RESUMEN
In Drosophila, a dedicated olfactory channel senses a male pheromone, cis-vaccenyl acetate (cVA), promoting female courtship while repelling males. Here, we show that separate cVA-processing streams extract qualitative and positional information. cVA sensory neurons respond to concentration differences in a 5-mm range around a male. Second-order projection neurons encode the angular position of a male by detecting inter-antennal differences in cVA concentration, which are amplified through contralateral inhibition. At the third circuit layer, we identify 47 cell types with diverse input-output connectivity. One population responds tonically to male flies, a second is tuned to olfactory looming, while a third integrates cVA and taste to coincidentally promote female mating. The separation of olfactory features resembles the mammalian what and where visual streams; together with multisensory integration, this enables behavioral responses appropriate to specific ethological contexts.
Asunto(s)
Proteínas de Drosophila , Receptores Odorantes , Animales , Femenino , Masculino , Drosophila melanogaster/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Conducta Sexual Animal/fisiología , Receptores Odorantes/metabolismo , Feromonas/metabolismo , Olfato/fisiología , Drosophila/metabolismo , Mamíferos/metabolismoRESUMEN
Previous studies have identified topologically associating domains (TADs) as basic units of genome organization. We present evidence of a previously unreported level of genome folding, where distant TAD pairs, megabases apart, interact to form meta-domains. Within meta-domains, gene promoters and structural intergenic elements present in distant TADs are specifically paired. The associated genes encode neuronal determinants, including those engaged in axonal guidance and adhesion. These long-range associations occur in a large fraction of neurons but support transcription in only a subset of neurons. Meta-domains are formed by diverse transcription factors that are able to pair over long and flexible distances. We present evidence that two such factors, GAF and CTCF, play direct roles in this process. The relative simplicity of higher-order meta-domain interactions in Drosophila, compared with those previously described in mammals, allowed the demonstration that genomes can fold into highly specialized cell-type-specific scaffolds that enable megabase-scale regulatory associations.
Asunto(s)
Cromosomas de Insectos , Drosophila , Animales , Cromatina/genética , Empaquetamiento del ADN , Drosophila/genética , Mamíferos/genética , Neurogénesis , Neuronas , Factores de Transcripción , Proteínas de Drosophila , Genoma de los Insectos , Regulación de la Expresión GénicaRESUMEN
Asymmetric localization of oskar ribonucleoprotein (RNP) granules to the oocyte posterior is crucial for abdominal patterning and germline formation in the Drosophila embryo. We show that oskar RNP granules in the oocyte are condensates with solid-like physical properties. Using purified oskar RNA and scaffold proteins Bruno and Hrp48, we confirm in vitro that oskar granules undergo a liquid-to-solid phase transition. Whereas the liquid phase allows RNA incorporation, the solid phase precludes incorporation of additional RNA while allowing RNA-dependent partitioning of client proteins. Genetic modification of scaffold granule proteins or tethering the intrinsically disordered region of human fused in sarcoma (FUS) to oskar mRNA allowed modulation of granule material properties in vivo. The resulting liquid-like properties impaired oskar localization and translation with severe consequences on embryonic development. Our study reflects how physiological phase transitions shape RNA-protein condensates to regulate the localization and expression of a maternal RNA that instructs germline formation.
Asunto(s)
Proteínas de Drosophila/metabolismo , Drosophila/metabolismo , Embrión no Mamífero/metabolismo , Animales , Gránulos de Ribonucleoproteínas Citoplasmáticas , Drosophila/embriología , Proteínas de Drosophila/genética , Desarrollo Embrionario , Oocitos/metabolismo , ARN/metabolismoRESUMEN
Predicting regulatory potential from primary DNA sequences or transcription factor binding patterns is not possible. However, the annotation of the genome by chromatin proteins, histone modifications, and differential compaction is largely sufficient to reveal the locations of genes and their differential activity states. The Polycomb Group (PcG) and Trithorax Group (TrxG) proteins are the central players in this cell type-specific chromatin organization. PcG function was originally viewed as being solely repressive and irreversible, as observed at the homeotic loci in flies and mammals. However, it is now clear that modular and reversible PcG function is essential at most developmental genes. Focusing mainly on recent advances, we review evidence for how PcG and TrxG patterns change dynamically during cell type transitions. The ability to implement cell type-specific transcriptional programming with exquisite fidelity is essential for normal development.
Asunto(s)
Proteínas Cromosómicas no Histona/genética , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Regulación del Desarrollo de la Expresión Génica , Histonas/metabolismo , Proteínas del Grupo Polycomb/genética , Transcripción Genética , Animales , Cromatina/química , Cromatina/metabolismo , Proteínas Cromosómicas no Histona/metabolismo , Metilación de ADN , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/citología , Drosophila melanogaster/crecimiento & desarrollo , Drosophila melanogaster/metabolismo , Embrión de Mamíferos , Embrión no Mamífero , Sitios Genéticos , Histonas/genética , Ratones , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas del Grupo Polycomb/clasificación , Proteínas del Grupo Polycomb/metabolismo , Elementos de Respuesta , Especificidad de la Especie , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
The accurate timing and execution of organelle biogenesis is crucial for cell physiology. Centriole biogenesis is regulated by Polo-like kinase 4 (Plk4) and initiates in S-phase when a daughter centriole grows from the side of a pre-existing mother. Here, we show that a Plk4 oscillation at the base of the growing centriole initiates and times centriole biogenesis to ensure that centrioles grow at the right time and to the right size. The Plk4 oscillation is normally entrained to the cell-cycle oscillator but can run autonomously of it-potentially explaining why centrioles can duplicate independently of cell-cycle progression. Mathematical modeling indicates that the Plk4 oscillation can be generated by a time-delayed negative feedback loop in which Plk4 inactivates the interaction with its centriolar receptor through multiple rounds of phosphorylation. We hypothesize that similar organelle-specific oscillations could regulate the timing and execution of organelle biogenesis more generally.
Asunto(s)
Relojes Biológicos/fisiología , Centriolos/metabolismo , Proteínas de Drosophila/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Animales , Ciclo Celular/fisiología , Proteínas de Ciclo Celular/metabolismo , Centrosoma/metabolismo , Proteínas de Drosophila/fisiología , Drosophila melanogaster/metabolismo , Biogénesis de Organelos , Fosforilación , Proteínas Serina-Treonina Quinasas/fisiologíaRESUMEN
Social impairment is frequently associated with mitochondrial dysfunction and altered neurotransmission. Although mitochondrial function is crucial for brain homeostasis, it remains unknown whether mitochondrial disruption contributes to social behavioral deficits. Here, we show that Drosophila mutants in the homolog of the human CYFIP1, a gene linked to autism and schizophrenia, exhibit mitochondrial hyperactivity and altered group behavior. We identify the regulation of GABA availability by mitochondrial activity as a biologically relevant mechanism and demonstrate its contribution to social behavior. Specifically, increased mitochondrial activity causes gamma aminobutyric acid (GABA) sequestration in the mitochondria, reducing GABAergic signaling and resulting in social deficits. Pharmacological and genetic manipulation of mitochondrial activity or GABA signaling corrects the observed abnormalities. We identify Aralar as the mitochondrial transporter that sequesters GABA upon increased mitochondrial activity. This study increases our understanding of how mitochondria modulate neuronal homeostasis and social behavior under physiopathological conditions.
Asunto(s)
Proteínas de Unión al Calcio/metabolismo , Proteínas de Drosophila/metabolismo , Mitocondrias/metabolismo , Ácido gamma-Aminobutírico/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Animales Modificados Genéticamente , Ácido Aspártico/metabolismo , Calcio/metabolismo , Proteínas de Unión al Calcio/fisiología , Proteínas de Drosophila/fisiología , Drosophila melanogaster/metabolismo , Glucosa/metabolismo , Homeostasis , Humanos , Masculino , Mitocondrias/genética , Proteínas de Transporte de Membrana Mitocondrial/genética , Proteínas Mitocondriales/metabolismo , Neuronas/metabolismo , Conducta Social , Transmisión Sináptica , Ácido gamma-Aminobutírico/genéticaRESUMEN
Before zygotic genome activation (ZGA), the quiescent genome undergoes reprogramming to transition into the transcriptionally active state. However, the mechanisms underlying euchromatin establishment during early embryogenesis remain poorly understood. Here, we show that histone H4 lysine 16 acetylation (H4K16ac) is maintained from oocytes to fertilized embryos in Drosophila and mammals. H4K16ac forms large domains that control nucleosome accessibility of promoters prior to ZGA in flies. Maternal depletion of MOF acetyltransferase leading to H4K16ac loss causes aberrant RNA Pol II recruitment, compromises the 3D organization of the active genomic compartments during ZGA, and causes downregulation of post-zygotically expressed genes. Germline depletion of histone deacetylases revealed that other acetyl marks cannot compensate for H4K16ac loss in the oocyte. Moreover, zygotic re-expression of MOF was neither able to restore embryonic viability nor onset of X chromosome dosage compensation. Thus, maternal H4K16ac provides an instructive function to the offspring, priming future gene activation.
Asunto(s)
Histonas/metabolismo , Lisina/metabolismo , Activación Transcripcional/genética , Acetilación , Animales , Secuencia de Bases , Segregación Cromosómica/genética , Secuencia Conservada , Compensación de Dosificación (Genética) , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/embriología , Drosophila melanogaster/genética , Embrión no Mamífero/metabolismo , Evolución Molecular , Femenino , Genoma , Histona Acetiltransferasas/genética , Histona Acetiltransferasas/metabolismo , Masculino , Mamíferos/genética , Ratones , Mutación/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Nucleosomas/metabolismo , Oocitos/metabolismo , Regiones Promotoras Genéticas , ARN Polimerasa II/metabolismo , Cromosoma X/metabolismo , Cigoto/metabolismoRESUMEN
This year's Gairdner Foundation Award for Biomedical Research goes to Roel Nusse for his pioneering work on the Wnt signaling pathway and its many roles in development, cancer, and stem cells.
Asunto(s)
Proteínas Wnt/metabolismo , Vía de Señalización Wnt , beta Catenina/metabolismo , Animales , Animales Modificados Genéticamente/metabolismo , Bibliografías como Asunto , Comunicación Celular , Drosophila , Proteínas de Drosophila/metabolismo , Femenino , Humanos , Neoplasias Mamarias Animales/metabolismo , Neoplasias Mamarias Animales/patología , Ratones , Proteína Wnt1/metabolismoRESUMEN
Metabolic reprogramming is a key feature of many cancers, but how and when it contributes to tumorigenesis remains unclear. Here we demonstrate that metabolic reprogramming induced by mitochondrial fusion can be rate-limiting for immortalization of tumor-initiating cells (TICs) and trigger their irreversible dedication to tumorigenesis. Using single-cell transcriptomics, we find that Drosophila brain tumors contain a rapidly dividing stem cell population defined by upregulation of oxidative phosphorylation (OxPhos). We combine targeted metabolomics and in vivo genetic screening to demonstrate that OxPhos is required for tumor cell immortalization but dispensable in neural stem cells (NSCs) giving rise to tumors. Employing an in vivo NADH/NAD+ sensor, we show that NSCs precisely increase OxPhos during immortalization. Blocking OxPhos or mitochondrial fusion stalls TICs in quiescence and prevents tumorigenesis through impaired NAD+ regeneration. Our work establishes a unique connection between cellular metabolism and immortalization of tumor-initiating cells.
Asunto(s)
Neoplasias Encefálicas/metabolismo , Carcinogénesis/metabolismo , Transformación Celular Neoplásica/metabolismo , Dinámicas Mitocondriales , NAD/metabolismo , Células Madre Neoplásicas/metabolismo , Células-Madre Neurales/metabolismo , Fosforilación Oxidativa , Animales , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/mortalidad , Neoplasias Encefálicas/patología , Carcinogénesis/genética , Carcinogénesis/patología , Transformación Celular Neoplásica/patología , Ciclo del Ácido Cítrico/genética , Biología Computacional , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Drosophila , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Glucólisis/genética , Espectrometría de Masas , Metabolómica , Microscopía Electrónica de Transmisión , Familia de Multigenes , Células-Madre Neurales/patología , Consumo de Oxígeno/genética , Interferencia de ARN , Especies Reactivas de Oxígeno/metabolismo , Análisis de la Célula Individual , Transcriptoma/genéticaRESUMEN
Molecular interactions at the cellular interface mediate organized assembly of single cells into tissues and, thus, govern the development and physiology of multicellular organisms. Here, we developed a cell-type-specific, spatiotemporally resolved approach to profile cell-surface proteomes in intact tissues. Quantitative profiling of cell-surface proteomes of Drosophila olfactory projection neurons (PNs) in pupae and adults revealed global downregulation of wiring molecules and upregulation of synaptic molecules in the transition from developing to mature PNs. A proteome-instructed in vivo screen identified 20 cell-surface molecules regulating neural circuit assembly, many of which belong to evolutionarily conserved protein families not previously linked to neural development. Genetic analysis further revealed that the lipoprotein receptor LRP1 cell-autonomously controls PN dendrite targeting, contributing to the formation of a precise olfactory map. These findings highlight the power of temporally resolved in situ cell-surface proteomic profiling in discovering regulators of brain wiring.
Asunto(s)
Vías Olfatorias/metabolismo , Neuronas Receptoras Olfatorias/metabolismo , Proteómica/métodos , Animales , Axones/metabolismo , Encéfalo/metabolismo , Dendritas/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Perfilación de la Expresión Génica/métodos , Regulación del Desarrollo de la Expresión Génica/genética , Proteínas de la Membrana/metabolismo , Neurogénesis/fisiología , Nervio Olfatorio/metabolismo , Vías Olfatorias/citología , Vías Olfatorias/fisiología , Receptores de Lipoproteína/metabolismo , Olfato/fisiologíaRESUMEN
Epithelial cells are the most common cell type in all animals, forming the sheets and tubes that compose most organs and tissues. Apical-basal polarity is essential for epithelial cell form and function, as it determines the localization of the adhesion molecules that hold the cells together laterally and the occluding junctions that act as barriers to paracellular diffusion. Polarity must also target the secretion of specific cargoes to the apical, lateral or basal membranes and organize the cytoskeleton and internal architecture of the cell. Apical-basal polarity in many cells is established by conserved polarity factors that define the apical (Crumbs, Stardust/PALS1, aPKC, PAR-6 and CDC42), junctional (PAR-3) and lateral (Scribble, DLG, LGL, Yurt and RhoGAP19D) domains, although recent evidence indicates that not all epithelia polarize by the same mechanism. Research has begun to reveal the dynamic interactions between polarity factors and how they contribute to polarity establishment and maintenance. Elucidating these mechanisms is essential to better understand the roles of apical-basal polarity in morphogenesis and how defects in polarity contribute to diseases such as cancer.
Asunto(s)
Polaridad Celular , Proteínas de Drosophila , Animales , Polaridad Celular/fisiología , Proteínas de Drosophila/metabolismo , Células Epiteliales , Epitelio/metabolismo , MorfogénesisRESUMEN
In developing organisms, spatially prescribed cell identities are thought to be determined by the expression levels of multiple genes. Quantitative tests of this idea, however, require a theoretical framework capable of exposing the rules and precision of cell specification over developmental time. We use the gap gene network in the early fly embryo as an example to show how expression levels of the four gap genes can be jointly decoded into an optimal specification of position with 1% accuracy. The decoder correctly predicts, with no free parameters, the dynamics of pair-rule expression patterns at different developmental time points and in various mutant backgrounds. Precise cellular identities are thus available at the earliest stages of development, contrasting the prevailing view of positional information being slowly refined across successive layers of the patterning network. Our results suggest that developmental enhancers closely approximate a mathematically optimal decoding strategy.
Asunto(s)
Proteínas Activadoras de GTPasa/genética , Regulación del Desarrollo de la Expresión Génica/genética , Redes Reguladoras de Genes/genética , Animales , Tipificación del Cuerpo/genética , Diferenciación Celular/genética , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Embrión no Mamífero/metabolismo , Desarrollo Embrionario/genética , Proteínas Activadoras de GTPasa/metabolismo , Regulación del Desarrollo de la Expresión Génica/fisiología , Modelos Genéticos , Factores de Transcripción/metabolismoRESUMEN
The molecular events that direct nuclear pore complex (NPC) assembly toward nuclear envelopes have been conceptualized in two pathways that occur during mitosis or interphase, respectively. In gametes and embryonic cells, NPCs also occur within stacked cytoplasmic membrane sheets, termed annulate lamellae (AL), which serve as NPC storage for early development. The mechanism of NPC biogenesis at cytoplasmic membranes remains unknown. Here, we show that during Drosophila oogenesis, Nucleoporins condense into different precursor granules that interact and progress into NPCs. Nup358 is a key player that condenses into NPC assembly platforms while its mRNA localizes to their surface in a translation-dependent manner. In concert, Microtubule-dependent transport, the small GTPase Ran and nuclear transport receptors regulate NPC biogenesis in oocytes. We delineate a non-canonical NPC assembly mechanism that relies on Nucleoporin condensates and occurs away from the nucleus under conditions of cell cycle arrest.
Asunto(s)
Proteínas de Drosophila/metabolismo , Chaperonas Moleculares/metabolismo , Proteínas de Complejo Poro Nuclear/metabolismo , Poro Nuclear/metabolismo , Oogénesis , Transporte Activo de Núcleo Celular , Animales , Proteínas de Drosophila/genética , Drosophila melanogaster , Femenino , Microtúbulos/metabolismo , Chaperonas Moleculares/genética , Proteínas de Complejo Poro Nuclear/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteína de Unión al GTP ran/genética , Proteína de Unión al GTP ran/metabolismoRESUMEN
Prion-like proteins can assume distinct conformational and physical states in the same cell. Sequence analysis suggests that prion-like proteins are prevalent in various species; however, it remains unclear what functional space they occupy in multicellular organisms. Here, we report the identification of a prion-like protein, Herzog (CG5830), through a multimodal screen in Drosophila melanogaster. Herzog functions as a membrane-associated phosphatase and controls embryonic patterning, likely being involved in TGF-ß/BMP and FGF/EGF signaling pathways. Remarkably, monomeric Herzog is enzymatically inactive and becomes active upon amyloid-like assembly. The prion-like domain of Herzog is necessary for both its assembly and membrane targeting. Removal of the prion-like domain impairs activity, while restoring assembly on the membrane using a heterologous prion-like domain and membrane-targeting motif can restore phosphatase activity. This study provides an example of a prion-like domain that allows an enzyme to gain essential functionality via amyloid-like assembly to control animal development.
Asunto(s)
Proteínas Amiloidogénicas/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/embriología , Desarrollo Embrionario , Fosfoproteínas Fosfatasas/metabolismo , Monoéster Fosfórico Hidrolasas/metabolismo , Proteínas Amiloidogénicas/química , Proteínas Amiloidogénicas/genética , Animales , Proteínas de Drosophila/química , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Fosfoproteínas Fosfatasas/química , Fosfoproteínas Fosfatasas/genética , Monoéster Fosfórico Hidrolasas/química , Monoéster Fosfórico Hidrolasas/genética , Priones/química , Dominios ProteicosRESUMEN
Physiology and metabolism are often sexually dimorphic, but the underlying mechanisms remain incompletely understood. Here, we use the intestine of Drosophila melanogaster to investigate how gut-derived signals contribute to sex differences in whole-body physiology. We find that carbohydrate handling is male-biased in a specific portion of the intestine. In contrast to known sexual dimorphisms in invertebrates, the sex differences in intestinal carbohydrate metabolism are extrinsically controlled by the adjacent male gonad, which activates JAK-STAT signaling in enterocytes within this intestinal portion. Sex reversal experiments establish roles for this male-biased intestinal metabolic state in controlling food intake and sperm production through gut-derived citrate. Our work uncovers a male gonad-gut axis coupling diet and sperm production, revealing that metabolic communication across organs is physiologically important. The instructive role of citrate in inter-organ communication might be significant in more biological contexts than previously recognized.
Asunto(s)
Metabolismo de los Hidratos de Carbono/fisiología , Drosophila melanogaster/metabolismo , Ingestión de Alimentos/fisiología , Mucosa Intestinal/metabolismo , Caracteres Sexuales , Maduración del Esperma/fisiología , Animales , Ácido Cítrico/metabolismo , Proteínas de Drosophila/metabolismo , Femenino , Expresión Génica , Quinasas Janus/metabolismo , Masculino , RNA-Seq , Factores de Transcripción STAT/metabolismo , Transducción de Señal , Azúcares/metabolismo , Testículo/metabolismoRESUMEN
Animals rely on the relative timing of events in their environment to form and update predictive associations, but the molecular and circuit mechanisms for this temporal sensitivity remain incompletely understood. Here, we show that olfactory associations in Drosophila can be written and reversed on a trial-by-trial basis depending on the temporal relationship between an odor cue and dopaminergic reinforcement. Through the synchronous recording of neural activity and behavior, we show that reversals in learned odor attraction correlate with bidirectional neural plasticity in the mushroom body, the associative olfactory center of the fly. Two dopamine receptors, DopR1 and DopR2, contribute to this temporal sensitivity by coupling to distinct second messengers and directing either synaptic depression or potentiation. Our results reveal how dopamine-receptor signaling pathways can detect the order of events to instruct opposing forms of synaptic and behavioral plasticity, allowing animals to flexibly update their associations in a dynamic environment.
Asunto(s)
Aprendizaje por Asociación/fisiología , Proteínas de Drosophila/metabolismo , Drosophila/fisiología , Cuerpos Pedunculados/fisiología , Receptores de Dopamina D1/metabolismo , Receptores Dopaminérgicos/metabolismo , Animales , Conducta Animal/fisiología , Condicionamiento Clásico/fisiología , Dopamina/metabolismo , Neuronas Dopaminérgicas/metabolismo , Plasticidad Neuronal , Odorantes , Recompensa , Olfato/fisiología , Potenciales Sinápticos/fisiología , Factores de TiempoRESUMEN
PIWI-interacting RNAs (piRNAs) guide transposon silencing in animals. The 22-30 nt piRNAs are processed in the cytoplasm from long non-coding RNAs that often lack RNA processing hallmarks of export-competent transcripts. By studying how these transcripts achieve nuclear export, we uncover an RNA export pathway specific for piRNA precursors in the Drosophila germline. This pathway requires Nxf3-Nxt1, a variant of the hetero-dimeric mRNA export receptor Nxf1-Nxt1. Nxf3 interacts with UAP56, a nuclear RNA helicase essential for mRNA export, and CG13741/Bootlegger, which recruits Nxf3-Nxt1 and UAP56 to heterochromatic piRNA source loci. Upon RNA cargo binding, Nxf3 achieves nuclear export via the exportin Crm1 and accumulates together with Bootlegger in peri-nuclear nuage, suggesting that after export, Nxf3-Bootlegger delivers precursor transcripts to the piRNA processing sites. These findings indicate that the piRNA pathway bypasses nuclear RNA surveillance systems to export unprocessed transcripts to the cytoplasm, a strategy also exploited by retroviruses.
Asunto(s)
Transporte Activo de Núcleo Celular/fisiología , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Heterocromatina/metabolismo , Proteínas de Transporte Nucleocitoplasmático/metabolismo , ARN Interferente Pequeño/metabolismo , Proteínas de Unión al ARN/metabolismo , Animales , Animales Modificados Genéticamente , Proteínas Argonautas/metabolismo , Línea Celular , Núcleo Celular/metabolismo , Citoplasma/metabolismo , ARN Helicasas DEAD-box/metabolismo , Elementos Transponibles de ADN , Silenciador del Gen , Células Germinativas/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Carioferinas/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Transcripción Genética , Proteína Exportina 1RESUMEN
The synchronous cleavage divisions of early embryogenesis require coordination of the cell-cycle oscillator, the dynamics of the cytoskeleton, and the cytoplasm. Yet, it remains unclear how spatially restricted biochemical signals are integrated with physical properties of the embryo to generate collective dynamics. Here, we show that synchronization of the cell cycle in Drosophila embryos requires accurate nuclear positioning, which is regulated by the cell-cycle oscillator through cortical contractility and cytoplasmic flows. We demonstrate that biochemical oscillations are initiated by local Cdk1 inactivation and spread through the activity of phosphatase PP1 to generate cortical myosin II gradients. These gradients cause cortical and cytoplasmic flows that control proper nuclear positioning. Perturbations of PP1 activity and optogenetic manipulations of cortical actomyosin disrupt nuclear spreading, resulting in loss of cell-cycle synchrony. We conclude that mitotic synchrony is established by a self-organized mechanism that integrates the cell-cycle oscillator and embryo mechanics.
Asunto(s)
Proteína Quinasa CDC2/metabolismo , Ciclo Celular/fisiología , División del Núcleo Celular/fisiología , Proteínas de Drosophila/metabolismo , Actomiosina/metabolismo , Animales , Núcleo Celular/metabolismo , Citocinesis/fisiología , Citoplasma , Citoesqueleto/metabolismo , Drosophila melanogaster/embriología , Embrión no Mamífero/metabolismo , Desarrollo Embrionario/fisiología , Microtúbulos/metabolismo , Mitosis , Miosina Tipo II/metabolismo , Monoéster Fosfórico Hidrolasas/metabolismoRESUMEN
X chromosome regulation represents a prime example of an epigenetic phenomenon where coordinated regulation of a whole chromosome is required. In flies, this is achieved by transcriptional upregulation of X chromosomal genes in males to equalize the gene dosage differences in females. Chromatin-bound proteins and long noncoding RNAs (lncRNAs) constituting a ribonucleoprotein complex known as the male-specific lethal (MSL) complex or the dosage compensation complex mediate this process. MSL complex members decorate the male X chromosome, and their absence leads to male lethality. The male X chromosome is also enriched with histone H4 lysine 16 acetylation (H4K16ac), indicating that the chromatin compaction status of the X chromosome also plays an important role in transcriptional activation. How the X chromosome is specifically targeted and how dosage compensation is mechanistically achieved are central questions for the field. Here, we review recent advances, which reveal a complex interplay among lncRNAs, the chromatin landscape, transcription, and chromosome conformation that fine-tune X chromosome gene expression.
Asunto(s)
Compensación de Dosificación (Genética) , Cromosoma X/genética , Animales , Cromatina/genética , Cromatina/metabolismo , Proteínas de Drosophila/química , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Epigénesis Genética , Femenino , Genes Ligados a X , Código de Histonas/genética , Humanos , Masculino , Modelos Genéticos , Modelos Moleculares , Proteínas Nucleares/química , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Factores de Transcripción/química , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Cromosoma X/metabolismoRESUMEN
In Drosophila, well-delineated circuits control circadian rhythms, but the electrophysiological patterns that occur within these circuits are not well understood. In this issue, Tabuchi et al. clarify the temporal coding within a circuit, linking patterns of neural activity to sleep behavior.