Mice with a targeted mutation in the myogenic basic helix-loop-helix regulatory protein myogenin have severe muscle defects resulting perinatal death. In this report, effect of myogenin's absence on embryonic and fetal development is investigated. The initial events somite differentiation occurred normally myogenin-mutant embryos. During primary myogenesis, masses mutant embryos developed simultaneously control siblings, although within was delayed. More dramatic effects were observed when...

In the preimplantation mouse embryo, TEAD4 is critical to establishing trophectoderm (TE)-specific transcriptional program and segregating TE from inner cell mass (ICM). However, expressed in ICM. Thus, differential function of rather than expression itself regulates specification first two lineages. We used ChIP sequencing define genomewide target genes asked how transcription specifically maintained TE. Our analyses revealed an evolutionarily conserved mechanism, which lack nuclear...

Significance Defective placentation, including impaired uterine spiral artery remodeling, leads to pregnancy disorders such as loss, preeclampsia, intrauterine growth restriction, and preterm birth, all of which cause significant morbidity mortality for the mother fetus. Trophoblast cells are central executing placental functions can differentiate into two conserved specialized lineages: invasive/extravillous trophoblast cells, guide transformation, syncytiotrophoblast, serve a barrier...

Significance Epithelial barrier integrity is dependent on progenitor cells that either divide to replenish themselves or differentiate into a functional epithelium. In the placenta, cytotrophoblast comprise this population, but differentiation program they undertake unlike any other in human tissues: acquisition of hormonogenesis and cell fusion form syncytialized (syncytio)trophoblast. Syncytiotrophoblast forms primary epithelial separating maternal fetal tissue performs functions vital for...

Estrogens are essential hormones for the regulation of fertility. Cellular responses to estrogens mediated by estrogen receptor α (ESR1) and β (ESR2). In mouse rat models, disruption Esr1 causes infertility in both males females. However, role ESR2 reproductive function remains undecided because a wide variation phenotypic observations among Esr2-mutant strains. Regulatory pathways independent binding its cognate DNA response element have also been implicated signaling. To clarify regulatory...

Significance Progesterone possesses an essential role in regulating female fertility, with prominent actions throughout the reproductive axis. The neuroendocrine of progesterone have been viewed as critical for control cycle. This basic principle has reinforced by vivo experimental paradigms, using hormone replacement well pharmacologic and genetic disruption receptor (PGR). Phenotypic characterization Pgr null rats strengthens roles regulation but not determinant cyclicity, challenging...

Estrogens play pivotal roles in development and function of many organ systems, including the reproductive system. We have generated estrogen receptor 1 (Esr1)-knockout rats using zinc finger nuclease (ZFN) genome targeting. mRNAs encoding ZFNs targeted to exon 3 Esr1 were microinjected into single-cell rat embryos transferred pseudopregnant recipients. Of 17 live births, 5 had biallelic monoallelic mutations. A founder with mutations was backcrossed a wild-type rat. Offspring possessed only...

Abstract Because of their deleterious effects on developing organisms, ribosomal protein (RP) mutations have been poorly described in mammals, and only a few heterozygous shown to be viable. This observation is believed due the fact that each RP an essential component assembly functional stable ribosome. Here, we created gene targeted mutant mice lacking HIP/RPL29, associated with translationally active ribosomes eukaryotes. In contrast other mutants, HIP/RPL29 null are viable but up 50%...

Members of the transforming growth factor-beta superfamily play essential roles in both pluripotency and differentiation embryonic stem (ES) cells. Although bone morphogenic proteins (BMPs) maintain undifferentiated mouse ES cells, role autocrine Nodal signaling is less clear. Pharmacological, molecular, genetic methods were used to further understand potential interactions these pathways. Treatment cells with SB431542, a pharmacological inhibitor Smad2 signaling, resulted rapid reduction...

Embryonic stem cells dynamically fluctuate between phenotypic states, as defined by expression levels of genes such Nanog, while remaining pluripotent. The dynamic phenotype is in part determined gene control and dictated various signaling pathways transcriptional regulators. We sought to define the activities two TGF-β-related pathways, bone morphogenetic protein (BMP) Nodal signaling, modulating mouse embryonic (ES) cell heterogeneity undifferentiated culture conditions. Both BMP were seen...

Objectives/Goals: Diamond Blackfan anemia (DBA) is caused by loss of ribosomal proteins leading to death red blood cell progenitors. We identified a novel heterozygous variant (c.167+769C>T) in RPL30 patient with DBA. hypothesized that this variant, gene not previously studied DBA, would demonstrate DBA phenotype and reveal early drivers disease. Methods/Study Population: To study the role our we developed an induced pluripotent stem (iPSC) model, including wild type (WT) CRISPR-edited...

Using selectable genes as proof of principle, a new high-throughput genotype-based mutation screen in mouse embryonic stem (ES) cells was developed [Chen et al. (2002) Nat. Genet. 24, 314–317]. If expanded to nonselectable genes, this approach would allow one proceed quickly from sequence whole-animal phenotypes. Here data are presented showing that cryopreserved library clonal, germ line competent, N -ethyl- -nitrosurea (ENU) mutagenized ES can identify large series allelic mutations Smad2...

Angiogenesis is induced by multiple growth factors including vascular endothelial factor (VEGF) and fibroblast 2 (FGF2). In endothelium VEGF signals through two receptor-tyrosine kinases, VEGFR1 VEGFR2. The gene encodes both a kinase secreted splice variant, soluble VEGFR1. Whereas essential for development, mechanisms that regulate expression in cells are poorly understood. We demonstrate here cells, FGF2 epidermal (EGF) signaling induce mRNA combinatorial fashion. EGF/FGF2-mediated...

The mitochondrial paradigm for common disease proposes that DNA (mtDNA) sequence variation can contribute to susceptibility and progression. To test this concept, we developed the Mitochondrial-nuclear eXchange (MNX) model, in which isolated embryonic pronuclei from one strain of species are implanted into an enucleated embryo a different same (e.g., C57BL/6 C3H/HeN, Mus musculus), generating re-constructed zygote harboring nuclear genomes strains. Two-cell embryos transferred ostia oviducts...

Prolactin (PRL) signaling has been implicated in the regulation of glucose homeostatic adaptations to pregnancy. In this report, PRL receptor (Prlr) gene was conditionally disrupted pancreas, creating an animal model which proved useful for investigating biology and pathology gestational diabetes including its impacts on fetal placental development. mice, pancreatic PRLR demonstrated be required pregnancy-associated changes maternal β cell mass function. Disruption Prlr pancreas resulted...

In polycystic kidney disease (PKD), persistent activation of cell proliferation and matrix production contributes to cyst growth fibrosis, leading progressive deterioration renal function. Previously, we showed that periostin, a matricellular protein involved in tissue repair, is overexpressed by cystic epithelial cells PKD kidneys. Periostin binds αVβ3-integrins activates integrin-linked kinase (ILK), Akt/mammalian target rapamycin (mTOR)-mediated human cells. By contrast, periostin does...

The prolactin (PRL) family of hormones and cytokines participates in the regulation optimal reproductive performance mouse rat. Members PRL are expressed anterior pituitary, uterus, and/or placenta. In present study, we investigated ontogeny 7, subfamily b, member 1 (PRL7B1; also called PRL-like protein-N, PLP-N) expression developing placenta established a model for investigating biological function PRL7B1. Transcripts Prl7b1 were first detected on Gestation Day (d) 8.5. From gestation d8.5...

DOT1-like (DOT1L) histone methyltransferase is essential for mammalian erythropoiesis. Loss of DOT1L in knockout (Dot1l-KO) mouse embryos resulted lethal anemia at midgestational age. The only recognized molecular function its methylation H3 lysine 79 (H3K79). We generated a Dot1l mutant (Dot1l-MM) model to determine the role activity early embryonic hematopoiesis. Dot1l-MM failed survive beyond day 13.5 (E13.5), similarly Dot1l-KO mice. However, when examined E10.5, did not exhibit overt...

The signaling cascades that direct the morphological differentiation of vascular system during early embryogenesis are not well defined. Several pathways, including Notch and VEGF signaling, critical for formation vasculature in mouse. To further understand role endothelial genes regulated by this pathway, both loss-of-function gain-of-function approaches were analyzed vivo.Conditional transgenic models used to expand ablate embryonic endothelium. Embryos with activated Notch1 displayed a...

DOT1L is essential for embryonic hematopoiesis but the precise mechanisms of its action remain unclear. The only recognized function histone H3 lysine 79 (H3K79) methylation, which has been implicated in both transcriptional activation and repression. We observed that deletion mouse

Mowat-Wilson syndrome is a rare genetic condition characterized by intellectual disability, structural anomalies, and dysmorphic features. It caused haploinsufficiency of the <i>ZEB2</i> gene in chromosome 2q22.3. Over 180 distinct mutations have been reported, including nonsense missense point mutations, deletions, large chromosomal rearrangements. We report on 14-year-old female with clinical diagnosis syndrome. Chromosomal microarray identified novel de novo 69-kb duplication...

Mitochondrial dysfunction is observed in Alzheimer's disease (AD). Altered mitochondrial respiration, cytochrome oxidase (COX) Vmax, and mitophagy are human subjects animal models of AD. Models derived from induced pluripotent stem cells (iPSCs) may not recapitulate these phenotypes after reprogramming differentiated adult cells.We examined function across iPSC including cerebral organoids, forebrain neurons, astrocytes. iPSCs were reprogrammed fibroblasts either the University Kansas...

The aromatase-Cre recombinase (Cyp19-Cre) transgenic mouse model has been extensively used for placenta-specific gene inactivation. In a pilot study, we observed unexpected phenotypes using this strain, which prompted an extensive characterization of Cyp19-Cre placental ROSAmT/mG reporter mice. two strains were mated to generate bi-transgenic Cyp19-Cre;ROSAmT/mG mice following standard breeding scheme, and fetal tissues analyzed on embryonic day 17.5. Both maternal paternal Cre inheritance...