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  • Essential role of DPPA3 for chromatin condensation in mouse oocytogenesis. 22034526

    Dynamic alterations in chromatin configuration occur in mammalian oocytogenesis. Based on chromatin configuration patterns, fully grown oocytes are classified into two types. One is surrounded nucleolus (SN)-type and the other is nonsurrounded nucleolus (NSN)-type oocytes. Although chromatin condensation during the transition from NSN- to SN-type oocytes is a prerequisite for normal early embryonic development, the molecular mechanisms remain unclear. In this study, we analyzed the role of DPPA3 (also known as PGC7/Stella) in this transition using Dppa3-null oocytes. The NSN-to-SN transition was significantly impaired, and transcriptional repression was incomplete in the Dppa3-null oocytes. Additionally, we revealed that prior transcriptional repression was necessary for the NSN-to-SN transition. These findings demonstrate that DPPA3 is an essential factor for the production of functional oocytes through transcriptional repression and chromatin condensation.
    Document Type:
    Reference
    Product Catalog Number:
    Multiple
    Product Catalog Name:
    Multiple

  • The molecular genetics of migraine. 15513297

    Within the past decade it has been possible to identify susceptibility gene loci that predispose to migraine using genetic markers distributed across the human genome. Five new loci with significant linkage to common types of migraine--migraine with or without aura--have been identified on four different chromosomes using a genome-wide screen approach. So far, only the locus on 4q has been replicated but no specific, disease-causing mutations have been described in these common forms of migraine. The best genetic evidence providing molecular insight into migraine still comes from the mutations detected in a rare Mendelian form of migraine with aura--familial hemiplegic migraine (FHM). In 50%-70% of FHM families, mutations in the calcium channel gene CACNA1A in chromosome 19p13 have been identified. In some families, mutations in the ATP1A2 gene encoding the alpha2 subunit of the Na+, K+-ATPase are associated with FHM, linked to 1q23. Here we discuss the current knowledge of the heritability of migraine and rare migraine variants as models for understanding the pathophysiology of common migraine and animal models that might contribute to understanding common forms of migraine.
    Document Type:
    Reference
    Product Catalog Number:
    07-674
    Product Catalog Name:
    Anti-Na+K+ ATPase α-2 Antibody

  • Increased susceptibility to cortical spreading depression in the mouse model of familial hemiplegic migraine type 2. 21731499

    Familial hemiplegic migraine type 2 (FHM2) is an autosomal dominant form of migraine with aura that is caused by mutations of the α2-subunit of the Na,K-ATPase, an isoform almost exclusively expressed in astrocytes in the adult brain. We generated the first FHM2 knock-in mouse model carrying the human W887R mutation in the Atp1a2 orthologous gene. Homozygous Atp1a2(R887/R887) mutants died just after birth, while heterozygous Atp1a2(+/R887) mice showed no apparent clinical phenotype. The mutant α2 Na,K-ATPase protein was barely detectable in the brain of homozygous mutants and strongly reduced in the brain of heterozygous mutants, likely as a consequence of endoplasmic reticulum retention and subsequent proteasomal degradation, as we demonstrate in transfected cells. In vivo analysis of cortical spreading depression (CSD), the phenomenon underlying migraine aura, revealed a decreased induction threshold and an increased velocity of propagation in the heterozygous FHM2 mouse. Since several lines of evidence involve a specific role of the glial α2 Na,K pump in active reuptake of glutamate from the synaptic cleft, we hypothesize that CSD facilitation in the FHM2 mouse model is sustained by inefficient glutamate clearance by astrocytes and consequent increased cortical excitatory neurotransmission. The demonstration that FHM2 and FHM1 mutations share the ability to facilitate induction and propagation of CSD in mouse models further support the role of CSD as a key migraine trigger.
    Document Type:
    Reference
    Product Catalog Number:
    AB9094

  • Functional analysis of human Na(+)/K(+)-ATPase familial or sporadic hemiplegic migraine mutations expressed in Xenopus oocytes. 24921013

    Functional characterization of ATP1A2 mutations that are related to familial or sporadic hemiplegic migraine (FHM2, SHM).cRNA of human Na(+)/K(+)-ATPase α2- and β1-subunits were injected in Xenopus laevis oocytes. FHM2 or SHM mutations of residues located in putative α/β interaction sites or in the α2-subunit's C-terminal region were investigated. Mutants were analyzed by the two-electrode voltage-clamp (TEVC) technique on Xenopus oocytes. Stationary K(+)-induced Na(+)/K(+) pump currents were measured, and the voltage dependence of apparent K(+) affinity was investigated. Transient currents were recorded as ouabain-sensitive currents in Na(+) buffers to analyze kinetics and voltage-dependent pre-steady state charge translocations. The expression of constructs was verified by preparation of plasma membrane and total membrane fractions of cRNA-injected oocytes.Compared to the wild-type enzyme, the mutants G900R and E902K showed no significant differences in the voltage dependence of K(+)-induced currents, and analysis of the transient currents indicated that the extracellular Na(+) affinity was not affected. Mutant G855R showed no pump activity detectable by TEVC. Also for L994del and Y1009X, pump currents could not be recorded. Analysis of the plasma and total membrane fractions showed that the expressed proteins were not or only minimally targeted to the plasma membrane. Whereas the mutation K1003E had no impact on K(+) interaction, D999H affected the voltage dependence of K(+)-induced currents. Furthermore, kinetics of the transient currents was altered compared to the wild-type enzyme, and the apparent affinity for extracellular Na(+) was reduced.The investigated FHM2/SHM mutations influence protein function differently depending on the structural impact of the mutated residue.
    Document Type:
    Reference
    Product Catalog Number:
    AB9094

  • Relationship between intracellular Na+ concentration and reduced Na+ affinity in Na+,K+-ATPase mutants causing neurological disease. 24356962

    The neurological disorders familial hemiplegic migraine type 2 (FHM2), alternating hemiplegia of childhood (AHC), and rapid-onset dystonia parkinsonism (RDP) are caused by mutations of Na(+),K(+)-ATPase α2 and α3 isoforms, expressed in glial and neuronal cells, respectively. Although these disorders are distinct, they overlap in phenotypical presentation. Two Na(+),K(+)-ATPase mutations, extending the C terminus by either 28 residues ("+28" mutation) or an extra tyrosine ("+Y"), are associated with FHM2 and RDP, respectively. We describe here functional consequences of these and other neurological disease mutations as well as an extension of the C terminus only by a single alanine. The dependence of the mutational effects on the specific α isoform in which the mutation is introduced was furthermore studied. At the cellular level we have characterized the C-terminal extension mutants and other mutants, addressing the question to what extent they cause a change of the intracellular Na(+) and K(+) concentrations ([Na(+)]i and [K(+)]i) in COS cells. C-terminal extension mutants generally showed dramatically reduced Na(+) affinity without disturbance of K(+) binding, as did other RDP mutants. No phosphorylation from ATP was observed for the +28 mutation of α2 despite a high expression level. A significant rise of [Na(+)]i and reduction of [K(+)]i was detected in cells expressing mutants with reduced Na(+) affinity and did not require a concomitant reduction of the maximal catalytic turnover rate or expression level. Moreover, two mutations that increase Na(+) affinity were found to reduce [Na(+)]i. It is concluded that the Na(+) affinity of the Na(+),K(+)-ATPase is an important determinant of [Na(+)]i.
    Document Type:
    Reference
    Product Catalog Number:
    07-674
    Product Catalog Name:
    Anti-Na+K+ ATPase α-2 Antibody
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