Fourth Chromosome Resource Project: a comprehensive resource for genetic analysis in Drosophila that includes humanized stocks.

The fourth chromosome is the final frontier for genetic analysis in Drosophila. Small, heterochromatic, and devoid of recombination the fourth has long been ignored. Nevertheless, its long arm contains 79 protein-coding genes.

Convergent Evolution in a Murine Intestinal Parasite Rapidly Created the TGM Family of Molecular Mimics to Suppress the Host Immune Response.

The Transforming Growth Factor-β mimic (TGM) multigene family was recently discovered in the murine intestinal parasite Heligmosomoides polygyrus. This family was shaped by an atypical set of organismal and molecular evolutionary mechanisms along its path through the adaptive landscape. The relevant mechanisms are mimicry, convergence, exon modularity, new gene origination, and gene family neofunctionalization.

dSmad2 differentially regulates dILP2 and dILP5 in insulin producing and circadian pacemaker cells in unmated adult females.

Much is known about environmental influences on metabolism and systemic insulin levels. Less is known about how those influences are translated into molecular mechanisms regulating insulin production. To better understand the molecular mechanisms we generated marked cells homozygous for a null mutation in the Drosophila TGF-β signal transducer dSmad2 in unmated adult females.

New aspects of TGF-β superfamily signaling in development and disease (2022 FASEB meeting review).

The 13th Federation of American Societies for Experimental Biology (FASEB) Summer Research Conference, "TGF-β superfamily signaling in development and disease" was convened at the Grand Hotel in Malahide, Ireland in July 2022. The Transforming Growth Factor-β (TGF-β) family of secreted proteins consists of agents of intercellular communication found in all multicellular animals. Attending the meeting was a diverse group of scholars with shared interests in understanding TGF-β signaling mechanisms, normal functions, and the diseases associated with misregulation and mutation.

Computational analysis of prodomain cysteines in human TGF-β proteins reveals frequent loss of disulfide-dependent regulation in tumors.

The functionally diverse members of the human Transforming Growth Factor-β (TGF-β) family are tightly regulated. TGF-β regulation includes 2 disulfide-dependent mechanisms-dimerization and partner protein binding. The specific cysteines participating in these regulatory mechanisms are known in just 3 of the 33 human TGF-β proteins.

New resources for the Drosophila 4th chromosome: FRT101F enabled mitotic clones and Bloom syndrome helicase enabled meiotic recombination.

Genes on the long arm of the Drosophila melanogaster 4th chromosome are difficult to study because the chromosome lacks mitotic and meiotic recombination. Without recombination numerous standard methods of genetic analysis are impossible. Here, we report new resources for the 4th.

Selective Disruption of Synaptic BMP Signaling by a Smad Mutation Adjacent to the Highly Conserved H2 Helix.

Bone morphogenetic proteins (BMPs) shape normal development and function via canonical and noncanonical signaling pathways. BMPs initiate canonical signaling by binding to transmembrane receptors that phosphorylate Smad proteins and induce their translocation into the nucleus and regulation of target genes. Phosphorylated Smads also accumulate at cellular junctions, but this noncanonical, local BMP signaling modality remains less defined.

Adult Movement Defects Associated with a CORL Mutation in Display Behavioral Plasticity.

The CORL family of CNS-specific proteins share a Smad-binding region with mammalian SnoN and c-Ski protooncogenes. In this family Drosophila CORL has two mouse and two human relatives. Roles for the mouse and human CORL proteins are largely unknown.

TGF-β Prodomain Alignments Reveal Unexpected Cysteine Conservation Consistent with Phylogenetic Predictions of Cross-Subfamily Heterodimerization.

Evolutionary relationships between prodomains in the TGF-β family have gone unanalyzed due to a perceived lack of conservation. We developed a novel approach, identified these relationships, and suggest hypotheses for new regulatory mechanisms in TGF-β signaling. First, a quantitative analysis placed each family member from flies, mice, and nematodes into the Activin, BMP, or TGF-β subfamily.

Transgenic Analyses in Drosophila Reveal That mCORL1 Is Functionally Distinct from mCORL2 and dCORL.

Uncovering how new members of multigene families acquire new functions is an important topic in evolutionary and developmental genetics. CORL proteins (SKOR in mice, Fussel in humans and fussel in Flybase) are a family of CNS specific proteins related to mammalian Sno/Ski oncogenes. Drosophila CORL (dCORL) participates in TGF-β and insulin signaling during development and in adult homeostasis but roles for the two mouse CORL proteins (mCORL) are essentially unknown.

Expression and Function in Insulin Producing Neurons Reversibly Influences Adult Longevity in .

CORL proteins (known as SKOR in mice, Fussel in humans and fussel in Flybase) are a family of CNS specific proteins related to Sno/Ski oncogenes. Their developmental and adult roles are largely unknown. A Drosophila (dCORL) reporter gene is expressed in all Drosophila insulin-like peptide 2 (dILP2) neurons of the pars intercerebralis (PI) of the larval and adult brain.

Expression in the Central Nervous System Is Regulated by Stage Specific Interactions of Intertwined Activators and Repressors.

CORL proteins (SKOR in mice and Fussel in humans) are a subfamily of central nervous system (CNS) specific proteins related to Sno/Ski oncogenes. Their developmental and homeostatic roles are largely unknown. We previously showed that Drosophila (; fussel in Flybase) functions between the Activin receptor Baboon and Ecdysone Receptor-B1 (EcR-B1) activation in mushroom body neurons of third instar larval brains.

lolal Is an Evolutionarily New Epigenetic Regulator of dpp Transcription during Dorsal-Ventral Axis Formation.

Secreted ligands in the Dpp/BMP family drive dorsal-ventral (D/V) axis formation in all Bilaterian species. However, maternal factors regulating Dpp/BMP transcription in this process are largely unknown. We identified the BTB domain protein longitudinals lacking-like (lolal) as a modifier of decapentaplegic (dpp) mutations.

New gene evolution in the bonus-TIF1-γ/TRIM33 family impacted the architecture of the vertebrate dorsal-ventral patterning network.

Uncovering how a new gene acquires its function and understanding how the function of a new gene influences existing genetic networks are important topics in evolutionary biology. Here, we demonstrate nonconservation for the embryonic functions of Drosophila Bonus and its newest vertebrate relative TIF1-γ/TRIM33. We showed previously that TIF1-γ/TRIM33 functions as an ubiquitin ligase for the Smad4 signal transducer and antagonizes the Bone Morphogenetic Protein (BMP) signaling network underlying vertebrate dorsal-ventral axis formation.

Automated annotation of developmental stages of Drosophila embryos in images containing spatial patterns of expression.

Motivation: Drosophila melanogaster is a major model organism for investigating the function and interconnection of animal genes in the earliest stages of embryogenesis. Today, images capturing Drosophila gene expression patterns are being produced at a higher throughput than ever before. The analysis of spatial patterns of gene expression is most biologically meaningful when images from a similar time point during development are compared.

Meeting report - TGF-β superfamily: signaling in development and disease.

The latest advances on the transforming growth factor β (TGF-β) and bone morphogenetic protein (BMP) signaling pathways were reported at the July 2013 FASEB Summer Research Conference 'The TGF-β Superfamily: Development and Disease'. The meeting was held in Steamboat Springs, Colorado, USA at 6700 feet above sea level in the Rocky Mountains. This was the seventh biannual meeting in the series.

New insights into extracellular and post-translational regulation of TGF-β family signalling pathways.

Members of the transforming growth factor-β (TGF-β) family of secreted proteins are present in all multicellular animals. TGF-β proteins are versatile intercellular signalling molecules that orchestrate cell fate decisions during development and maintain homeostasis in adults. The Smad family of signal transducers implements TGF-β signals in responsive cells.

Hippo pathway phylogenetics predicts monoubiquitylation of Salvador and Merlin/Nf2.

Recently we employed phylogenetics to predict that the cellular interpretation of TGF-β signals is modulated by monoubiquitylation cycles affecting the Smad4 signal transducer/tumor suppressor. This prediction was subsequently validated by experiments in flies, frogs and mammalian cells. Here we apply a phylogenetic approach to the Hippo pathway and predict that two of its signal transducers, Salvador and Merlin/Nf2 (also a tumor suppressor) are regulated by monoubiquitylation.

Drosophila CORL is required for Smad2-mediated activation of Ecdysone Receptor expression in the mushroom body.

CORL proteins (FUSSEL/SKOR proteins in humans) are related to Sno/Ski oncogenes but their developmental roles are unknown. We have cloned Drosophila CORL and show that its expression is restricted to distinct subsets of cells in the central nervous system. We generated a deletion of CORL and noted that homozygous individuals rarely survive to adulthood.

Fat facets deubiquitylation of Medea/Smad4 modulates interpretation of a Dpp morphogen gradient.

The ability of secreted Transforming Growth Factor β (TGFβ) proteins to act as morphogens dictates that their influence be strictly regulated. Here, we report that maternally contributed fat facets (faf; a homolog of USP9X/FAM) is essential for proper interpretation of the zygotic Decapentaplegic (Dpp) morphogen gradient that patterns the embryonic dorsal-ventral axis. The data suggest that the loss of faf reduces the activity of Medea (a homolog of Smad4) below the minimum necessary for adequate Dpp signaling and that this is likely due to excessive ubiquitylation on a specific lysine.

Regulation of TGF-β signal transduction by mono- and deubiquitylation of Smads.

Polyubiquitylation leading to proteasomal degradation is a well-established mechanism for regulating TGF-β signal transduction components such as receptors and Smads. Recently, an equally important role was suggested for monoubiquitylation of both Smad4 and receptor-associated Smads that regulates their function without protein degradation. Monoubiquitylation of Smads was discovered following the identification of deubiquitylases required for TGF-β signaling, suggesting that continuous cycles of Smad mono- and deubiquitylation are required for proper TGF-β signal transduction.

FlyExpress: visual mining of spatiotemporal patterns for genes and publications in Drosophila embryogenesis.

Summary: Images containing spatial expression patterns illuminate the roles of different genes during embryogenesis. In order to generate initial clues to regulatory interactions, biologists frequently need to know the set of genes expressed at the same time at specific locations in a developing embryo, as well as related research publications. However, text-based mining of image annotations and research articles cannot produce all relevant results, because the primary data are images that exist as graphical objects.

Comparison of embryonic expression within multigene families using the FlyExpress discovery platform reveals more spatial than temporal divergence.

Background: Overlaps in spatial patterns of gene expression are frequently an initial clue to genetic interactions during embryonic development. However, manual inspection of images requires considerable time and resources impeding the discovery of important interactions because tens of thousands of images exist. The FlyExpress discovery platform was developed to facilitate data-driven comparative analysis of expression pattern images from Drosophila embryos.

Wg signaling via Zw3 and mad restricts self-renewal of sensory organ precursor cells in Drosophila.

It is well known that the Dpp signal transducer Mad is activated by phosphorylation at its carboxy-terminus. The role of phosphorylation on other regions of Mad is not as well understood. Here we report that the phosphorylation of Mad in the linker region by the Wg antagonist Zw3 (homolog of vertebrate Gsk3-β) regulates the development of sensory organs in the anterior-dorsal quadrant of the wing.

The Sno oncogene antagonizes Wingless signaling during wing development in Drosophila.

The Sno oncogene (Snoo or dSno in Drosophila) is a highly conserved protein and a well-established antagonist of Transforming Growth Factor-beta signaling in overexpression assays. However, analyses of Sno mutants in flies and mice have proven enigmatic in revealing developmental roles for Sno proteins. Thus, to identify developmental roles for dSno we first reconciled conflicting data on the lethality of dSno mutations.