Unraveling the link between neuropathy target esterase NTE/SWS, lysosomal storage diseases, inflammation, abnormal fatty acid metabolism, and leaky brain barrier.

Mutations in Drosophila Swiss cheese (SWS) gene or its vertebrate orthologue neuropathy target esterase (NTE) lead to progressive neuronal degeneration in flies and humans. Despite its enzymatic function as a phospholipase is well established, the molecular mechanism responsible for maintaining nervous system integrity remains unclear. In this study, we found that NTE/SWS is present in surface glia that forms the blood-brain barrier (BBB) and that NTE/SWS is important to maintain its structure and permeability. Importantly, BBB glia-specific expression of Drosophila NTE/SWS or human NTE in the sws mutant background fully rescues surface glial organization and partially restores BBB integrity, suggesting a conserved function of NTE/SWS. Interestingly, sws mutant glia showed abnormal organization of plasma membrane domains and tight junction rafts accompanied by the accumulation of lipid droplets, lysosomes, and multilamellar bodies. Since the observed cellular phenotypes closely resemble the characteristics described in a group of metabolic disorders known as lysosomal storage diseases (LSDs), our data established a novel connection between NTE/SWS and these conditions. We found that mutants with defective BBB exhibit elevated levels of fatty acids, which are precursors of eicosanoids and are involved in the inflammatory response. Also, as a consequence of a permeable BBB, several innate immunity factors are upregulated in an age-dependent manner, while BBB glia-specific expression of NTE/SWS normalizes inflammatory response. Treatment with anti-inflammatory agents prevents the abnormal architecture of the BBB, suggesting that inflammation contributes to the maintenance of a healthy brain barrier. Considering the link between a malfunctioning BBB and various neurodegenerative diseases, gaining a deeper understanding of the molecular mechanisms causing inflammation due to a defective BBB could help to promote the use of anti-inflammatory therapies for age-related neurodegeneration.

Drosophila MIC10b can polymerize into cristae-shaping filaments.

Cristae are invaginations of the mitochondrial inner membrane that are crucial for cellular energy metabolism. The formation of cristae requires the presence of a protein complex known as MICOS, which is conserved across eukaryotic species. One of the subunits of this complex, MIC10, is a transmembrane protein that supports cristae formation by oligomerization. In Drosophila melanogaster, three MIC10-like proteins with different tissue-specific expression patterns exist. We demonstrate that CG41128/MINOS1b/DmMIC10b is the major MIC10 orthologue in flies. Its loss destabilizes MICOS, disturbs cristae architecture, and reduces the life span and fertility of flies. We show that DmMIC10b has a unique ability to polymerize into bundles of filaments, which can remodel mitochondrial crista membranes. The formation of these filaments relies on conserved glycine and cysteine residues, and can be suppressed by the co-expression of other Drosophila MICOS proteins. These findings provide new insights into the regulation of MICOS in flies, and suggest potential mechanisms for the maintenance of mitochondrial ultrastructure.

Signaling through the dystrophin glycoprotein complex affects the stress-dependent transcriptome in Drosophila.

Deficiencies in the human dystrophin glycoprotein complex (DGC), which links the extracellular matrix with the intracellular cytoskeleton, cause muscular dystrophies, a group of incurable disorders associated with heterogeneous muscle, brain and eye abnormalities. Stresses such as nutrient deprivation and aging cause muscle wasting, which can be exacerbated by reduced levels of the DGC in membranes, the integrity of which is vital for muscle health and function. Moreover, the DGC operates in multiple signaling pathways, demonstrating an important function in gene expression regulation. To advance disease diagnostics and treatment strategies, we strive to understand the genetic pathways that are perturbed by DGC mutations. Here, we utilized a Drosophila model to investigate the transcriptomic changes in mutants of four DGC components under temperature and metabolic stress. We identified DGC-dependent genes, stress-dependent genes and genes dependent on the DGC for a proper stress response, confirming a novel function of the DGC in stress-response signaling. This perspective yields new insights into the etiology of muscular dystrophy symptoms, possible treatment directions and a better understanding of DGC signaling and regulation under normal and stress conditions.

The Russian invasion of Ukraine: a humanitarian tragedy and a tragedy for science.

The Invasion of Ukraine prompts us to support our Ukranian colleagues but also to keep open communication with the Russian scientists who oppose the war.

The voices of Ukrainian and Russian scientists.

The brutal attack on Ukraine by the Russian Federation has shocked the world. While the world works to end the violence and help refugees, as a scientific journal, our thoughts are also with those in the scientific community who are directly or indirectly impacted by the war. We have been inspired by and applaud the labs around the world that have opened their doors to displaced scientists and remain committed to supporting scientists, whoever and wherever they are. Because science requires collaboration and trust, we urge the scientific community to continue efforts like this and to remain united, especially in times as difficult as these. In this Voices piece, we feature short comments from scientists from Ukraine and scientists from Russia. This small sampling is far from exhaustive, but our sincere thanks go to those scientists who were willing to share their thoughts on this volatile and emotionally charged situation; the views expressed are those of the contributors alone. We join the world in hoping for a swift resolution to the conflict, for the good of humanity.

Notch signaling sculpts the stem cell niche.

Adult stem cells depend on their niches for regulatory signaling that controls their maintenance, division, and their progeny differentiation. While communication between various types of stem cells and their niches is becoming clearer, the process of stem cell niche establishment is still not very well understood. Model genetic organisms provide simplified systems to address various complex questions, for example, how is a stem cell niche formed? What signaling cascades induce the stem cell niche formation? Are the mechanisms of stem cell niche formation conserved? Notch signaling is an evolutionarily conserved pathway first identified in fruit flies, crucial in fate acquisition and spatiotemporal patterning. While the core logic behind its activity is fairly simple and requires direct cell-cell interaction, it reaches an astonishing complexity and versatility by combining its different modes of action. Subtleties such as equivalency between communicating cells, their physical distance, receptor and ligand processing, and endocytosis can have an effect on the way the events unfold, and this review explores some important general mechanisms of action, later on focusing on its involvement in stem cell niche formation. First, looking at invertebrates, we will examine how Notch signaling induces the formation of germline stem cell niche in male and female Drosophila. In the developing testis, a group of somatic gonadal precursor cells receive Delta signals from the gut, activating Notch signaling and sealing their fate as niche cells even before larval hatching. Meanwhile, the ovarian germline stem cell niche is built later during late larval stages and requires a two-step process that involves terminal filament formation and cap cell specification. Intriguingly, double security mechanisms of Notch signaling activation coordinated by the soma or the germline control both steps to ensure the robustness of niche assembly. Second, in the vast domains of mammalian cellular signaling, there is an emerging picture of Notch being an active player in a variety of tissues in health and disease. Notch involvement has been shown in stem cell niche establishment in multiple organs, including the brain, muscle, and intestine, where the stem cell niches are essential for the maintenance of adult stem cells. But adult stem cells are not the only cells looking for a home. Cancer stem cells use Notch signaling at specific stages to gain an advantage over endogenous tissue and overpower it, at the same time acquiring migratory and invasive abilities to claim new tissues (e.g., bone) as their territory. Moreover, in vitro models such as organoids reveal similar Notch employment when it comes to the developing stem cell niches. Therefore, a better understanding of the processes regulating stem cell niche assembly is key for the fields of stem cell biology and regenerative medicines.

Tissue-specific regulation of translational readthrough tunes functions of the traffic jam transcription factor.

Translational readthrough (TR) occurs when the ribosome decodes a stop codon as a sense codon, resulting in two protein isoforms synthesized from the same mRNA. TR has been identified in several eukaryotic organisms; however, its biological significance and mechanism remain unclear. Here, we quantify TR of several candidate genes in Drosophila melanogaster and characterize the regulation of TR in the large Maf transcription factor Traffic jam (Tj). Using CRISPR/Cas9-generated mutant flies, we show that the TR-generated Tj isoform is expressed in a subset of neural cells of the central nervous system and is excluded from the somatic cells of gonads. Control of TR in Tj is critical for preservation of neuronal integrity and maintenance of reproductive health. The tissue-specific distribution of a release factor splice variant, eRF1H, plays a critical role in modulating differential TR of leaky stop codon contexts. Fine-tuning of gene regulatory functions of transcription factors by TR provides a potential mechanism for cell-specific regulation of gene expression.

Loss of swiss cheese in Neurons Contributes to Neurodegeneration with Mitochondria Abnormalities, Reactive Oxygen Species Acceleration and Accumulation of Lipid Droplets in Drosophila Brain.

Various neurodegenerative disorders are associated with human NTE/PNPLA6 dysfunction. Mechanisms of neuropathogenesis in these diseases are far from clearly elucidated. Hereditary spastic paraplegia belongs to a type of neurodegeneration associated with NTE/PNLPLA6 and is implicated in neuron death. In this study, we used Drosophila melanogaster to investigate the consequences of neuronal knockdown of swiss cheese (sws)-the evolutionarily conserved ortholog of human NTE/PNPLA6-in vivo. Adult flies with the knockdown show longevity decline, locomotor and memory deficits, severe neurodegeneration progression in the brain, reactive oxygen species level acceleration, mitochondria abnormalities and lipid droplet accumulation. Our results suggest that SWS/NTE/PNPLA6 dysfunction in neurons induces oxidative stress and lipid metabolism alterations, involving mitochondria dynamics and lipid droplet turnover in neurodegeneration pathogenesis. We propose that there is a complex mechanism in neurological diseases such as hereditary spastic paraplegia, which includes a stress reaction, engaging mitochondria, lipid droplets and endoplasmic reticulum interplay.

Morpho-Functional Consequences of Swiss Cheese Knockdown in Glia of Drosophila melanogaster.

Glia are crucial for the normal development and functioning of the nervous system in many animals. Insects are widely used for studies of glia genetics and physiology. Drosophila melanogaster surface glia (perineurial and subperineurial) form a blood-brain barrier in the central nervous system and blood-nerve barrier in the peripheral nervous system. Under the subperineurial glia layer, in the cortical region of the central nervous system, cortex glia encapsulate neuronal cell bodies, whilst in the peripheral nervous system, wrapping glia ensheath axons of peripheral nerves. Here, we show that the expression of the evolutionarily conserved swiss cheese gene is important in several types of glia. swiss cheese knockdown in subperineurial glia leads to morphological abnormalities of these cells. We found that the number of subperineurial glia nuclei is reduced under swiss cheese knockdown, possibly due to apoptosis. In addition, the downregulation of swiss cheese in wrapping glia causes a loss of its integrity. We reveal transcriptome changes under swiss cheese knockdown in subperineurial glia and in cortex + wrapping glia and show that the downregulation of swiss cheese in these types of glia provokes reactive oxygen species acceleration. These results are accompanied by a decline in animal mobility measured by the negative geotaxis performance assay.

Distant activation of Notch signaling induces stem cell niche assembly.

Here we show that multiple modes of Notch signaling activation specify the complexity of spatial cellular interactions necessary for stem cell niche assembly. In particular, we studied the formation of the germline stem cell niche in Drosophila ovaries, which is a two-step process whereby terminal filaments are formed first. Then, terminal filaments signal to the adjacent cap cell precursors, resulting in Notch signaling activation, which is necessary for the lifelong acquisition of stem cell niche cell fate. The genetic data suggest that in order to initiate the process of stem cell niche assembly, Notch signaling is activated among non-equipotent cells via distant induction, where germline Delta is delivered to somatic cells located several diameters away via cellular projections generated by primordial germ cells. At the same time, to ensure the robustness of niche formation, terminal filament cell fate can also be induced by somatic Delta via cis- or trans-inhibition. This exemplifies a double security mechanism that guarantees that the germline stem cell niche is formed, since it is indispensable for the adjacent germline precursor cells to acquire and maintain stemness necessary for successful reproduction. These findings contribute to our understanding of the formation of stem cell niches in their natural environment, which is important for stem cell biology and regenerative medicine.

Exocyst-mediated membrane trafficking of the lissencephaly-associated ECM receptor dystroglycan is required for proper brain compartmentalization.

To assemble a brain, differentiating neurons must make proper connections and establish specialized brain compartments. Abnormal levels of cell adhesion molecules disrupt these processes. Dystroglycan (Dg) is a major non-integrin cell adhesion receptor, deregulation of which is associated with dramatic neuroanatomical defects such as lissencephaly type II or cobblestone brain. The previously established Drosophila model for cobblestone lissencephaly was used to understand how Dg is regulated in the brain. During development, Dg has a spatiotemporally dynamic expression pattern, fine-tuning of which is crucial for accurate brain assembly. In addition, mass spectrometry analyses identified numerous components associated with Dg in neurons, including several proteins of the exocyst complex. Data show that exocyst-based membrane trafficking of Dg allows its distinct expression pattern, essential for proper brain morphogenesis. Further studies of the Dg neuronal interactome will allow identification of new factors involved in the development of dystroglycanopathies and advance disease diagnostics in humans.

Increase of α-dicarbonyls in liver and receptor for advanced glycation end products on immune cells are linked to nonalcoholic fatty liver disease and liver cancer.

Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver with a very poor prognosis and constantly growing incidence. Among other primary risks of HCC, metabolic disorders and obesity have been extensively investigated over recent decades. The latter can promote nonalcoholic fatty liver disease (NAFLD) leading to the inflammatory form of nonalcoholic steatohepatitis (NASH), that, in turn, promotes HCC. Molecular determinants of this pathogenic progression, however, remain largely undefined. In this study, we have focussed on the investigation of α-dicarbonyl compounds (α-dC), highly reactive and tightly associated with overweight-induced metabolic disorders, and studied their potential role in NAFLD and progression toward HCC using murine models. NAFLD was induced using high-fat diet (HFD). Autochthonous HCC was induced using transposon-based stable intrahepatic overexpression of oncogenic NRASG12V in mice lacking p19Arf tumor suppressor. Our study demonstrates that the HFD regimen and HCC resulted in strong upregulation of α-dC in the liver, heart, and muscles. In addition, an increase in α-dC was confirmed in sera of NAFLD and NASH patients. Furthermore, higher expression of the receptor for advanced glycation products (RAGE) was detected exclusively on immune cells and not on stroma cells in livers of mice with liver cancer progression. Our work confirms astable interplay of liver inflammation, carbonyl stress mediated by α-dC, and upregulated RAGE expression on CD8+ Tand natural killer (NK) cells in situ in NAFLD and HCC, as key factors/determinants in liver disease progression. The obtained findings underline the role of α-dC and RAGE+CD8+ Tand RAGE+ NK cells as biomarkers and candidates for a local therapeutic intervention in NAFLD and malignant liver disease.

Profiling of the muscle-specific dystroglycan interactome reveals the role of Hippo signaling in muscular dystrophy and age-dependent muscle atrophy.

BACKGROUND: Dystroglycanopathies are a group of inherited disorders characterized by vast clinical and genetic heterogeneity and caused by abnormal functioning of the ECM receptor dystroglycan (Dg). Remarkably, among many cases of diagnosed dystroglycanopathies, only a small fraction can be linked directly to mutations in Dg or its regulatory enzymes, implying the involvement of other, not-yet-characterized, Dg-regulating factors. To advance disease diagnostics and develop new treatment strategies, new approaches to find dystroglycanopathy-related factors should be considered. The Dg complex is highly evolutionarily conserved; therefore, model genetic organisms provide excellent systems to address this challenge. In particular, Drosophila is amenable to experiments not feasible in any other system, allowing original insights about the functional interactors of the Dg complex. METHODS: To identify new players contributing to dystroglycanopathies, we used Drosophila as a genetic muscular dystrophy model. Using mass spectrometry, we searched for muscle-specific Dg interactors. Next, in silico analyses allowed us to determine their association with diseases and pathological conditions in humans. Using immunohistochemical, biochemical, and genetic interaction approaches followed by the detailed analysis of the muscle tissue architecture, we verified Dg interaction with some of the discovered factors. Analyses of mouse muscles and myocytes were used to test if interactions are conserved in vertebrates. RESULTS: The muscle-specific Dg complexome revealed novel components that influence the efficiency of Dg function in the muscles. We identified the closest human homologs for Dg-interacting partners, determined their significant enrichment in disease-associations, and verified some of the newly identified Dg interactions. We found that Dg associates with two components of the mechanosignaling Hippo pathway: the WW domain-containing proteins Kibra and Yorkie. Importantly, this conserved interaction manages adult muscle size and integrity. CONCLUSIONS: The results presented in this study provide a new list of muscle-specific Dg interactors, further analysis of which could aid not only in the diagnosis of muscular dystrophies, but also in the development of new therapeutics. To regulate muscle fitness during aging and disease, Dg associates with Kibra and Yorkie and acts as a transmembrane Hippo signaling receptor that transmits extracellular information to intracellular signaling cascades, regulating muscle gene expression.

miRNA functions in stem cells and their niches: lessons from the Drosophila ovary.

From the very beginning of the miRNA era, Drosophila has served as an excellent model for explanation of miRNA biogenesis. Now Drosophila continues to be used in numerous studies aiming to decipher biological roles of individual miRNAs in a living organism. MiRNAs have emerged as an important regulatory class that adjusts gene expression in response to stress; therefore, it is particularly important to elucidate miRNA-based regulatory networks that appear in response to fluctuations in intrinsic and extrinsic environments. This review explores the major advances in understanding condition-dependent roles of miRNAs in adult stem cell biology using the Drosophila ovarian germline stem cell niche community as a model system.

miRNA targeting and alternative splicing in the stress response - events hosted by membrane-less compartments.

Stress can be temporary or chronic, and mild or acute. Depending on its extent and severity, cells either alter their metabolism, and adopt a new state, or die. Fluctuations in environmental conditions occur frequently, and such stress disturbs cellular homeostasis, but in general, stresses are reversible and last only a short time. There is increasing evidence that regulation of gene expression in response to temporal stress happens post-transcriptionally in specialized subcellular membrane-less compartments called ribonucleoprotein (RNP) granules. RNP granules assemble through a concentration-dependent liquid-liquid phase separation of RNA-binding proteins that contain low-complexity sequence domains (LCDs). Interestingly, many factors that regulate microRNA (miRNA) biogenesis and alternative splicing are RNA-binding proteins that contain LCDs and localize to stress-induced liquid-like compartments. Consequently, gene silencing through miRNAs and alternative splicing of pre-mRNAs are emerging as crucial post-transcriptional mechanisms that function on a genome-wide scale to regulate the cellular stress response. In this Review, we describe the interplay between these two post-transcriptional processes that occur in liquid-like compartments as an adaptive cellular response to stress.

Stress-dependent miR-980 regulation of Rbfox1/A2bp1 promotes ribonucleoprotein granule formation and cell survival.

Upon stress, profound post-transcriptional adjustments of gene expression occur in spatially restricted, subcellular, membraneless compartments, or ribonucleoprotein (RNP) granules, which are formed by liquid phase separation of RNA-binding proteins with low complexity sequence domains (LCDs). Here, we show that Rbfox1 is an LCD-containing protein that aggregates into liquid droplets and amyloid-like fibers and promiscuously joins different nuclear and cytoplasmic RNP granules. Using Drosophila oogenesis as an in vivo system for stress response, we demonstrate a mechanism by which Rbfox1 promotes cell survival. The stress-dependent miRNA miR-980 acts to buffer Rbfox1 levels, since it targets only those Rbfox1 transcripts that contain extended 3'UTRs. Reduced miR-980 expression during stress leads to increased Rbfox1 levels, widespread formation of various RNP granules, and increased cell viability. We show that human RBFOX proteins also contain multiple LCDs and form membraneless compartments, suggesting that the RNP granule-linked control of cellular adaptive responses may contribute to a wide range of RBFOX-associated pathologies in humans.

Stereotypical architecture of the stem cell niche is spatiotemporally established by miR-125-dependent coordination of Notch and steroid signaling.

Stem cell niches act as signaling platforms that regulate stem cell self-renewal and sustain stem cells throughout life; however, the specific developmental events controlling their assembly are not well understood. Here, we show that during Drosophila ovarian germline stem cell niche formation, the status of Notch signaling in the cell can be reprogrammed. This is controlled via steroid-induced miR-125, which targets a negative regulator of Notch signaling, Tom. Thus, miR-125 acts as a spatiotemporal coordinator between paracrine Notch and endocrine steroid signaling. Moreover, a dual security mechanism for Notch signaling activation exists to ensure the robustness of niche assembly. Particularly, stem cell niche cells can be specified either via lateral inhibition, in which a niche cell precursor acquires Notch signal-sending status randomly, or via peripheral induction, whereby Delta is produced by a specific cell. When one mechanism is perturbed due to mutations, developmental defects or environmental stress, the remaining mechanism ensures that the niche is formed, perhaps abnormally, but still functional. This guarantees that the germline stem cells will have their residence, thereby securing progressive oogenesis and, thus, organism reproduction.

TfAP-2 is required for night sleep in Drosophila.

BACKGROUND: The AP-2 transcription factor APTF-1 is crucially required for developmentally controlled sleep behavior in Caenorhabditis elegans larvae. Its human ortholog, TFAP-2beta, causes Char disease and has also been linked to sleep disorders. These data suggest that AP-2 transcription factors may be highly conserved regulators of various types of sleep behavior. Here, we tested the idea that AP-2 controls adult sleep in Drosophila. RESULTS: Drosophila has one AP-2 ortholog called TfAP-2, which is essential for viability. To investigate its potential role in sleep behavior and neural development, we specifically downregulated TfAP-2 in the nervous system. We found that neuronal TfAP-2 knockdown almost completely abolished night sleep but did not affect day sleep. TfAP-2 insufficiency affected nervous system development. Conditional TfAP-2 knockdown in the adult also produced a modest sleep phenotype, suggesting that TfAP-2 acts both in larval as well as in differentiated neurons. CONCLUSIONS: Thus, our results show that AP-2 transcription factors are highly conserved regulators of development and sleep.

Hedgehog Signaling Strength Is Orchestrated by the mir-310 Cluster of MicroRNAs in Response to Diet.

Since the discovery of microRNAs (miRNAs) only two decades ago, they have emerged as an essential component of the gene regulatory machinery. miRNAs have seemingly paradoxical features: a single miRNA is able to simultaneously target hundreds of genes, while its presence is mostly dispensable for animal viability under normal conditions. It is known that miRNAs act as stress response factors; however, it remains challenging to determine their relevant targets and the conditions under which they function. To address this challenge, we propose a new workflow for miRNA function analysis, by which we found that the evolutionarily young miRNA family, the mir-310s (mir-310/mir-311/mir-312/mir-313), are important regulators of Drosophila metabolic status. mir-310s-deficient animals have an abnormal diet-dependent expression profile for numerous diet-sensitive components, accumulate fats, and show various physiological defects. We found that the mir-310s simultaneously repress the production of several regulatory factors (Rab23, DHR96, and Ttk) of the evolutionarily conserved Hedgehog (Hh) pathway to sharpen dietary response. As the mir-310s expression is highly dynamic and nutrition sensitive, this signal relay model helps to explain the molecular mechanism governing quick and robust Hh signaling responses to nutritional changes. Additionally, we discovered a new component of the Hh signaling pathway in Drosophila, Rab23, which cell autonomously regulates Hh ligand trafficking in the germline stem cell niche. How organisms adjust to dietary fluctuations to sustain healthy homeostasis is an intriguing research topic. These data are the first to report that miRNAs can act as executives that transduce nutritional signals to an essential signaling pathway. This suggests miRNAs as plausible therapeutic agents that can be used in combination with low calorie and cholesterol diets to manage quick and precise tissue-specific responses to nutritional changes.

Soma influences GSC progeny differentiation via the cell adhesion-mediated steroid-let-7-Wingless signaling cascade that regulates chromatin dynamics.

It is known that signaling from the germline stem cell niche is required to maintain germline stem cell identity in Drosophila. However, it is not clear whether the germline stem-cell daughters differentiate by default (because they are physically distant from the niche) or whether additional signaling is necessary to initiate the differentiation program. Previously, we showed that ecdysteroid signaling cell non-autonomously regulates early germline differentiation via its soma-specific co-activator and co-repressor, Taiman and Abrupt. Now, we demonstrate that this regulation is modulated by the miRNA let-7, which acts in a positive feedback loop to confer ecdysone signaling robustness via targeting its repressor, the transcription factor Abrupt. This feedback loop adjusts ecdysteroid signaling in response to some stressful alterations in the external and internal conditions, which include temperature stress and aging, but not nutritional deprivation. Upon let-7 deficit, escort cells fail to properly differentiate: their shape, division, and cell adhesive characteristics are perturbed. These cells have confused cellular identity and form columnar-like rather than squamous epithelium and fail to send protrusions in between differentiating germline cysts, affecting soma-germline communication. Particularly, levels of the homophilic cell adhesion protein Cadherin, which recruits Wg signaling transducer ß-catenin, are increased in mutant escort cells and, correspondingly, in the adjacent germline cells. Readjustment of heterotypic (soma-germline) cell adhesion modulates Wg signaling intensity in the germline, which in turn regulates histone modifications that promote expression of the genes necessary to trigger early germline differentiation. Thus, our data first show the intrinsic role for Wg signaling in the germline and support a model where the soma influences the tempo of germline differentiation in response to external conditions.