Mutations in genes encoding chromatin-remodeling proteins, such as the ATRX gene, underlie a number of genetic disorders including several X-linked mental retardation syndromes; however, role these proteins normal CNS development is unknown. Here, we used conditional gene-targeting approach to inactivate Atrx, specifically forebrain mice. Loss protein caused widespread hypocellularity neocortex and hippocampus pronounced reduction size. Neuronal "birthdating" confirmed that fewer neurons...

Mutations in genes encoding chromatin-remodeling proteins, such as the ATRX gene, underlie a number of genetic disorders including several X-linked mental retardation syndromes; however, role these proteins normal CNS development is unknown. Here, we used conditional gene-targeting approach to inactivate Atrx, specifically forebrain mice. Loss protein caused widespread hypocellularity neocortex and hippocampus pronounced reduction size. Neuronal "birthdating" confirmed that fewer neurons...

αThalassemia/mental retardation X linked (ATRX) is a switch/sucrose nonfermenting-type ATPase localized at pericentromeric heterochromatin in mouse and human cells. Human ATRX mutations give rise to mental syndromes characterized by developmental delay, facial dysmorphisms, cognitive deficits, microcephaly the loss of brain leads reduced cortical size. We find that required for normal mitotic progression cultured cells neuroprogenitors. Using live cell imaging, we show transition from...

Condensation and segregation of mitotic chromosomes is a critical process for cellular propagation, and, in mammals, errors can contribute to the pathogenesis cancer. In this report, we demonstrate that retinoblastoma protein (pRB), well-known regulator progression through G1 phase cell cycle, plays role chromosome condensation independent G1-to-S-phase regulation. Using gene targeted mutant mice, studied aspect pRB function isolation, it an essential part pRB-mediated tumor suppression....

Human ATRX mutations are associated with cognitive deficits, developmental abnormalities, and cancer. We show that the Atrx-null embryonic mouse brain accumulates replicative damage at telomeres pericentromeric heterochromatin, which is exacerbated by loss of p53 linked to ATM activation. ATRX-deficient neuroprogenitors exhibited higher incidence telomere fusions increased sensitivity replication stress–inducing drugs. Treatment G-quadruplex (G4) ligand telomestatin DNA damage, indicating...

Porcine epidemic diarrhea virus (PEDV) is a highly contagious infecting pigs of all ages with high morbidity and mortality among newborn piglets. Currently, there no effective vaccine available to protect the from PEDV. The N-terminal subunit spike protein (S1) responsible for binding cellular receptor contains number neutralizing antibody epitopes. Thus, we expressed produced recombinant S1 piglets by immunization sows. Affinity tagged PEDV was in secretory form yeast, insect mammalian...

Infection of highly pathogenic avian influenza (HPAI) H5N1 clade 2.3.4.4b in dairy cows causes severe mastitis and milk production losses. Whether can develop protective immunity is unclear. Here we infected three lactating with HPAI genotype B3.13 via the hindquarters udder to mimic intra-mammary infection. Inoculated displayed clinical responses consistent affected herds United States including virus shedding almost exclusively inoculated that peaked between Days 2-4 post inoculation...

Mutations in the ATRX gene are associated with an X‐linked mental retardation (XLMR) syndrome most often accompanied by α-thalassaemia (ATR-X syndrome). The encodes a predicted protein of 280 kDa featuring PHD zinc finger motif and ATPase/helicase domain SWI/SNF type; vast majority mutations fall within these two motifs. Although domains suggestive role for transcriptional regulation affecting chromatin structure and/or function, precise cellular remains undefined. Using indirect...

Based on the dominance of cellular senescence over immortality, immortal human cell lines have been assigned to four complementation groups for indefinite division. Human chromosomes carrying genes identified, including chromosome 4. We report cloning and identification a gene, mortality factor 4 (MORF 4), which induces senescent-like phenotype in group B with concomitant changes two markers senescence. MORF is member novel family transcription factor-like motifs. present here sequences...

The retinoblastoma protein (pRb) has been proposed to regulate cell cycle progression in part through its ability interact with enzymes that modify histone tails and create a repressed chromatin structure. We created mutation the murine Rb1 gene disrupted pRb's these determine if it affected control. Here, we show loss of this interaction slows mitosis causes aneuploidy. Our experiments reveal while LXCXE binding site does not disrupt Suv4-20h methyltransferases, dramatically reduces H4-K20...

ATRX is a chromatin remodeling protein involved in deposition of the histone variant H3.3 at telomeres and pericentromeric heterochromatin. It also influences expression level specific genes; however, transcribed genes currently thought to occur independently ATRX. We focused on set genes, including autism susceptibility gene Neuroligin 4 (Nlgn4), that exhibit decreased ATRX-null cells investigate mechanisms used by promote transcription. Overall TERRA levels, as well DNA methylation...

An increasing number of proteins involved in genome organization have been implicated neurodevelopmental disorders, highlighting the importance chromatin architecture developing CNS. The CCCTC-binding factor (CTCF) is a zinc finger DNA binding protein higher-order organization, and mutations human CTCF gene cause an intellectual disability syndrome associated with microcephaly. However, information on function vivo brain lacking. To address this gap, we conditionally inactivated Ctcf at...

The hypothalamic kisspeptin signaling system is a major positive regulator of the reproductive neuroendocrine axis, and loss Kiss1 in mouse results infertility, condition generally attributed to its hypogonadotropic hypogonadism. We demonstrate that Kiss1−/− female mice, acute replacement gonadotropins estradiol restores ovulation, mating, fertilization; however, these mice are still unable achieve pregnancy because embryos fail implant. Progesterone treatment did not overcome this defect....

Alpha thalassemia/mental retardation X-linked syndrome (ATR-X) is caused by a mutation at the chromatin regulator gene ATRX. The mechanisms involved in ATR-X pathology are not completely understood, but may involve epigenetic modifications. ATRX has been linked to regulation of histone H3 and DNA methylation, while mutations lead downstream transcriptional effects. Elucidating underlying altered will provide better understanding about pathobiology this disease, as well novel diagnostic...

ATRX and MeCP2 belong to an expanding group of chromatin-associated proteins implicated in human neurodevelopmental disorders, although their gene-regulatory activities are not fully resolved. Loss prevents full repression imprinted gene network the postnatal brain this study we address mechanistic aspects regulation. We show that binds many domains individually but transient co-localization between nuclei neurons does require ATRX. demonstrate is required for recruitment deficiency either...

Studies in mice showed that African Zika virus (ZIKV) strains cause more damage embryos. These studies, however, were limited to the mouse-adapted MR766 strain or infection at early gestation. Here, we compared of Asian and fetal pig model midgestation. Both caused infection. ZIKV was detected placenta, amniotic membrane, fluid, blood, brain. The produced vigorous utero as represented by efficient transmission between siblings, higher viral loads organs membranes. Infection with both...

Abstract Cell fusion occurs when several cells combine to form a multinuclear aggregate (syncytium). In human placenta, syncytialized trophoblast (syncytiotrophoblast) layer forms the primary interface between maternal and fetal tissue, facilitates nutrient gas exchange, produces hormones vital for pregnancy. Syncytiotrophoblast development by differentiation of underlying progenitor called cytotrophoblasts, which then fuse into syncytiotrophoblast layer. Differentiation is associated with...

ATRX, a chromatin remodeling protein of the Snf2 family, participates in diverse cellular functions including regulation gene expression and chromosome alignment during mitosis meiosis. Mutations human cause alpha thalassemia mental retardation, X-linked (ATR-X) syndrome, rare disorder characterized by severe cognitive deficits, microcephaly epileptic seizures. Conditional inactivation Atrx mouse forebrain leads to neonatal lethality defective neurogenesis manifested increased cell death...

Idiopathic epilepsy is a common human disorder with strong genetic component, usually exhibiting complex inheritance. We describe new mouse mutation in C57BL/6J mice, called frequent-flyer (Ff), which disruption of the gene encoding RNA-binding protein Bruno-like 4 (Brunol4) leads to limbic and severe tonic–clonic seizures heterozygous mutants beginning their third month. Younger adults have reduced seizure threshold. Although homozygotes do not survive well on background, mixed backgrounds...

Experimental increase of CpG dinucleotides in an RNA virus genome impairs infection providing a promising approach for vaccine development. While recoding is emerging and approach, little known about phenotypes caused by recoded viruses vivo. For example, phenotypes, immunogenicity, protective efficacy induced CpG-recoded different age groups were not studied yet. This important, because attenuation may depend on the population-based expression cellular components targeting viral...

We studied whether cytosine phosphate-guanine (CpG) recoding in a viral genome may provide oncolytic candidates with reduced infection kinetics nonmalignant brain cells, but high virulence glioblastoma stem cells (GSCs). As model, we used well-characterized CpG-recoded Zika virus vaccine that previously showed genetic stability and safety animal models. In vitro, one of the variants had infectivity activity GSCs as represented by cell proliferation. The recoded also efficiently replicated...

Abstract Purpose: Cluster-of-differentiation antigen 9 (CD9) protein, a member of the tetraspanin family, has been implicated in carcinogenesis various human tumors. Although decreased expression CD82 close CD9 relative, is associated with prostate cancer progression, not analyzed this malignancy. Experimental Design: prostatic adenocarcinoma was by immunohistochemistry on 167 primary tumors and 88 lymph node or bone metastases. cDNA sequenced from two cell lines, adenocarcinoma, high-grade...