DALILEH NABI - Academia.edu (original) (raw)

Papers by DALILEH NABI

Research paper thumbnail of Multidrug resistance transporter-1 dysfunction perturbs meiosis and Ca2+ homeostasis in oocytes

Reproduction

MDR-1 is a transmembrane ATP-dependent effluxer present in organs that transport a variety of xen... more MDR-1 is a transmembrane ATP-dependent effluxer present in organs that transport a variety of xenobiotics and byproducts. Previous findings by our group demonstrated that this transporter is also present in the oocyte mitochondrial membrane and that its mutation led to abnormal mitochondrial homeostasis. Considering the importance of these organelles in the female gamete, we assessed the impact of MDR-1 dysfunction on mouse oocyte quality, with a particular focus on the meiotic spindle organization, aneuploidies, Ca2+ homeostasis, ATP production and mtDNA mutations. Our results demonstrate that young Mdr1 mutant mice produce oocytes characterized by lower quality, with a significant delay in the germinal vesicle (GV) to germinal vesicle breakdown (GVBD) transition, an increased percentage of symmetric divisions, chromosome mis-alignments and a severely altered meiotic spindle shape compared to the wild types. Mutant oocytes exhibit 7000 more single nucleotide polymorphisms (SNPs) in...

Research paper thumbnail of The Role of T Cells in Ovarian Physiology and Infertility

Frontiers in Cell and Developmental Biology

Infertility affects one in six couples worldwide, with more than 48 million couples affected inte... more Infertility affects one in six couples worldwide, with more than 48 million couples affected internationally. The prevalence of infertility is increasing which is thought to be attributed to delayed child-bearing due to socioeconomic factors. Since women are more prone to autoimmune diseases, we sought to describe the correlation between ovarian-mediated infertility and autoimmunity, and more specifically, the role of T cells in infertility. T cells prevent autoimmune diseases and allow maternal immune tolerance of the semi-allogeneic fetus during pregnancy. However, the role of T cells in ovarian physiology has yet to be fully understood.

Research paper thumbnail of CENP-V is required for proper chromosome segregation through interaction with spindle microtubules in mouse oocytes

Nature Communications, 2021

Proper chromosome segregation is essential to avoid aneuploidy, yet this process fails with incre... more Proper chromosome segregation is essential to avoid aneuploidy, yet this process fails with increasing age in mammalian oocytes. Here we report a role for the scarcely described protein CENP-V in oocyte spindle formation and chromosome segregation. We show that depending on the oocyte maturation state, CENP-V localizes to centromeres, to microtubule organizing centers, and to spindle microtubules. We find that Cenp-V−/− oocytes feature severe deficiencies, including metaphase I arrest, strongly reduced polar body extrusion, increased numbers of mis-aligned chromosomes and aneuploidy, multipolar spindles, unfocused spindle poles and loss of kinetochore spindle fibres. We also show that CENP-V protein binds, diffuses along, and bundles microtubules in vitro. The spindle assembly checkpoint arrests about half of metaphase I Cenp-V−/− oocytes from young adults only. This finding suggests checkpoint weakening in ageing oocytes, which mature despite carrying mis-aligned chromosomes. Thus,...

Research paper thumbnail of Germline POT1 Deregulation Can Predispose to Myeloid Malignancies in Childhood

International Journal of Molecular Sciences, 2021

While the shelterin complex guards and coordinates the mechanism of telomere regulation, deregula... more While the shelterin complex guards and coordinates the mechanism of telomere regulation, deregulation of this process is tightly linked to malignant transformation and cancer. Here, we present the novel finding of a germline stop-gain variant (p.Q199*) in the shelterin complex gene POT1, which was identified in a child with acute myeloid leukemia. We show that the cells overexpressing the mutated POT1 display increased DNA damage and chromosomal instabilities compared to the wildtype counterpart. Protein and mRNA expression analyses in the primary patient cells further confirm that, physiologically, the variant leads to a nonfunctional POT1 allele in the patient. Subsequent telomere length measurements in the primary cells carrying heterozygous POT1 p.Q199* as well as POT1 knockdown AML cells revealed telomeric elongation as the main functional effect. These results show a connection between POT1 p.Q199* and telomeric dysregulation and highlight POT1 germline deficiency as a predisp...

Research paper thumbnail of Bisphenols disrupt differentiation of the pigmented cells during larval brain formation in the ascidian

Aquatic Toxicology, 2019

The endocrine disruptor Bisphenol A (BPA), a widely employed molecule in plastics, has been shown... more The endocrine disruptor Bisphenol A (BPA), a widely employed molecule in plastics, has been shown to affect several biological processes in vertebrates, mostly via binding to nuclear receptors. Neurodevelopmental effects of BPA have been documented in vertebrates and linked to neurodevelopmental disorders, probably because some nuclear receptors are present in the vertebrate brain. Similarly, endocrine disruptors have been shown to affect neurodevelopment in marine invertebrates such as ascidians, mollusks or echinoderms, but whether invertebrate nuclear receptors are involved in the mode-of-action is largely unknown. In this study, we assessed the effect of BPA on larval brain development of the ascidian Phallusia mammillata. We found that BPA is toxic to P. mammillata embryos in a dose-dependent manner (EC 50 : 11.8µM; LC 50 : 21µM). Furthermore, micromolar doses of BPA impaired differentiation of the ascidian pigmented cells, by inhibiting otolith movement within the sensory vesicle. We further show that this phenotype is specific to other two bisphenols (BPE and BPF) over a bisphenyl (2,2 DPP). Because in vertebrates the estrogen-related receptor gamma (ERRγ) can bind bisphenols with high affinity but not bisphenyls, we tested whether the ascidian ERR participates in the neurodevelopmental phenotype induced by BPA. Interestingly, P. mammillata ERR is expressed in the larval brain, adjacent to the differentiating otolith. Furthermore, antagonists of vertebrate ERRs also inhibited the otolith movement but not pigmentation. Together our observations suggest that BPA may affect ascidian otolith differentiation by altering Pm-ERR activity whereas otolith pigmentation defects might be due to the known inhibitory effect of bisphenols on tyrosinase enzymatic activity.

Research paper thumbnail of P-689 Mutated MDR-1 impairs chromosome alignment and reduces oocyte quality

Human Reproduction

Study question With this study we aim to assess the link between oocyte mitochondrial physiology ... more Study question With this study we aim to assess the link between oocyte mitochondrial physiology and spindle formation with respect to Multidrug Resistance transporter 1 (MDR-1) function. Summary answer Our most recent data suggest that oocyte quality is compromised in young and old Mdr1 mutant mice. What is known already MDR-1 is a transmembrane ATP-dependent effluxer present in different organs that transport a variety of xenobiotics and byproducts from one side of the membrane to the other. Previous findings by Clark et al. 2019 demonstrated that this transporter is also present in the oocyte mitochondrial membrane and that its mutation led to abnormal mitochondrial homeostasis. Mitochondria are essential for normal oocyte physiology, quality and competence for fertilization and blastocyst development (Chappel, 2013; Dumollard et al., 2007). Therefore, any alteration of their bioenergetics and functions affects the quality of the egg, eventually compromising fertility. Study desi...

Research paper thumbnail of The spindle assembly checkpoint functions during early development in non-chordate embryos

In eukaryotic cells, a spindle assembly checkpoint (SAC) ensures accurate chromosome segregation.... more In eukaryotic cells, a spindle assembly checkpoint (SAC) ensures accurate chromosome segregation. This control mechanism monitors proper attachment of chromosomes to spindle microtubules and delays mitotic progression if connections are erroneous or absent. The SAC operates in all eukaryotic cells tested so far, but is thought to be relaxed during early embryonic development in animals. Here, we evaluate the checkpoint response to lack of kinetochore-spindle microtubule interactions in early embryos of diverse animal species from the main metazoan groups. Our analysis shows that there are two classes of embryos, either proficient or deficient for SAC activation during cleavage. Sea urchins, mussels and jellyfish embryos show a prolonged mitotic block in the absence of spindle microtubules from the first cleavage division, while ascidian and amphioxus embryos, like those of Xenopus and zebrafish, continue mitotic cycling without delay. SAC competence during early development shows no...

Research paper thumbnail of Multidrug resistance transporter-1 dysfunction perturbs meiosis and Ca2+ homeostasis in oocytes

Reproduction

MDR-1 is a transmembrane ATP-dependent effluxer present in organs that transport a variety of xen... more MDR-1 is a transmembrane ATP-dependent effluxer present in organs that transport a variety of xenobiotics and byproducts. Previous findings by our group demonstrated that this transporter is also present in the oocyte mitochondrial membrane and that its mutation led to abnormal mitochondrial homeostasis. Considering the importance of these organelles in the female gamete, we assessed the impact of MDR-1 dysfunction on mouse oocyte quality, with a particular focus on the meiotic spindle organization, aneuploidies, Ca2+ homeostasis, ATP production and mtDNA mutations. Our results demonstrate that young Mdr1 mutant mice produce oocytes characterized by lower quality, with a significant delay in the germinal vesicle (GV) to germinal vesicle breakdown (GVBD) transition, an increased percentage of symmetric divisions, chromosome mis-alignments and a severely altered meiotic spindle shape compared to the wild types. Mutant oocytes exhibit 7000 more single nucleotide polymorphisms (SNPs) in...

Research paper thumbnail of The Role of T Cells in Ovarian Physiology and Infertility

Frontiers in Cell and Developmental Biology

Infertility affects one in six couples worldwide, with more than 48 million couples affected inte... more Infertility affects one in six couples worldwide, with more than 48 million couples affected internationally. The prevalence of infertility is increasing which is thought to be attributed to delayed child-bearing due to socioeconomic factors. Since women are more prone to autoimmune diseases, we sought to describe the correlation between ovarian-mediated infertility and autoimmunity, and more specifically, the role of T cells in infertility. T cells prevent autoimmune diseases and allow maternal immune tolerance of the semi-allogeneic fetus during pregnancy. However, the role of T cells in ovarian physiology has yet to be fully understood.

Research paper thumbnail of CENP-V is required for proper chromosome segregation through interaction with spindle microtubules in mouse oocytes

Nature Communications, 2021

Proper chromosome segregation is essential to avoid aneuploidy, yet this process fails with incre... more Proper chromosome segregation is essential to avoid aneuploidy, yet this process fails with increasing age in mammalian oocytes. Here we report a role for the scarcely described protein CENP-V in oocyte spindle formation and chromosome segregation. We show that depending on the oocyte maturation state, CENP-V localizes to centromeres, to microtubule organizing centers, and to spindle microtubules. We find that Cenp-V−/− oocytes feature severe deficiencies, including metaphase I arrest, strongly reduced polar body extrusion, increased numbers of mis-aligned chromosomes and aneuploidy, multipolar spindles, unfocused spindle poles and loss of kinetochore spindle fibres. We also show that CENP-V protein binds, diffuses along, and bundles microtubules in vitro. The spindle assembly checkpoint arrests about half of metaphase I Cenp-V−/− oocytes from young adults only. This finding suggests checkpoint weakening in ageing oocytes, which mature despite carrying mis-aligned chromosomes. Thus,...

Research paper thumbnail of Germline POT1 Deregulation Can Predispose to Myeloid Malignancies in Childhood

International Journal of Molecular Sciences, 2021

While the shelterin complex guards and coordinates the mechanism of telomere regulation, deregula... more While the shelterin complex guards and coordinates the mechanism of telomere regulation, deregulation of this process is tightly linked to malignant transformation and cancer. Here, we present the novel finding of a germline stop-gain variant (p.Q199*) in the shelterin complex gene POT1, which was identified in a child with acute myeloid leukemia. We show that the cells overexpressing the mutated POT1 display increased DNA damage and chromosomal instabilities compared to the wildtype counterpart. Protein and mRNA expression analyses in the primary patient cells further confirm that, physiologically, the variant leads to a nonfunctional POT1 allele in the patient. Subsequent telomere length measurements in the primary cells carrying heterozygous POT1 p.Q199* as well as POT1 knockdown AML cells revealed telomeric elongation as the main functional effect. These results show a connection between POT1 p.Q199* and telomeric dysregulation and highlight POT1 germline deficiency as a predisp...

Research paper thumbnail of Bisphenols disrupt differentiation of the pigmented cells during larval brain formation in the ascidian

Aquatic Toxicology, 2019

The endocrine disruptor Bisphenol A (BPA), a widely employed molecule in plastics, has been shown... more The endocrine disruptor Bisphenol A (BPA), a widely employed molecule in plastics, has been shown to affect several biological processes in vertebrates, mostly via binding to nuclear receptors. Neurodevelopmental effects of BPA have been documented in vertebrates and linked to neurodevelopmental disorders, probably because some nuclear receptors are present in the vertebrate brain. Similarly, endocrine disruptors have been shown to affect neurodevelopment in marine invertebrates such as ascidians, mollusks or echinoderms, but whether invertebrate nuclear receptors are involved in the mode-of-action is largely unknown. In this study, we assessed the effect of BPA on larval brain development of the ascidian Phallusia mammillata. We found that BPA is toxic to P. mammillata embryos in a dose-dependent manner (EC 50 : 11.8µM; LC 50 : 21µM). Furthermore, micromolar doses of BPA impaired differentiation of the ascidian pigmented cells, by inhibiting otolith movement within the sensory vesicle. We further show that this phenotype is specific to other two bisphenols (BPE and BPF) over a bisphenyl (2,2 DPP). Because in vertebrates the estrogen-related receptor gamma (ERRγ) can bind bisphenols with high affinity but not bisphenyls, we tested whether the ascidian ERR participates in the neurodevelopmental phenotype induced by BPA. Interestingly, P. mammillata ERR is expressed in the larval brain, adjacent to the differentiating otolith. Furthermore, antagonists of vertebrate ERRs also inhibited the otolith movement but not pigmentation. Together our observations suggest that BPA may affect ascidian otolith differentiation by altering Pm-ERR activity whereas otolith pigmentation defects might be due to the known inhibitory effect of bisphenols on tyrosinase enzymatic activity.

Research paper thumbnail of P-689 Mutated MDR-1 impairs chromosome alignment and reduces oocyte quality

Human Reproduction

Study question With this study we aim to assess the link between oocyte mitochondrial physiology ... more Study question With this study we aim to assess the link between oocyte mitochondrial physiology and spindle formation with respect to Multidrug Resistance transporter 1 (MDR-1) function. Summary answer Our most recent data suggest that oocyte quality is compromised in young and old Mdr1 mutant mice. What is known already MDR-1 is a transmembrane ATP-dependent effluxer present in different organs that transport a variety of xenobiotics and byproducts from one side of the membrane to the other. Previous findings by Clark et al. 2019 demonstrated that this transporter is also present in the oocyte mitochondrial membrane and that its mutation led to abnormal mitochondrial homeostasis. Mitochondria are essential for normal oocyte physiology, quality and competence for fertilization and blastocyst development (Chappel, 2013; Dumollard et al., 2007). Therefore, any alteration of their bioenergetics and functions affects the quality of the egg, eventually compromising fertility. Study desi...

Research paper thumbnail of The spindle assembly checkpoint functions during early development in non-chordate embryos

In eukaryotic cells, a spindle assembly checkpoint (SAC) ensures accurate chromosome segregation.... more In eukaryotic cells, a spindle assembly checkpoint (SAC) ensures accurate chromosome segregation. This control mechanism monitors proper attachment of chromosomes to spindle microtubules and delays mitotic progression if connections are erroneous or absent. The SAC operates in all eukaryotic cells tested so far, but is thought to be relaxed during early embryonic development in animals. Here, we evaluate the checkpoint response to lack of kinetochore-spindle microtubule interactions in early embryos of diverse animal species from the main metazoan groups. Our analysis shows that there are two classes of embryos, either proficient or deficient for SAC activation during cleavage. Sea urchins, mussels and jellyfish embryos show a prolonged mitotic block in the absence of spindle microtubules from the first cleavage division, while ascidian and amphioxus embryos, like those of Xenopus and zebrafish, continue mitotic cycling without delay. SAC competence during early development shows no...