modifier of mdg4 encodes a protein involved in homologous chromosome pairing in Drosophila melanogaster males

Our research interest is to uncover mechanisms underlying meiotic chromosome pairing and segregation. pairing failure 2 (pf-2) is a gene involved in this process during meiosis I of male Drosophila. The three pf-2 alleles recovered in a screen for chemically induced (EMS) mutations on chromosome III that cause paternal loss of chromosome IV display strong meiotic phenotypes. Cytological analysis of testes of pf-2 mutant flies revealed unpaired chromosomes at prophase and metaphase I and “laggard chromosomes” at anaphase I in primary spermatocytes. Meiosis II appears relatively normal. Genetic data confirm that non-disjunction occurs at the first meiotic division and affects the segregation of sex chromosomes as well as autosomes. By deficiency complementation pf-2 was mapped to region 93D6; 93E1 on chromosome arm 3R and shown to be allelic to modifier of mdg4 [mod(mdg4)], a complex locus that encodes a large family of chromosomal proteins by alternative and trans-splicing. The encoded proteins together occupy more than 500 sites on the polytene chromosomes. We show that the pf-2 mutations disrupt the function of a single isoform, Mod(mdg4)56.3, that is expressed in primary spermatocytes at all stages. Both a GFP-tagged Mod(mdg4)56.3 transgene and the native Mod(mdg4)56.3 protein localize as discrete foci to the major autosomes, and as an intensely fluorescent cluster of foci to the nucleolus throughout prophase. The nucleolar cluster resolves into a sharply defined structure associate with the X-Y bivalent. We conclude that Mod(mdg4)56.3 plays a critical role in homologous chromosome pairing in Drosophila male meiosis. Transgenic flies with a pf-2 null genetic background and carrying [hsp70-pf2 cDNA] fragment on their chromosome II display a complete rescue of the pairing failure phenotype. The expression pattern of the GFP-labeled Mod(mdg4)56.3 in transgenic flies’ meiotic cells implies a role for this novel gene in chromosomal cohesion during meiosis

The Adipose Renin-Angiotensin System Modulates Systemic Markers of Insulin Sensitivity and Activates the Intrarenal Renin-Angiotensin System

Background. The adipose tissue renin-angiotensin system (RAS) contributes to regulation of fat mass and may also impact systemic functions such as blood pressure and metabolism. Methods and results. A panel of mouse models including mice lacking angiotensinogen, Agt (Agt-KO), mice expressing Agt solely in adipose tissue (aP2-Agt/Agt-KO), and mice overexpressing Agt in adipose tissue (aP2-Agt) was studied. Total body weight, epididymal fat pad weight, and circulating levels of leptin, insulin, and resistin were significantly decreased in Agt-KO mice, while plasma adiponectin levels were increased. aP2-Agt mice exhibited increased adiposity and plasma leptin and insulin levels compared to wild type (WT) controls. Angiotensinogen and type I Ang II receptor protein levels were also elevated in kidney of aP2-Agt mice. Conclusion. These findings demonstrate that alterations in adipose RAS activity significantly impact both local and systemic physiology in a way that may contribute to the detrimental health effects of obesity

Role of the mod(mdg4) Common Region in Homolog Segregation in Drosophila Male Meiosis

Homologous chromosomes must pair and establish stable connections during prophase I of meiosis to segregate reliably from each other at anaphase I. In most organisms, the stable connections, called chiasmata, arise from crossovers. In Drosophila males, homologs pair and segregate without crossing over. Chiasmata are replaced by a homolog conjunction complex that includes the Stromalin in Meiosis (SNM) and Modifier of Mdg4 in Meiosis (MNM) proteins. MNM is one of 31 alternative splice products of mod(mdg4), all of which share a common 402-amino-acid N terminus and differ at their C termini. Previous data demonstrated that an MNM-specific exon is required for homolog conjunction, but did not address whether the N-terminal common region, which includes a BTB domain that can mediate coalescence of protein-DNA complexes, is also required. Here we describe a mutation in the common region of mod(mdg4), Z3-3401, that causes qualitatively similar phenotypes as the MNM-specific alleles but disrupts X–Y segregation much more drastically than autosomal segregation. The mutant MNM protein in Z3-3401 is expressed throughout prophase I in spermatocytes but the protein is confined to the cytoplasm, suggesting that the Z3-3401 mutation disrupts a signal required for nuclear localization or retention. Z3-3401 fails to complement a large battery of lethal and semilethal alleles in the common region for meiotic nondisjunction, including an allele containing an amino acid substitution at a conserved residue in the BTB/POZ domain, consistent with a general requirement for the mod(mdg4) common region in homolog segregation