The Distinct Roles of NEIL1 and XPA in Limiting Aflatoxin B1-Induced Mutagenesis in Mice.

Dietary exposure to aflatoxin B1 (AFB1) is a risk factor for the development of hepatocellular carcinomas. Following metabolic activation, AFB1 reacts with guanines to form covalent DNA adducts, which induce high-frequency G > T transversions. The molecular signature associated with these mutational events aligns with the single-base substitution signature 24 (SBS24) in the Catalog of Somatic Mutations in Cancer database.

Deletion of an evolutionarily conserved TAD boundary compromises spermatogenesis in mice.

Spermatogenesis is a complex process that can be disrupted by genetic and epigenetic changes, potentially leading to male infertility. Recent research has rapidly increased the number of protein coding mutations causally linked to impaired spermatogenesis in humans and mice. However, the role of non-coding mutations remains largely unexplored.

Grb7 Ablation in Mice Improved Glycemic Control, Enhanced Insulin Signaling, and Increased Abdominal fat Mass in Females.

Objectives: Growth factor receptor bound protein 7 (GRB7) is a multidomain signaling adaptor. Members of the Grb7/10/14 family, specifically Gbrb10/14, have important roles in metabolism. We ablated the Grb7 gene in mice to examine its metabolic function.

Influence of the storage conditions of embryo culture media on mouse development.

The culture of preimplantation embryos in vitro is an important method for human and mouse reproductive technology. This study aims to investigate the influence of different conditions of culture media on the preimplantation stage of mouse embryos cultured in vitro, and monitor the post-implantation development of new mice after embryo transfer to surrogate females. We demonstrated here that mouse embryos cultured in vitro in fresh M16, KSOM, Global, and HTF embryo culture media from one cell to the blastocyst stage and the subsequent embryo transfer to surrogate females are able to proceed through post-implantation development and, after birth, develop into healthy mice.

TAD evolutionary and functional characterization reveals diversity in mammalian TAD boundary properties and function.

Topological associating domains (TADs) are self-interacting genomic units crucial for shaping gene regulation patterns. Despite their importance, the extent of their evolutionary conservation and its functional implications remain largely unknown. In this study, we generate Hi-C and ChIP-seq data and compare TAD organization across four primate and four rodent species and characterize the genetic and epigenetic properties of TAD boundaries in correspondence to their evolutionary conservation.

TAD Evolutionary and functional characterization reveals diversity in mammalian TAD boundary properties and function.

Topological associating domains (TADs) are self-interacting genomic units crucial for shaping gene regulation patterns. Despite their importance, the extent of their evolutionary conservation and its functional implications remain largely unknown. In this study, we generate Hi-C and ChIP-seq data and compare TAD organization across four primate and four rodent species, and characterize the genetic and epigenetic properties of TAD boundaries in correspondence to their evolutionary conservation.

Gait Abnormalities and Aberrant D2 Receptor Expression and Signaling in Mice Carrying the Human Pathogenic Mutation .

A dopamine D2 receptor mutation was recently identified in a family with a novel hyperkinetic movement disorder. That allelic variant D2-IF is a constitutively active and G protein-biased receptor. We now describe mice engineered using CRISPR-Cas9-mediated gene editing technology to carry the D2-IF variant.

GPR39 Knockout Worsens Microcirculatory Response to Experimental Stroke in a Sex-Dependent Manner.

No current treatments target microvascular reperfusion after stroke, which can contribute to poor outcomes even after successful clot retrieval. The G protein-coupled receptor GPR39 is expressed in brain peri-capillary pericytes, and has been implicated in microvascular regulation, but its role in stroke is unknown. We tested the hypothesis that GPR39 plays a protective role after stroke, in part due to preservation of microvascular perfusion.

Shared and Distinct Functional Effects of Patient-Specific Mutations on Cortical Development.

T-Box Brain Transcription Factor 1 (TBR1) plays essential roles in brain development, mediating neuronal migration, fate specification, and axon tract formation. While heterozygous loss-of-function and missense mutations are associated with neurodevelopmental conditions, the effects of these heterogeneous mutations on brain development have yet to be fully explored. We characterized multiple mouse lines carrying mutations differing by type and exonic location, including the previously generated exon 2-3 knock-out (KO) line, and we analyzed male and female mice at neonatal and adult stages.

Distinct roles for the Charcot-Marie-Tooth disease-causing endosomal regulators Mtmr5 and Mtmr13 in axon radial sorting and Schwann cell myelination.

The form of Charcot-Marie-Tooth type 4B (CMT4B) disease caused by mutations in myotubularin-related 5 (MTMR5; also called SET binding factor 1, SBF1) shows a spectrum of axonal and demyelinating nerve phenotypes. This contrasts with the CMT4B subtypes caused by MTMR2 or MTMR13 (SBF2) mutations, which are characterized by myelin outfoldings and classic demyelination. Thus, it is unclear whether MTMR5 plays an analogous or distinct role from that of its homolog, MTMR13, in the peripheral nervous system (PNS).

The deubiquitinase USP36 promotes snoRNP group SUMOylation and is essential for ribosome biogenesis.

SUMOylation plays a crucial role in regulating diverse cellular processes including ribosome biogenesis. Proteomic analyses and experimental evidence showed that a number of nucleolar proteins involved in ribosome biogenesis are modified by SUMO. However, how these proteins are SUMOylated in cells is less understood.

A novel Pah-exon1 deleted murine model of phenylalanine hydroxylase (PAH) deficiency.

Phenylalanine hydroxylase (PAH) deficiency, colloquially known as phenylketonuria (PKU), is among the most common inborn errors of metabolism and in the past decade has become a target for the development of novel therapeutics such as gene therapy. PAH deficient mouse models have been key to new treatment development, but all prior existing models natively express liver PAH polypeptide as inactive or partially active PAH monomers, which complicates the experimental assessment of protein expression following therapeutic gene, mRNA, protein, or cell transfer. The mutant PAH monomers are able to form hetero-tetramers with and inhibit the overall holoenzyme activity of wild type PAH monomers produced from a therapeutic vector.

gene variants have a causal role in methamphetamine intake and response and interact with .

We identified a locus on mouse chromosome 10 that accounts for 60% of the genetic variance in methamphetamine intake in mice selectively bred for high versus low methamphetamine consumption. We nominated the trace amine-associated receptor 1 gene, , as the strongest candidate and identified regulation of the mu-opioid receptor 1 gene, , as another contributor. This study exploited CRISPR-Cas9 to test the causal role of in methamphetamine intake and a genetically-associated thermal response to methamphetamine.

RHEB1 insufficiency in aged male mice is associated with stress-induced seizures.

The mechanistic target of rapamycin (mTOR), a protein kinase, is a central regulator of mammalian metabolism and physiology. Protein mTOR complex 1 (mTORC1) functions as a major sensor for the nutrient, energy, and redox state of a cell and is activated by ras homolog enriched in brain (RHEB1), a GTP-binding protein. Increased activation of mTORC1 pathway has been associated with developmental abnormalities, certain form of epilepsy (tuberous sclerosis), and cancer.

RHEB1 expression in embryonic and postnatal mouse.

Ras homolog enriched in brain (RHEB1) is a member within the superfamily of GTP-binding proteins encoded by the RAS oncogenes. RHEB1 is located at the crossroad of several important pathways including the insulin-signaling pathways and thus plays an important role in different physiological processes. To understand better the physiological relevance of RHEB1 protein, the expression pattern of RHEB1 was analyzed in both embryonic (at E3.

Fibroblast Growth Factor Signaling Controls Liver Size in Mice With Humanized Livers.

Background & Aims: The ratio of liver size to body weight (hepatostat) is tightly controlled, but little is known about how the physiologic functions of the liver help determine its size. Livers of mice repopulated with human hepatocytes (humanized livers) grow to larger than normal; the human hepatocytes do not recognize the fibroblast growth factor (FGF)-15 produced by mouse intestine. This results in up-regulation of bile acid synthesis in the human hepatocytes and enlargement of the bile acid pool.

Mosaic variegated aneuploidy in mouse BubR1 deficient embryos and pregnancy loss in human.

Chromosome aberrations (aneuploidies mostly) are the cause of the majority of spontaneous abortions in humans. However, little is known about defects in the underlying molecular mechanisms resulting in chromosome aberrations and following failure of preimplantation embryo development, initiation of implantation and postimplantation pregnancy loss. We suggest that defects of the spindle assembly checkpoint (SAC) are responsible for aneuploidy and the following abortions.

Complex cytogenetic analysis of early lethality mouse embryos.

An increasing interest in the molecular mechanisms governing cell division has resulted in the discovery of several groups of genes that participate in the regulation of mitosis and meiosis in eukaryotes. Inactivation of these genes in mice often leads to early embryonic lethality. To show direct causality between mutations of these genes, chromosomal instability and embryonic death, a technique enabling detailed cytogenetic analysis of embryonic cells is required.

Renal failure causes early death of bcl-2 deficient mice.

BCL-2 functions as a death repressor molecule in an evolutionary conserved cell death pathway. Inactivation of bcl-2 in mice results in pleiotropic effects including postnatal growth retardation, massive apoptosis in lymphoid tissues, polycystic kidney disease (PKD) and shortened lifespan. To evaluate the influence of the affected bcl-2 deficient kidneys on the postnatal development and lifespan of bcl-2 knockout mice we used "the rescue of (n-1) affected tissues" strategy.

Apoptotic signaling proteins: possible participation in the regulation of vasopressin and catecholamines biosynthesis in the hypothalamus.

The role of apoptotic signaling proteins for long-lived neurons in the mature brain is poorly understood. Recently, we have shown that water deprivation leads to the activation of vasopressin (VP) secretion and expression of Bcl-2 and caspase-9 apototic proteins in the hypothalamus of the rat brain. In the present work, we continued to study a possible relationship between the functional activity of neurosecretory cells of the hypothalamus and apoptosis related proteins.

Loss of p53 in craf-induced transgenic lung adenoma leads to tumor acceleration and phenotypic switch.

One of the most frequent malignancies in humans is lung adenocarcinoma.To develop novel diagnostic and therapeutic approaches for the management of this disease, animal models are required. We have used transgenic mice with lung-targeted expression of the CRaf kinase to evaluate genes altered frequently in human lung adenocarcinoma for their effect on tumor progression.

Bcl-2 determines susceptibility to induction of lung cancer by oncogenic CRaf.

The efficiency of tumor induction by oncogenes is influenced by modifier genes that determine individual susceptibility. We have used a transgenic mouse model to examine the role of a candidate susceptibility gene, bcl-2, for development of Raf oncogene-induced lung adenomas. Loss of bcl-2 greatly retarded tumor development without affecting tumor phenotype.