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1.
Elife ; 132024 Jul 22.
Artículo en Inglés | MEDLINE | ID: mdl-39037919

RESUMEN

Sleep and feeding patterns lack strong daily rhythms during early life. As diurnal animals mature, feeding is consolidated to the day and sleep to the night. In Drosophila, circadian sleep patterns are initiated with formation of a circuit connecting the central clock to arousal output neurons; emergence of circadian sleep also enables long-term memory (LTM). However, the cues that trigger the development of this clock-arousal circuit are unknown. Here, we identify a role for nutritional status in driving sleep-wake rhythm development in Drosophila larvae. We find that in the 2nd instar larval period (L2), sleep and feeding are spread across the day; these behaviors become organized into daily patterns by the 3rd instar larval stage (L3). Forcing mature (L3) animals to adopt immature (L2) feeding strategies disrupts sleep-wake rhythms and the ability to exhibit LTM. In addition, the development of the clock (DN1a)-arousal (Dh44) circuit itself is influenced by the larval nutritional environment. Finally, we demonstrate that larval arousal Dh44 neurons act through glucose metabolic genes to drive onset of daily sleep-wake rhythms. Together, our data suggest that changes to energetic demands in developing organisms trigger the formation of sleep-circadian circuits and behaviors.


Like most young animals, babies must obtain enough nutrients and energy to grow, yet they also need to rest for their brains to mature properly. As many exhausted new parents know first-hand, balancing these conflicting needs results in frequent, rapid switches between eating and sleeping. Eventually, new-borns' internal biological clock system, which is aligned with the 24-hour light cycle, becomes fully operational. Exactly how this then translates into allowing them to stay alert during the day and be sleepy at night is still unclear. Like humans, the larvae of fruit flies first sleep haphazardly before developing a circadian pattern whereby they sleep at night and eat during the day. This shift occurs when a group of nerve cells called DN1a, whose job is to 'keep time', connects with Dh44, a subset of neurons which, when active, promote wakefulness. The trigger for these changes, however, has remained elusive. In response, Poe et al. hypothesized that feeding behaviour and nutrient availability coordinated the emergence of sleep rhythms in fruit flies. Forcing fruit fly larvae to keep feeding in an 'immature' pattern ­ by either genetic manipulations or reducing the sugar content of their food ­ not only prevented them from developing 'mature' sleeping rhythms but also resulted in memory problems. These experiments also showed that the DN1a-Dh44 connection depends on nutrient availability, as it did not form in larvae raised on the low-sugar food. Further genetic experiments showed that the Dh44 cells themselves act like nutrient sensors during the emergence of sleeping patterns. These results shed new light on the factors triggering sleep rhythm development. Poe et al. hope that the understanding gained can be extended to humans and eventually help manage nervous system disorders and health problems associated with disrupted sleep during early life.


Asunto(s)
Ritmo Circadiano , Drosophila melanogaster , Larva , Sueño , Animales , Sueño/fisiología , Larva/crecimiento & desarrollo , Larva/fisiología , Ritmo Circadiano/fisiología , Drosophila melanogaster/fisiología , Drosophila melanogaster/genética , Drosophila melanogaster/crecimiento & desarrollo , Neuronas/fisiología , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/genética , Conducta Alimentaria/fisiología , Vigilia/fisiología , Metabolismo Energético
2.
bioRxiv ; 2023 Sep 22.
Artículo en Inglés | MEDLINE | ID: mdl-37786713

RESUMEN

Sleep and feeding patterns lack a clear daily rhythm during early life. As diurnal animals mature, feeding is consolidated to the day and sleep to the night. Circadian sleep patterns begin with formation of a circuit connecting the central clock to arousal output neurons; emergence of circadian sleep also enables long-term memory (LTM). However, the cues that trigger the development of this clock-arousal circuit are unknown. Here, we identify a role for nutritional status in driving sleep-wake rhythm development in Drosophila larvae. We find that in the 2nd instar (L2) period, sleep and feeding are spread across the day; these behaviors become organized into daily patterns by L3. Forcing mature (L3) animals to adopt immature (L2) feeding strategies disrupts sleep-wake rhythms and the ability to exhibit LTM. In addition, the development of the clock (DN1a)-arousal (Dh44) circuit itself is influenced by the larval nutritional environment. Finally, we demonstrate that larval arousal Dh44 neurons act through glucose metabolic genes to drive onset of daily sleep-wake rhythms. Together, our data suggest that changes to energetic demands in developing organisms triggers the formation of sleep-circadian circuits and behaviors.

3.
Sci Adv ; 9(36): eadh2301, 2023 09 08.
Artículo en Inglés | MEDLINE | ID: mdl-37683005

RESUMEN

In adulthood, sleep-wake rhythms are one of the most prominent behaviors under circadian control. However, during early life, sleep is spread across the 24-hour day. The mechanism through which sleep rhythms emerge, and consequent advantage conferred to a juvenile animal, is unknown. In the second-instar Drosophila larvae (L2), like in human infants, sleep is not under circadian control. We identify the precise developmental time point when the clock begins to regulate sleep in Drosophila, leading to emergence of sleep rhythms in early third-instars (L3). At this stage, a cellular connection forms between DN1a clock neurons and arousal-promoting Dh44 neurons, bringing arousal under clock control to drive emergence of circadian sleep. Last, we demonstrate that L3 but not L2 larvae exhibit long-term memory (LTM) of aversive cues and that this LTM depends upon deep sleep generated once sleep rhythms begin. We propose that the developmental emergence of circadian sleep enables more complex cognitive processes, including the onset of enduring memories.


Asunto(s)
Drosophila , Memoria a Largo Plazo , Animales , Lactante , Humanos , Afecto , Nivel de Alerta , Larva , Sueño
4.
Neurobiol Sleep Circadian Rhythms ; 15: 100101, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37593040

RESUMEN

Sleep disturbances are common in neurodevelopmental disorders, but knowledge of molecular factors that govern sleep in young animals is lacking. Evidence across species, including Drosophila, suggests that juvenile sleep has distinct functions and regulatory mechanisms in comparison to sleep in maturity. In flies, manipulation of most known adult sleep regulatory genes is not associated with sleep phenotypes during early developmental (larval) stages. Here, we examine the role of the neurodevelopmental disorder-associated gene Neurofibromin 1 (Nf1) in sleep during numerous developmental periods. Mutations in Neurofibromin 1 (Nf1) are associated with sleep and circadian disorders in humans and adult flies. We find in flies that Nf1 acts to regulate sleep across the lifespan, beginning during larval stages. Nf1 is required in neurons for this function, as is signaling via the Alk pathway. These findings identify Nf1 as one of a small number of genes positioned to regulate sleep across developmental periods.

5.
FEBS J ; 289(21): 6576-6588, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-34375504

RESUMEN

Circadian clocks keep time to coordinate diverse behaviors and physiological functions. While molecular circadian rhythms are evident during early development, most behavioral rhythms, such as sleep-wake, do not emerge until far later. Here, we examine the development of circadian clocks, outputs, and behaviors across phylogeny, with a particular focus on Drosophila. We explore potential mechanisms for how central clocks and circadian output loci establish communication, and discuss why from an evolutionary perspective sleep-wake and other behavioral rhythms emerge long after central clocks begin keeping time.


Asunto(s)
Relojes Circadianos , Proteínas de Drosophila , Animales , Relojes Circadianos/genética , Ritmo Circadiano/genética , Sueño/genética , Drosophila/genética
6.
Elife ; 92020 05 19.
Artículo en Inglés | MEDLINE | ID: mdl-32427101

RESUMEN

During prolonged nutrient restriction, developing animals redistribute vital nutrients to favor brain growth at the expense of other organs. In Drosophila, such brain sparing relies on a glia-derived growth factor to sustain proliferation of neural stem cells. However, whether other aspects of neural development are also spared under nutrient restriction is unknown. Here we show that dynamically growing somatosensory neurons in the Drosophila peripheral nervous system exhibit organ sparing at the level of arbor growth: Under nutrient stress, sensory dendrites preferentially grow as compared to neighboring non-neural tissues, resulting in dendrite overgrowth. These neurons express lower levels of the stress sensor FoxO than neighboring epidermal cells, and hence exhibit no marked induction of autophagy and a milder suppression of Tor signaling under nutrient stress. Preferential dendrite growth allows for heightened animal responses to sensory stimuli, indicative of a potential survival advantage under environmental challenges.


The organs of a young animal develop in a carefully controlled way to reach the right size relative to each other. However, if the animal's diet does not contain the right amount of nutrients ­ a condition known as malnutrition ­ the body prioritizes the needs of the brain and other vital organs. This means that certain organs keep on growing while others stop. The brain is at the center of the nervous system, which is formed of networks of nerve cells (or neurons) that rapidly carry messages around the body. In the larvae of malnourished fruit flies, a molecular signal allows the nervous system to continue making new neurons as other parts of the body slow down their growth. During development, neurons also connect to each other by growing tree-like structures known as dendrites. However, it remained unclear whether the growth of dendrites was also protected during episodes of malnutrition. To address this question, Poe, Xu et al. performed experiments in the larvae of fruit flies, focusing on a type of neuron whose dendrites extend into the skin. When nutrients were scarce, the neurons grew more rapidly than the surrounding skin cells, resulting in dendrite overgrowth. Compared to neurons, the skin cells had higher levels of a stress sensor known as FoxO, which stops cell growth when nutrients are scarce. Conversely, low quantities of FoxO in neurons allow these cells to keep on growing dendrites, which ultimately helps the starved animals to better react to their environment. These results suggest that the growth of neurons and their connecting structures is preserved during malnutrition. Ultimately, dissecting how organisms prioritize resources can help to develop new approaches to treat human conditions that emerge during malnutrition.


Asunto(s)
Dendritas/fisiología , Proteínas de Drosophila/fisiología , Drosophila/crecimiento & desarrollo , Privación de Alimentos , Factores de Transcripción Forkhead/fisiología , Neurogénesis/fisiología , Células Receptoras Sensoriales/fisiología , Animales , Autofagia , Proteínas de Drosophila/biosíntesis , Proteínas de Drosophila/metabolismo , Células Epidérmicas/fisiología , Femenino , Factores de Transcripción Forkhead/biosíntesis , Sistema de Señalización de MAP Quinasas , Masculino , Nutrientes , Proteínas Tirosina Quinasas Receptoras/metabolismo , Estrés Fisiológico
7.
Genetics ; 211(2): 459-472, 2019 02.
Artículo en Inglés | MEDLINE | ID: mdl-30504366

RESUMEN

Tissue-specific loss-of-function (LOF) analysis is essential for characterizing gene function. Here, we present a simple, yet highly efficient, clustered regularly interspaced short palindromic repeats (CRISPR)-mediated tissue-restricted mutagenesis (CRISPR-TRiM) method for ablating gene function in Drosophila This binary system consists of a tissue-specific Cas9 and a ubiquitously expressed multi-guide RNA (gRNA) transgene. We describe convenient toolkits for making enhancer-driven Cas9 lines and multi-gRNAs that are optimized for mutagenizing somatic cells. We demonstrate that insertions or deletions in coding sequences more reliably cause somatic mutations than DNA excisions induced by two gRNAs. We further show that enhancer-driven Cas9 is less cytotoxic yet results in more complete LOF than Gal4-driven Cas9 in larval sensory neurons. Finally, CRISPR-TRiM efficiently unmasks redundant soluble N-ethylmaleimide-sensitive factor attachment protein receptor gene functions in neurons and epidermal cells. Importantly, Cas9 transgenes expressed at different times in the neuronal lineage reveal the extent to which gene products persist in cells after tissue-specific gene knockout. These CRISPR tools can be applied to analyze tissue-specific gene function in many biological processes.


Asunto(s)
Sistemas CRISPR-Cas , Dosificación de Gen , Técnicas Genéticas , Mutagénesis , Animales , Drosophila/genética , Epidermis/metabolismo , Mutación con Pérdida de Función , Neuronas/metabolismo , Especificidad de Órganos , ARN Guía de Kinetoplastida/genética , Transgenes
8.
Cell Rep ; 24(9): 2273-2286, 2018 08 28.
Artículo en Inglés | MEDLINE | ID: mdl-30157423

RESUMEN

Phagocytic clearance of degenerating dendrites or axons is critical for maintaining tissue homeostasis and preventing neuroinflammation. Externalized phosphatidylserine (PS) has been postulated to be an "eat-me" signal allowing recognition of degenerating neurites by phagocytes. Here we show that in Drosophila, PS is dynamically exposed on degenerating dendrites during developmental pruning and after physical injury, but PS exposure is suppressed when dendrite degeneration is genetically blocked. Ectopic PS exposure via phospholipid flippase knockout and scramblase overexpression induced PS exposure preferentially at distal dendrites and caused distinct modes of neurite loss that differ in larval sensory dendrites and in adult olfactory axons. Surprisingly, extracellular lactadherin that lacks the integrin-interaction domain induced phagocyte-dependent degeneration of PS-exposing dendrites, revealing an unidentified bridging function that potentiates phagocytes. Our findings establish a direct causal relationship between PS exposure and neurite degeneration in vivo.


Asunto(s)
Proteínas de Drosophila/metabolismo , Drosophila/patogenicidad , Degeneración Nerviosa/patología , Neuritas/metabolismo , Fosfatidilserinas/metabolismo , Animales
9.
Proc Natl Acad Sci U S A ; 114(38): E8062-E8071, 2017 09 19.
Artículo en Inglés | MEDLINE | ID: mdl-28874572

RESUMEN

Neurons sometimes completely fill available space in their receptive fields with evenly spaced dendrites to uniformly sample sensory or synaptic information. The mechanisms that enable neurons to sense and innervate all space in their target tissues are poorly understood. Using Drosophila somatosensory neurons as a model, we show that heparan sulfate proteoglycans (HSPGs) Dally and Syndecan on the surface of epidermal cells act as local permissive signals for the dendritic growth and maintenance of space-filling nociceptive C4da neurons, allowing them to innervate the entire skin. Using long-term time-lapse imaging with intact Drosophila larvae, we found that dendrites grow into HSPG-deficient areas but fail to stay there. HSPGs are necessary to stabilize microtubules in newly formed high-order dendrites. In contrast to C4da neurons, non-space-filling sensory neurons that develop in the same microenvironment do not rely on HSPGs for their dendritic growth. Furthermore, HSPGs do not act by transporting extracellular diffusible ligands or require leukocyte antigen-related (Lar), a receptor protein tyrosine phosphatase (RPTP) and the only known Drosophila HSPG receptor, for promoting dendritic growth of space-filling neurons. Interestingly, another RPTP, Ptp69D, promotes dendritic growth of C4da neurons in parallel to HSPGs. Together, our data reveal an HSPG-dependent pathway that specifically allows dendrites of space-filling neurons to innervate all target tissues in Drosophila.


Asunto(s)
Dendritas/metabolismo , Proteínas de Drosophila/metabolismo , Heparina/análogos & derivados , Nociceptores/metabolismo , Proteoglicanos/metabolismo , Proteínas Tirosina Fosfatasas Similares a Receptores/metabolismo , Transducción de Señal , Animales , Proteínas de Drosophila/genética , Drosophila melanogaster , Heparina/genética , Heparina/metabolismo , Nociceptores/citología , Proteoglicanos/genética , Proteínas Tirosina Fosfatasas Similares a Receptores/genética
10.
PLoS One ; 7(11): e48964, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-23139826

RESUMEN

BACKGROUND: Distributed robustness is thought to influence the buffering of random phenotypic variation through the scale-free topology of gene regulatory, metabolic, and protein-protein interaction networks. If this hypothesis is true, then the phenotypic response to the perturbation of particular nodes in such a network should be proportional to the number of links those nodes make with neighboring nodes. This suggests a probability distribution approximating an inverse power-law of random phenotypic variation. Zero phenotypic variation, however, is impossible, because random molecular and cellular processes are essential to normal development. Consequently, a more realistic distribution should have a y-intercept close to zero in the lower tail, a mode greater than zero, and a long (fat) upper tail. The double Pareto-lognormal (DPLN) distribution is an ideal candidate distribution. It consists of a mixture of a lognormal body and upper and lower power-law tails. OBJECTIVE AND METHODS: If our assumptions are true, the DPLN distribution should provide a better fit to random phenotypic variation in a large series of single-gene knockout lines than other skewed or symmetrical distributions. We fit a large published data set of single-gene knockout lines in Saccharomyces cerevisiae to seven different probability distributions: DPLN, right Pareto-lognormal (RPLN), left Pareto-lognormal (LPLN), normal, lognormal, exponential, and Pareto. The best model was judged by the Akaike Information Criterion (AIC). RESULTS: Phenotypic variation among gene knockouts in S. cerevisiae fits a double Pareto-lognormal (DPLN) distribution better than any of the alternative distributions, including the right Pareto-lognormal and lognormal distributions. CONCLUSIONS AND SIGNIFICANCE: A DPLN distribution is consistent with the hypothesis that developmental stability is mediated, in part, by distributed robustness, the resilience of gene regulatory, metabolic, and protein-protein interaction networks. Alternatively, multiplicative cell growth, and the mixing of lognormal distributions having different variances, may generate a DPLN distribution.


Asunto(s)
Técnicas de Inactivación de Genes , Saccharomyces cerevisiae/citología , Saccharomyces cerevisiae/genética , Distribuciones Estadísticas , Bases de Datos Genéticas , Genes Fúngicos , Fenotipo , Probabilidad
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