Wildtype epidermal growth factor receptor (Egfr) is not required for daily locomotor or masking behavior in mice

BACKGROUND: Recent studies have implicated the epidermal growth factor receptor (EGFR) within the subparaventricular zone as being a major mediator of locomotor and masking behaviors in mice. The results were based on small cohorts of mice homozygous for the hypomorphic Egfr(wa2 )allele on a mixed, genetically uncontrolled background, and on intraventricular infusion of exogenous EGFR ligands. Subsequenlty, a larger study using the same genetically mixed background failed to replicate the original findings. Since both previous approaches were susceptible to experimental artifacts related to an uncontrolled genetic background, we analyzed the locomotor behaviors in Egfr(wa2 )mutant mice on genetically defined, congenic backgrounds. METHODS: Mice carrying the Egfr(wa2 )hypomorphic allele were bred to congenicity by backcrossing greater than ten generations onto C57BL/6J and 129S1/SvImJ genetic backgrounds. Homozygous Egfr(wa2 )mutant and wildtype littermates were evaluated for defects in locomotor and masking behaviors. RESULTS: Mice homozygous for Egfr(wa2 )showed normal daily locomotor activity and masking indistinguishable from wildtype littermates at two light intensities (200–300 lux and 400–500 lux). CONCLUSION: Our results demonstrate that reduced EGFR activity alone is insufficient to perturb locomotor and masking behaviors in mice. Our results also suggest that other uncontrolled genetic or environmental parameters confounded previous experiments linking EGFR activity to daily locomotor activity and provide a cautionary tale for genetically uncontrolled studies

Deficient NRG1-ERBB signaling alters social approach: relevance to genetic mouse models of schizophrenia

Growth factor Neuregulin 1 (NRG1) plays an essential role in development and organization of the cerebral cortex. NRG1 and its receptors, ERBB3 and ERBB4, have been implicated in genetic susceptibility for schizophrenia. Disease symptoms include asociality and altered social interaction. To investigate the role of NRG1-ERBB signaling in social behavior, mice heterozygous for an Nrg1 null allele (Nrg1+/−), and mice with conditional ablation of Erbb3 or Erbb4 in the central nervous system, were evaluated for sociability and social novelty preference in a three-chambered choice task. Results showed that deficiencies in NRG1 or ERBB3 significantly enhanced sociability. All of the mutant groups demonstrated a lack of social novelty preference, in contrast to their respective wild-type controls. Effects of NRG1, ERBB3, or ERBB4 deficiency on social behavior could not be attributed to general changes in anxiety-like behavior, activity, or loss of olfactory ability. Nrg1+/− pups did not exhibit changes in isolation-induced ultrasonic vocalizations, a measure of emotional reactivity. Overall, these findings provide evidence that social behavior is mediated by NRG1-ERBB signaling

Tumor-Promoting Role of GNA14 in Colon Cancer Development

Recent studies have shown that mutations in members of the G-protein α family contribute to the onset and progression of cancer. However, the role of GNA14 in CRC remains unknown. In this study, we examined the effect of GNA14 on CRC through genetic approaches in vitro and in vivo. We found that GNA14 knockdown by small interfering RNA (siRNA) inhibited the proliferation of CRC cells SW403 and HT29. Gna14 knockout mice developed normally without obvious abnormalities. However, the number of polyps in the small intestine was significantly reduced in Gna14 knockout mice compared to control mice after mating with ApcMin mice, a representative CRC mouse model. In particular, deletion of the Gna14 inhibited polyp growth, especially in the distal end of the small intestine. Histological examination showed that Gna14 knockout mice suppressed malignant tumor progression due to decreased proliferation and increased apoptosis in polyps compared to controls. In addition, GNA14 knockdown in CRC cells resulted in downregulation of ERK phosphorylation and β-catenin and β-catenin phosphorylation at S675. Similarly, ERK phosphorylation and phospho-β-catenin phosphorylation at S675 were decreased in polyps of Gna14 knockout mice. Collectively, these analyses show that GNA14 may accelerate CRC cell proliferation and malignant tumor progression through ERK and β-catenin pathways

Angioimmunoblastic T-cell lymphoma-like lymphadenopathy in mice transgenic for human RHOA with p.Gly17Val mutation

A missense mutation in RHOA encoding p.Gly17 Val has been reported to occur frequently in angioimmunoblastic T-cell lymphoma (AITL). Here, we describe a murine model which expresses the human RHOA mutant gene product in a T-cell specific manner and develops AITL-like symptoms. Most transgenic mice feature with latency one or two enlarged lymph nodes characterized by aberrant lymph node architecture, extensive lymphocytic infiltration, extrafollicular meshwork of follicular dendritic cells (FDC) and arborized endothelial venules. Importantly, we provide evidence for expansion of PD-1+ follicular helper T (Tfh) cells which are the neoplastic cells of AITL. In addition, we saw proliferation of B-cells leading to hypergammaglobulinemia and the presence of dominant T cell clonal populations. Transplantation of lymph node cells to immunocompromised mice partly recreated lymphadenopathy after a long latency and with low penetrance suggesting that cells have undergone partial transformation to a premalignant state. Transcriptomic profiling revealed that the gene expression pattern within affected lymph nodes of the mice closely resembles that of AITL patients with the identical RHOA p.Gly17 Val mutation. The murine model should, therefore, be useful in dissecting pathogenesis of AITL at the molecular level particularly for the cases with the RHOA p.Gly17Val mutation

Epiregulin Is Not Essential for Development of Intestinal Tumors but Is Required for Protection from Intestinal Damage

Epiregulin, an epidermal growth factor family member, acts as a local signal mediator and shows dual biological activity, stimulating the proliferation of fibroblasts, hepatocytes, smooth muscle cells, and keratinocytes while inhibiting the growth of several tumor-derived epithelial cell lines. The epiregulin gene (Ereg) is located on mouse chromosome 5 adjacent to three other epidermal growth factor family members, epigen, amphiregulin, and betacellulin. Gene targeting was used to insert a lacZ reporter into the mouse Ereg locus and to ablate its function. Although epiregulin is broadly expressed and regulated both spatially and temporally, Ereg null mice show no overt developmental defects, reproductive abnormalities, or altered liver regeneration. Additionally, in contrast to previous hypotheses, Ereg deficiency does not alter intestinal cancer susceptibility, as assayed in the Apc(Min) model, despite showing robust expression in developing tumors. However, Ereg null mice are highly susceptible to cancer-predisposing intestinal damage caused by oral administration of dextran sulfate sodium

PGC1α Loss Promotes Lung Cancer Metastasis through Epithelial-Mesenchymal Transition

PGC1α oppositely regulates cancer metastasis in melanoma, breast, and pancreatic cancer; however, little is known about its impact on lung cancer metastasis. Transcriptome and in vivo xenograft analysis show that a decreased PGC1α correlates with the epithelial–mesenchymal transition (EMT) and lung cancer metastasis. The deletion of a single Pgc1α allele in mice promotes bone metastasis of KrasG12D-driven lung cancer. Mechanistically, PGC1α predominantly activates ID1 expression, which interferes with TCF4-TWIST1 cooperation during EMT. Bioinformatic and clinical studies have shown that PGC1α and ID1 are downregulated in lung cancer, and correlate with a poor survival rate. Our study indicates that TCF4-TWIST1-mediated EMT, which is regulated by the PGC1α-ID1 transcriptional axis, is a potential diagnostic and therapeutic target for metastatic lung cancer

An essential complementary role of NF-κB pathway to microbicidal oxidants in Drosophila gut immunity

In the Drosophila gut, reactive oxygen species (ROS)-dependent immunity is critical to host survival. This is in contrast to the NF-κB pathway whose physiological function in the microbe-laden epithelia has yet to be convincingly demonstrated despite playing a critical role during systemic infections. We used a novel in vivo approach to reveal the physiological role of gut NF-κB/antimicrobial peptide (AMP) system, which has been ‘masked' in the presence of the dominant intestinal ROS-dependent immunity. When fed with ROS-resistant microbes, NF-κB pathway mutant flies, but not wild-type flies, become highly susceptible to gut infection. This high lethality can be significantly reduced by either re-introducing Relish expression to Relish mutants or by constitutively expressing a single AMP to the NF-κB pathway mutants in the intestine. These results imply that the local ‘NF-κB/AMP' system acts as an essential ‘fail-safe' system, complementary to the ROS-dependent gut immunity, during gut infection with ROS-resistant pathogens. This system provides the Drosophila gut immunity the versatility necessary to manage sporadic invasion of virulent pathogens that somehow counteract or evade the ROS-dependent immunity

Culture of hESCs on Cx43 siRNA-treated hASCs.

<p>Compared with treatment of hASCs with control or scrambled-siRNA, the Cx43-siRNA treatment of hASC feeder cells did not alter adhesion (A), colony growth (n = 20; B), gene expression (i.e., <i>OCT4</i>, <i>SOX2</i>, and <i>NANOG</i>) (C), AP-positive colony numbers (D), OCT4 expression (E), or chromosomal stability (F) of co-cultured hESCs. Nuclei were counterstained with DAPI (E). All data are shown as the mean ± the SD. (n = 4; ^#, p>0.05). Scale bar, 100 μm.</p