular, there has been considerable debate regarding whether retinoic acid is required, in vivo, to initiate Stra8 expression in the mouse fetal ovary. We show that the distinctive anterior-to-posterior pattern of Stra8 initiation, characteristic of germ cells in the fetal ovary, is faithfully recapitulated when 2.9 kb of the Stra8 promoter is used to drive eGFP expression. Using in vitro transfection assays of cut-down and mutant constructs we identified two functional retinoic acid responsive elements (RAREs) within this 2.9 kb regulatory element. We also show that the transcription factor DMRT1 enhances Stra8 expression, but only in the presence of RA and the most proximal RARE. Finally, we used CRISPR/Cas9-mediated targeted mutation studies to demonstrate that both RAREs are required for optimal Stra8 expression levels, in vivo.

scholarly journals Divergent Roles of CYP26B1 and Endogenous Retinoic Acid in Mouse Fetal Gonads

Biomolecules ◽  
2019 ◽  
Vol 9 (10) ◽  
pp. 536 ◽  
Author(s):  
Laura Bellutti ◽  
Emilie Abby ◽  
Sophie Tourpin ◽  
Sébastien Messiaen ◽  
Delphine Moison ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Retinoic Acid ◽  
Organ Culture ◽  
Germ Cells ◽  
Female Meiosis ◽  
Short Term ◽  
Function Model ◽  
Degrading Enzyme

In female mammals, germ cells enter meiosis in the fetal ovaries, while in males, meiosis is prevented until postnatal development. Retinoic acid (RA) is considered the main inducer of meiotic entry, as it stimulates Stra8 which is required for the mitotic/meiotic switch. In fetal testes, the RA-degrading enzyme CYP26B1 prevents meiosis initiation. However, the role of endogenous RA in female meiosis entry has never been demonstrated in vivo. In this study, we demonstrate that some effects of RA in mouse fetal gonads are not recapitulated by the invalidation or up-regulation of CYP26B1. In organ culture of fetal testes, RA stimulates testosterone production and inhibits Sertoli cell proliferation. In the ovaries, short-term inhibition of RA-signaling does not decrease Stra8 expression. We develop a gain-of-function model to express CYP26A1 or CYP26B1. Only CYP26B1 fully prevents STRA8 induction in female germ cells, confirming its role as part of the meiotic prevention machinery. CYP26A1, a very potent RA degrading enzyme, does not impair the formation of STRA8-positive cells, but decreases Stra8 transcription. Collectively, our data reveal that CYP26B1 has other activities apart from metabolizing RA in fetal gonads and suggest a role of endogenous RA in amplifying Stra8, rather than being the initial inducer of Stra8. These findings should reactivate the quest to identify meiotic preventing or inducing substances.

scholarly journals All-Trans Retinoic Acid Modulates TLR4/NF-κB Signaling Pathway Targeting TNF-αand Nitric Oxide Synthase 2 Expression in Colonic Mucosa during Ulcerative Colitis and Colitis Associated Cancer

2017 ◽  
Vol 2017 ◽  
pp. 1-16 ◽  
Author(s):  
Hayet Rafa ◽  
Sarra Benkhelifa ◽  
Sonia AitYounes ◽  
Houria Saoula ◽  
Said Belhadef ◽  
...  
Keyword(s):  
Ulcerative Colitis ◽  
Retinoic Acid ◽  
Signaling Pathway ◽  
Colonic Mucosa ◽  
Ex Vivo ◽  
Current Therapy ◽  
No Production ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid

Colitis associated cancer (CAC) is the colorectal cancer (CRC) subtype that is associated with bowel disease such as ulcerative colitis (UC). The data on role of NF-κB signaling in development and progression of CAC were derived from preclinical studies, whereas data from human are rare. The aim of this work was to study the contribution of NF-κB pathway during UC and CAC, as well as the immunomodulatory effect of all-trans retinoic acid (AtRA). We analyzed the expression of NOS2, TNF-α, TLR4, and NF-κB, in colonic mucosa. We also studied NO/TNF-αmodulation by LPS in colonic mucosa pretreated with AtRA. A marked increase in TLR4, NF-κB, TNF-α, and NOS2 expression was reported in colonic mucosa. The relationship between LPS/TLR4 and TNF-α/NO production, as well as the role of NF-κB signaling, was confirmed by ex vivo experiments and the role of LPS/TLR4 in NOS2/TNF-αinduction through NF-κB pathway was suggested. AtRA downregulates NOS2 and TNF-αexpression. Collectively, our study indicates that AtRA modulates in situ LPS/TLR4/NF-κB signaling pathway targeting NOS2 and TNF-αexpression. Therefore, we suggest that AtRA has a potential value in new strategies to improve the current therapy, as well as in the clinical prevention of CAC development and progression.

scholarly journals Retinoic Acid and Germ Cell Development in the Ovary and Testis

Biomolecules ◽  
2019 ◽  
Vol 9 (12) ◽  
pp. 775 ◽  
Author(s):  
Tsutomu Endo ◽  
Maria M. Mikedis ◽  
Peter K. Nicholls ◽  
David C. Page ◽  
Dirk G. de Rooij
Keyword(s):  
Retinoic Acid ◽  
Germ Cells ◽  
Sexual Differentiation ◽  
Fetal Development ◽  
Primordial Germ Cells ◽  
Male Germ Cells ◽  
Developmental Transitions ◽  
Cycle Arrest ◽  
Meiotic Initiation

Retinoic acid (RA), a derivative of vitamin A, is critical for the production of oocytes and sperm in mammals. These gametes derive from primordial germ cells, which colonize the nascent gonad, and later undertake sexual differentiation to produce oocytes or sperm. During fetal development, germ cells in the ovary initiate meiosis in response to RA, whereas those in the testis do not yet initiate meiosis, as they are insulated from RA, and undergo cell cycle arrest. After birth, male germ cells resume proliferation and undergo a transition to spermatogonia, which are destined to develop into haploid spermatozoa via spermatogenesis. Recent findings indicate that RA levels change periodically in adult testes to direct not only meiotic initiation, but also other key developmental transitions to ensure that spermatogenesis is precisely organized for the prodigious output of sperm. This review focuses on how female and male germ cells develop in the ovary and testis, respectively, and the role of RA in this process.

scholarly journals Calcineurin mediates homeostatic synaptic plasticity by regulating retinoic acid synthesis

2015 ◽  
Vol 112 (42) ◽  
pp. E5744-E5752 ◽  
Author(s):  
Kristin L. Arendt ◽  
Zhenjie Zhang ◽  
Subhashree Ganesan ◽  
Maik Hintze ◽  
Maggie M. Shin ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Synaptic Plasticity ◽  
Synaptic Transmission ◽  
Critical Role ◽  
Signal Transduction Pathway ◽  
Acid Synthesis ◽  
Synaptic Activity ◽  
Homeostatic Synaptic Plasticity ◽  
Dependent Protein

Homeostatic synaptic plasticity is a form of non-Hebbian plasticity that maintains stability of the network and fidelity for information processing in response to prolonged perturbation of network and synaptic activity. Prolonged blockade of synaptic activity decreases resting Ca2+ levels in neurons, thereby inducing retinoic acid (RA) synthesis and RA-dependent homeostatic synaptic plasticity; however, the signal transduction pathway that links reduced Ca2+-levels to RA synthesis remains unknown. Here we identify the Ca2+-dependent protein phosphatase calcineurin (CaN) as a key regulator for RA synthesis and homeostatic synaptic plasticity. Prolonged inhibition of CaN activity promotes RA synthesis in neurons, and leads to increased excitatory and decreased inhibitory synaptic transmission. These effects of CaN inhibitors on synaptic transmission are blocked by pharmacological inhibitors of RA synthesis or acute genetic deletion of the RA receptor RARα. Thus, CaN, acting upstream of RA, plays a critical role in gating RA signaling pathway in response to synaptic activity. Moreover, activity blockade-induced homeostatic synaptic plasticity is absent in CaN knockout neurons, demonstrating the essential role of CaN in RA-dependent homeostatic synaptic plasticity. Interestingly, in GluA1 S831A and S845A knockin mice, CaN inhibitor- and RA-induced regulation of synaptic transmission is intact, suggesting that phosphorylation of GluA1 C-terminal serine residues S831 and S845 is not required for CaN inhibitor- or RA-induced homeostatic synaptic plasticity. Thus, our study uncovers an unforeseen role of CaN in postsynaptic signaling, and defines CaN as the Ca2+-sensing signaling molecule that mediates RA-dependent homeostatic synaptic plasticity.

Retinoic acid derived from the fetal ovary initiates meiosis in mouse germ cells

2012 ◽  
Vol 228 (3) ◽  
pp. 627-639 ◽  
Author(s):  
Xinyi Mu ◽  
Jing Wen ◽  
Meng Guo ◽  
Jianwei Wang ◽  
Ge Li ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Germ Cells ◽  
Fetal Ovary
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