GFRAL-expressing neurons suppress food intake via aversive pathways

The TGFβ cytokine family member, GDF-15, reduces food intake and body weight and represents a potential treatment for obesity. Because the brainstem-restricted expression pattern of its receptor, GDNF Family Receptor α–like (GFRAL), presents an exciting opportunity to understand mechanisms of action for area postrema neurons in food intake; we generated GfralCre and conditional GfralCreERT mice to visualize and manipulate GFRAL neurons. We found infection or pathophysiologic states (rather than meal ingestion) stimulate GFRAL neurons. TRAP-Seq analysis of GFRAL neurons revealed their expression of a wide range of neurotransmitters and neuropeptides. Artificially activating GfralCre-expressing neurons inhibited feeding, decreased gastric emptying, and promoted a conditioned taste aversion (CTA). GFRAL neurons most strongly innervate the parabrachial nucleus (PBN), where they target CGRP-expressing (CGRPPBN) neurons. Silencing CGRPPBN neurons abrogated the aversive and anorexic effects of GDF-15. These findings suggest that GFRAL neurons link non–meal-associated pathophysiologic signals to suppress nutrient uptake and absorption.

Emerging roles of the MAGE protein family in stress response pathways

The melanoma antigen (MAGE) proteins all contain a MAGE homology domain. MAGE genes are conserved in all eukaryotes and have expanded from a single gene in lower eukaryotes to ∼40 genes in humans and mice. Whereas some MAGEs are ubiquitously expressed in tissues, others are expressed in only germ cells with aberrant reactivation in multiple cancers. Much of the initial research on MAGEs focused on exploiting their antigenicity and restricted expression pattern to target them with cancer immunotherapy. Beyond their potential clinical application and role in tumorigenesis, recent studies have shown that MAGE proteins regulate diverse cellular and developmental pathways, implicating them in many diseases besides cancer, including lung, renal, and neurodevelopmental disorders. At the molecular level, many MAGEs bind to E3 RING ubiquitin ligases and, thus, regulate their substrate specificity, ligase activity, and subcellular localization. On a broader scale, the MAGE genes likely expanded in eutherian mammals to protect the germline from environmental stress and aid in stress adaptation, and this stress tolerance may explain why many cancers aberrantly express MAGEs. Here, we present an updated, comprehensive review on the MAGE family that highlights general characteristics, emphasizes recent comparative studies in mice, and describes the diverse functions exerted by individual MAGEs.

Association of Ddx5/p68 protein with the upstream erythroid enhancer element (EHS1) of the Klf1 gene

EKLF/KLF1 is an essential transcription factor that plays a global role in erythroid transcriptional activation. It’s own regulation is of interest, as it displays a highly restricted expression pattern, limited to erythroid cells and its progenitors. Here we use biochemical affinity purification to identify the Ddx5/p68 protein as a potential activator of KLF1 by virtue of its interaction with the erythroid-specific DNAse hypersensitive site (EHS1) upstream enhancer element. We postulate that its range of interactions with other proteins known to interact with this element render it part of the enhanseosome complex critical for optimal expression of KLF1.

Nucleosome Positioning in the Upstream of TSS from Different Expression Pattern Gene during Drosophila embryogenesis

Some significant differences about nucleosome positioning of different expression patterns gene have been found while researching the nucleosome positioning of Drosophila embryogenesis. The difference from the previous study was the restricted expression pattern gene incorporating H2A.Z into the-1 nucleosome in the upstream of Transcription Start Sites (TSS). Interestingly, compared with the nucleosome positioning of yeast genes, this nucleosome arrangement at gene of restricted expression pattern is similar with the characteristic found in yeast.

Pleitrophin Is Highly Expressed by Myeloma Cells, Elevated in the Serum of Myeloma Patients, and Is a New Autocrine Growth Factor for This B Cell Malignancy.

Pleitrophin (PTN) was originally described as a development regulatory cytokine. This protein regulates the growth of neuroectodermal and mesodermal cell lineages during early embryogenesis but becomes down-regulated during late phase of embryogenesis and shows a very restricted expression pattern in adult neural system. This protein has been recently shown to both induce angiogenesis and bind to syndecan. Thus, we determined whether this protein may be found in tumor cells from myeloma patients and its potential to influence their growth. First, we measured serum levels of PTN in myeloma (n=115) and age-matched controls (n=50) using an ELISA-based technique. PTN levels in the serum of myeloma patients were markedly elevated compared to the normal control group (P<0.02). The serum concentration of PTN in MM patients averaged 28 pg (range, 8 to 110 pg). In contrast, the control serum levels averaged only 12 pg (range, 0 to 20 pg. Interestingly, the PTN concentration in two patients with plasma leukemia was much higher than other multiple myeloma patients. Next, we analyzed the expression of PTN using RT-PCR on RNA from myeloma cell lines (RPMI8226, U266), and multiple myeloma patients’ and normal control bone marrow aspirates. Results showed that the PTN mRNA was strongly expressed in multiple myeloma cell lines, myeloma bone marrow samples but not in the normal control bone marrow specimens. In order to determine whether PTN stimulates multiple myeloma growth, we further cloned a whole PTN sense or anti-sense sequencing DNA into the multiple myeloma cell lines RPMI8226 and U266. Cells transduced with sense PTN showed markedly increased proliferation compared to cells transduced with antisense or vector alone. The role of PTN in hematological malignancies has not been previously defined. Due to the restricted expression pattern of PTN in adults, PTN is suggested as a potential new target for treatment of multiple myeloma. Further investigations are defining the prognostic value of PTN serum levels and the mechanism by which this cytokine drives myeloma growth.