scholarly journals HIRA contributes to zygote formation in mice and is implicated in human 1PN zygote phenotype

Reproduction ◽  
2021 ◽  
Author(s):  
Rowena Smith ◽  
Susan J Pickering ◽  
Anna Kopakaki ◽  
Kj Thong ◽  
Richard A Anderson ◽  
...  
Keyword(s):  
Mouse Models ◽  
Sperm Chromatin ◽  
Zygote Formation ◽  
Loss Of Function ◽  
Phenotype Correlation ◽  
Male Pronucleus ◽  
Histone H3.3 ◽  
Chromatin Reprogramming ◽  
Histone Exchange

Elucidating the mechanisms underpinning fertilisation is essential to optimising IVF procedures. One of the critical steps involves paternal chromatin reprogramming, in which compacted sperm chromatin packed by protamines is removed by oocyte factors and new histones, including histone H3.3, are incorporated. HIRA is the main H3.3 chaperone governing this protamine-to-histone exchange. Failure of this step results in abnormally fertilised zygotes containing only 1 pronucleus (1PN), in contrast to normal two-pronuclei (2PN) zygotes. 1PN zygotes are frequently observed in IVF treatments, but the genotype-phenotype correlation remains elusive. We investigated the maternal functions of two other molecules of the Hira complex, Cabin1 and Ubn1, in mouse. Loss-of-function Cabin1 and Ubn1 mouse models were developed: their zygotes displayed an abnormal 1PN zygote phenotype. We then studied human 1PN zygotes and found that the HIRA complex was absent in 1PN zygotes that lacked the male pronucleus. This shows that the role of the HIRA complex in male pronucleus formation potentially has coherence from mice to humans. Furthermore, rescue experiments in mouse showed that the abnormal 1PN phenotype derived from Hira mutants could be resolved by overexpression of HIRA. We have demonstrated that HIRA complex regulates male pronucleus formation in mice and is implicated in humans, that both CABIN1 and UBN1 components of the HIRA complex are equally essential for male pronucleus formation, and that rescue is feasible.

scholarly journals Histone H3.3 Hira chaperone complex contributes to zygote formation in mice and humans

2020 ◽  
Author(s):  
Rowena Smith ◽  
Sue Pickering ◽  
Anna Kopakaki ◽  
K Joo Thong ◽  
Richard A Anderson ◽  
...  
Keyword(s):  
Sperm Chromatin ◽  
Proof Of Concept ◽  
Loss Of Function ◽  
Male Pronucleus ◽  
Histone H3.3 ◽  
Infertile Couples ◽  
Chaperone Complex ◽  
Chromatin Reprogramming ◽  
Histone Exchange

AbstractElucidating the underlining mechanisms underpinning successful fertilisation is imperative in optimising IVF treatments, and may lead to a specific diagnosis and therefore potential treatment for some infertile couples. One of the critical steps involves paternal chromatin reprogramming, in which compacted sperm chromatin packed by protamines is removed by oocyte factors and new histones, including histone H3.3, are incorporated. This step is critical for the formation of the male pronucleus, without which the zygote contains only 1 pronucleus (1PN), in contrast to normally fertilised zygotes with two-pronuclei (2PN). 1PN zygotes are a frequently observed phenomenon in IVF treatments, therefore aberrant mechanism of action controlling paternal chromatin repackaging may be an important cause of abnormal fertilisation. Hira is the main H3.3 chaperone that governs this protamine-to-histone exchange. In this study, we investigated the maternal functions of two other molecules of the Hira complex, Cabin1 and Ubn1 in the mouse. Loss-of-function Cabin1 and Ubn1 mouse models were developed: their zygotes displayed abnormal 1PN zygote phenotypes, similar to the phenotype of Hira mutants. We then studied human 1PN zygotes, and found that the Hira complex was absent in 1PN zygotes which were lacking the male pronucleus. This result confirms that the role of the Hira complex in male pronucleus formation has coherence from mice to humans. Furthermore, rescue experiments showed that the abnormal 1PN phenotype derived from Hira mutants could be resolved by overexpression of Hira in the mouse oocytes. In summary, we have provided evidence of the role of Hira complex in regulating male pronucleus formation in both mice and humans, that both Cabin1 and Ubn1 components of the Hira complex are equally essential for male pronucleus formation, and that this can be rescued. We present a proof-of-concept experiment that could potentially lead to a personalised IVF therapy for oocyte defects.

scholarly journals The Involvement ofNRF2in Lung Cancer

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Alison K. Bauer ◽  
Thomas Hill ◽  
Carla-Maria Alexander
Keyword(s):  
Lung Cancer ◽  
Mouse Models ◽  
Stress Responses ◽  
Loss Of Function ◽  
Mutation Status ◽  
Activating Mutations ◽  
Cellular Stress Responses ◽  
Xenograft Models ◽  
Pulmonary Neoplasia

Nuclear factor, erythroid-derived 2, like 2 (NRF2) is a key regulator of antioxidants and cellular stress responses. The role ofNRF2in pulmonary neoplasia, a diverse disease for which few biomarkers exist, is complicated and appears to depend on several main factors including the existence of activating mutations inNRF2and/or loss of function mutations inKEAP1and the stage of carcinogenesis studied, particularly in the mouse models tested. Therapeutic strategies for lung cancer targetingNRF2have observed mixed results, both anti- and protumorigenic effects; however, these differences seem to reflect the mutation status ofNRF2orKEAP1. In this paper, we will discuss the studies on humanNRF2and the mechanisms proposed, several mouse models using various mice deficient inNRF2, as well as xenograft models, and the chemotherapeutic strategies using theNRF2pathway.

scholarly journals Mouse models of altered gonadotrophin action: insight into male reproductive disorders

Reproduction ◽  
2014 ◽  
Vol 148 (4) ◽  
pp. R63-R70 ◽  
Author(s):  
Kim C Jonas ◽  
Olayiwola O Oduwole ◽  
Hellevi Peltoketo ◽  
Susana B Rulli ◽  
Ilpo T Huhtaniemi
Keyword(s):  
Mouse Models ◽  
Molecular Mechanisms ◽  
Pituitary Hormones ◽  
Loss Of Function ◽  
Reproductive Disorders ◽  
Human Reproductive ◽  
Multiple Loss ◽  
The Relationship

The advent of technologies to genetically manipulate the mouse genome has revolutionised research approaches, providing a unique platform to study the causality of reproductive disorders in vivo. With the relative ease of generating genetically modified (GM) mouse models, the last two decades have yielded multiple loss-of-function and gain-of-function mutation mouse models to explore the role of gonadotrophins and their receptors in reproductive pathologies. This work has provided key insights into the molecular mechanisms underlying reproductive disorders with altered gonadotrophin action, revealing the fundamental roles of these pituitary hormones and their receptors in the hypothalamic–pituitary–gonadal axis. This review will describe GM mouse models of gonadotrophins and their receptors with enhanced or diminished actions, specifically focusing on the male. We will discuss the mechanistic insights gained from these models into male reproductive disorders, and the relationship and understanding provided into male human reproductive disorders originating from altered gonadotrophin action.

scholarly journals The role of aTp-dependent chromatin remodeling factors in chromatin assembly in vivo

2019 ◽  
Vol 23 (2) ◽  
pp. 160-167
Author(s):  
Iu. A. Il’ina ◽  
A. Yu. Konev
Keyword(s):  
Dna Repair ◽  
Chromatin Remodeling ◽  
Molecular Motor ◽  
Chromatin Assembly ◽  
Histone Chaperones ◽  
Nucleosome Assembly ◽  
Male Pronucleus ◽  
Histone Exchange

Chromatin assembly is a fundamental process essential for chromosome duplication subsequent to DNA replication. In addition, histone removal and incorporation take place constantly throughout the cell cycle in the course of DNA-utilizing processes, such as transcription, damage repair or recombination. In vitro studies have revealed that nucleosome assembly relies on the combined action of core histone chaperones and ATP-utilizing molecular motor proteins such as ACF or CHD1. Despite extensive biochemical characterization of ATP-dependent chromatin assembly and remodeling factors, it has remained unclear to what extent nucleosome assembly is an ATP-dependent process in vivo. Our original and published data about the functions of ATP-dependent chromatin assembly and remodeling factors clearly demonstrated that these proteins are important for nucleosome assembly and histone exchange in vivo. During male pronucleus reorganization after fertilization CHD1 has a critical role in the genomescale, replication-independent nucleosome assembly involving the histone variant H3.3. Thus, the molecular motor proteins, such as CHD1, function not only in the remodeling of existing nucleosomes but also in de novo nucleosome assembly from DNA and histones in vivo. ATP-dependent chromatin assembly and remodeling factors have been implicated in the process of histone exchange during transcription and DNA repair, in the maintenance of centromeric chromatin and in the loading and remodeling of nucleosomes behind a replication fork. Thus, chromatin remodeling factors are involved in the processes of both replication-dependent and replication-independent chromatin assembly. The role of these proteins is especially prominent in the processes of large-scale chromatin reorganization; for example, during male pronucleus formation or in DNA repair. Together, ATP-dependent chromatin assembly factors, histone chaperones and chromatin modifying enzymes form a “chromatin integrity network” to ensure proper maintenance and propagation of chromatin landscape.

Investigating the role of BAFF in different mouse models of allergic asthma

Pneumologie ◽  
2014 ◽  
Vol 68 (06) ◽  
Author(s):  
A Lorenz ◽  
M Busse ◽  
K Dalüge ◽  
AK Behrendt ◽  
G Hansen ◽  
...  
Keyword(s):  
Allergic Asthma ◽  
Mouse Models

scholarly journals A family harboring an MLKL loss of function variant implicates impaired necroptosis in diabetes

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Joanne M. Hildebrand ◽  
Bernice Lo ◽  
Sara Tomei ◽  
Valentina Mattei ◽  
Samuel N. Young ◽  
...  
Keyword(s):  
Potential Role ◽  
Autosomal Dominant ◽  
Inflammatory Diseases ◽  
Diabetic Patients ◽  
Incomplete Penetrance ◽  
Loss Of Function ◽  
Healthy Sibling ◽  
Dominant Disease ◽  
Terminal Effector

AbstractMaturity-onset diabetes of the young, MODY, is an autosomal dominant disease with incomplete penetrance. In a family with multiple generations of diabetes and several early onset diabetic siblings, we found the previously reported P33T PDX1 damaging mutation. Interestingly, this substitution was also present in a healthy sibling. In contrast, a second very rare heterozygous damaging mutation in the necroptosis terminal effector, MLKL, was found exclusively in the diabetic family members. Aberrant cell death by necroptosis is a cause of inflammatory diseases and has been widely implicated in human pathologies, but has not yet been attributed functions in diabetes. Here, we report that the MLKL substitution observed in diabetic patients, G316D, results in diminished phosphorylation by its upstream activator, the RIPK3 kinase, and no capacity to reconstitute necroptosis in two distinct MLKL−/− human cell lines. This MLKL mutation may act as a modifier to the P33T PDX1 mutation, and points to a potential role of impairment of necroptosis in diabetes. Our findings highlight the importance of family studies in unraveling MODY’s incomplete penetrance, and provide further support for the involvement of dysregulated necroptosis in human disease.

scholarly journals Non-productive angiogenesis disassembles Aß plaque-associated blood vessels

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Maria I. Alvarez-Vergara ◽  
Alicia E. Rosales-Nieves ◽  
Rosana March-Diaz ◽  
Guiomar Rodriguez-Perinan ◽  
Nieves Lara-Ureña ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Blood Vessels ◽  
Molecular Signature ◽  
Loss Of Function ◽  
Local Loss ◽  
Microglial Phagocytosis ◽  
Vascular Phenotype ◽  
Cerebral Microvasculature ◽  
Vascular Component

AbstractThe human Alzheimer’s disease (AD) brain accumulates angiogenic markers but paradoxically, the cerebral microvasculature is reduced around Aß plaques. Here we demonstrate that angiogenesis is started near Aß plaques in both AD mouse models and human AD samples. However, endothelial cells express the molecular signature of non-productive angiogenesis (NPA) and accumulate, around Aß plaques, a tip cell marker and IB4 reactive vascular anomalies with reduced NOTCH activity. Notably, NPA induction by endothelial loss of presenilin, whose mutations cause familial AD and which activity has been shown to decrease with age, produced a similar vascular phenotype in the absence of Aß pathology. We also show that Aß plaque-associated NPA locally disassembles blood vessels, leaving behind vascular scars, and that microglial phagocytosis contributes to the local loss of endothelial cells. These results define the role of NPA and microglia in local blood vessel disassembly and highlight the vascular component of presenilin loss of function in AD.

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