no circadian temperature entrainment: Biological Overview | References
Gene name - no circadian temperature entrainment
Cytological map position - 9C6-9D1
Function - signaling
Symbol - nocte
FlyBase ID: FBgn0261710
Genetic map position - X:10,357,851..10,367,618 [-]
Classification - large glutamine-rich protein
Cellular location - cytoplasmic
Circadian clocks are synchronized by the natural day/night and temperature cycles. Synchronization by temperature is a tissue autonomous process, similar to synchronization by light. This study shows that this is indeed the case, with the important exception of the brain. Using luciferase imaging it was demonstrated that brain clock neurons depend on signals from peripheral tissues in order to be synchronized by temperature. Reducing the function of the gene nocte in chordotonal organs changes their structure and function and dramatically interferes with temperature synchronization of behavioral activity. Other mutants known to affect the function of these sensory organs also interfere with temperature synchronization, demonstrating the importance of nocte in this process and identifying the chordotonal organs as relevant sensory structures. This work reveals surprising and important mechanistic differences between light- and temperature-synchronization and advances the understanding of how clock resetting is accomplished in nature (Sehadova, 2009).
Circadian clocks regulate many biological processes so that they occur at beneficial times for the organism. Although these clocks are self-sustained and continue to run under constant conditions, they are synchronized with the environment by so called 'Zeitgebers' (Dunlap, 2004). Two prominent Zeitgebers are the natural light-dark and temperature cycles that are able to synchronize the circadian clock of Drosophila and other organisms (see Boothroyd, 2008; Dubruille, 2008; Glaser, 2007]). Although knowledge regarding light entrainment of both fly and mammalian clocks is quite advanced, relatively little is known about temperature synchronization. Light is generally considered to be the more powerful Zeitgeber, but a temperature cycle with only 2°C-3°C amplitude robustly synchronizes Drosophila behavioral rhythms. In mammals, chick, and zebrafish, similar low-amplitude temperature rhythms (equivalent to body-temperature rhythms) are able to synchronize clock gene expression in the suprachiasmatic nucleus (SCN) and peripheral clock cells, exemplifying the potential strength of this Zeitgeber (namely, temperature cycles). Moreover, as shown for Drosophila (Glaser, 2005), temperature synchronization of clock gene expression in these organisms occurs in tissue- or cell-autonomous manners, indicating that similar mechanisms are involved in ectothermic and endothermic animals (Sehadova, 2009).
Drosophila's daily locomotor rhythmicity profile is bimodal, exhibiting major activity peaks in the morning and evening. This bimodality is regulated by several groups of clock neurons in the fly brain. Recent work has revealed that a group of ventrally located neurons controls mainly the morning activity peak of fly behavior (M-cells), whereas more dorsally located cells regulate evening activity (E-cells) (Sheeba, 2008). These neurons control locomotor rhythms, and cyclically express several clock genes and proteins in synchrony with light-dark or temperature cycles (Sehadova, 2009).
While clock neurons are mainly cell autonomously synchronized by light via Cry, it is not known how temperature signals reach the brain clock. It is formally possible that temperature sensitive neurons express a circadian temperature receptor that is able to synchronize the molecular clock within the pacemaker neurons (Hamada, 2008). Alternatively, temperature could be sensed by other neurons in the brain or by sensory structures in other parts of the fly, which then signal to the clock neurons. Two mutations that interfere with temperature entrainment, both molecularly and behaviorally, have been identified and could therefore shed light on the temperature entrainment mechanism (Glaser, 2005). Mutants in the norpA gene, which encodes for the enzyme phospholipase C, are not able to synchronize to temperature cycles (Glaser, 2005), indicating that a G protein-coupled signal transduction cascade might be involved. The mutated gene of the other temperature-entrainment-deficient variant (nocte) was not known until now (Sehadova, 2009).
This study demonstrates that isolated Drosophila brains are not able to synchronize to temperature cycles. Since they do synchronize to light-dark cycles, these findings indicate that the brain requires temperature input from the periphery. The molecular identity of the nocte gene, which encodes a large glutamine-rich protein with unknown function, is revealed in this study. Downregulation of nocte in peripheral tissues, including neurons of specific sensory structures (chordotonal [ch] organs), thoroughly disrupts temperature entrainment of behavioral rhythms. Similarly, other mutants known to affect the structure and function of ch organs also interfere with temperature entrainment, and mutant nocte alleles exhibit structural as well as physiological defects of sensory organ function. Moreover a functional clock within these sensory structures is not required for behavioral temperature entrainment to occur, indicating that temperature information must be interpreted in a temporal fashion by downstream clock neurons in the thoracic central nervous system (CNS), or by the brain pacemaker neurons themselves. These findings demonstrate the existence of a periphery-to-brain signaling pathway, identify the responsible sensory structures, and uncover fundamental differences between the light- and temperature-entrainment pathways of the fly circadian clock (Sehadova, 2009).
This study shows that isolated brains are not able to synchronize their circadian clock to temperature cycles, whereas they do entrain to LD. Tissue-autonomous synchronization to LD cycles is very likely mediated by the blue light photoreceptor Cry, which is expressed within a large subset of lateral and dorsal clock neurons. Likewise, synchronization of peripheral clock cells to light-dark and temperature cycles is tissue autonomous. In contrast, brains depend on signals from the periphery for temperature entrainment to occur, indicating different temperature entrainment mechanisms for peripheral clock cells and central brain clock neurons. A possible reason for this may be that clock neurons need to be 'protected' from imminent influences of temperature changes, which can occur very sporadically in nature. In fact, even within the brain, a certain subset of light-responsive clock neurons that mainly controls the behavioral morning activity (M-cells) seems to repress temperature responsiveness of a different group of clock neurons (Busza, 2007). Molecularly, this block could be mediated by Cry expression in the clock neurons, because it has been shown that the cryb mutation enhances the amplitude of temperature-entrained clock gene expression (Glaser, 2007). This suggests that some neurons are more responsive to a certain Zeitgeber than others and vice versa. For example, the Cry-negative neurons may be more important as temperature sensors as it was shown for the DN2 and Lateral Posterior Neurons (LPNs) located in the dorsal and lateral brain (Miyasako, 2007). These two neuronal groups do not (so far) belong to the M- and E-cell groups, and they can mediate aspects of temperature-entrained behavior in the absence of the M- and E-cells (Busza, 2007). In larvae the Cry-negative DN2 also play a prominent role under temperature entrainment conditions, where they seem to determine the phase of the other clock neurons in the larval brain (Picot, 2009; Sehadova, 2009).
It is conceivable that such a division of sensitivity to environmental signals, including complex protection from temperature signals in certain neurons, is required for stable synchronization to natural light-dark and temperature cycles. Since temperature cycles are a less reliable Zeitgeber compared to light-dark cycles, it would make sense that a peripheral temperature input is received only by a subset of clock neurons. These Cry-negative neurons are usually entrained by the light-responsive Cry-positive neurons, but under certain environmental conditions they could turn into the dominant neurons -- now synchronizing the light-responsive neurons and activity rhythms to temperature cycles. The fact that temperature reception in these neurons occurs non-cell-autonomously (i.e., via the periphery) perhaps ensures that their input can more easily be controlled (i.e., shut off) by the clock-neuronal network (Sehadova, 2009).
A set of PNS-gal4 driver lines was applied to home in on the tissues responsible for circadianly relevant temperature reception. This strategy was based on three observations: (1) PNS cells have been reported to express per, although a function for this expression is not known; (2) isolated tissues containing these PNS cells are able to synchronize per expression to temperature cycles, and (3) nocte expression is also found within PNS cells of these tissues. F-gal4, previously reported to be expressed specifically in ch organs, leads to disruption of temperature synchronization when crossed to nocte-RNAi. Although this immediately suggested that ch organs are crucial for this form of entrainment, careful inspection of the F-gal4 expression pattern revealed that this driver is also active in es organs. Although nocte is also expressed in the brain, the spatial expression pattern of both genes appears to be distinct. Nevertheless, it cannot be ruled out that nocte and F-gal4 are coexpressed in a few brain neurons and that F-gal4-mediated downregulation in brain neurons contributes to the observed temperature entrainment phenotype in F-gal4/nocteRNAi flies. In fact, nocte's broad expression pattern in the brain does include the LNvs, and it could be shown that one LNv is also positive for F-gal4. But several observations strongly suggest that it is the prominent expression of F-gal4 and nocte in ch organs that is mediating temperature entrainment. (1) Isolated brains do not synchronize to temperature cycles, indicating that nocte expression in the brain is not sufficient to mediate entrainment. (2) It was found that mutations known to affect ch organ structure and function (tilB, eys/spam, smet) also interfere with temperature entrainment. (3) Expression or function in the brain for any of these genes has not been described, and even if they do act in the brain it seems very unlikely that they are all expressed in the same putative 'temperature entrainment cells.' (4) If clock function is compromised in the one F-gal4-positive LNv via expression of the dominant-negative form of cyc, behavioral synchronization to temperature cycles is not affected (Sehadova, 2009).
The tilB and smet mutants applied in this study are known to specifically affect ch function and leave es organ function intact. Similarly, the eys734/395 alleles retain normal mechanosensory function, but are thought to exhibit a molecular defect of the sensory dendrite of ch organs. All these mutations interfere with entrainment to temperature, but not to light-dark, cycles. Together with the prominent expression of F-gal4 and nocte in ch organs, these findings strongly implicate ch organs as mediators of temperature entrainment, at least within the temperature interval applied in this study (Sehadova, 2009).
Ch organs can function as stretch receptors and have been implicated in mediating proprioception, gravireception, and vibration detection. In contrast to external sensory cells, adult ch organs do not contain external bristles, and are attached to the inside of the cuticle. They consist of one to several hundred sensory units (scolopodia), and each of them contains a liquid-filled capsule (scolopale) that harbors the sensory endings of one to three neurons (Kernan, 2007). Interestingly, the Eys/Spam protein can be detected at the border between the ch neuron cell body and the lumen of the scolopale, and close to a characteristic dilation of the ch cilia. spam mutants exhibit a massive cellular deformation of the scolopale after exposure to 37°C (Cook, 2008). This deformation can be prevented by exposing the mutants to >90% humidity during the high temperature period. This suggests that the cellular deformation is caused by water loss from the hemolymph, which leads to water loss from the scolopale and subsequent neuronal deformation (Cook, 2008). eys/spam mutants show normal mechanoreceptor responses at room temperature, indicating that the presence of Eys/Spam protects the scolopale from excessive heat, probably by preventing water loss (Cook, 2008; Husain, 2006). nocte mutants exhibit the same temperature- and humidity-dependent uncoordinated phenotype as spam mutants, indicating a similar cellular deformation induced by excessive heat. Given that mutants of both genes also fail to synchronize to temperature cycles, it is suspected that both phenotypes are related. As is shown in this study, both nocte alleles lead to a structural defect in the dendritic cap of the ch organ (or misexpression of the dendritic cap protein NompA). It is conceivable that this defect also leads to excessive water loss at high temperatures, which would explain nocte's uncoordinated phenotype. For temperature entrainment to work properly it seems therefore absolutely crucial that the scolopale is protected from effects of extreme temperatures (Sehadova, 2009).
In contrast, the ch organs must be able to sense subtle changes of temperature alterations in the fly's physiological range in order to function as circadian temperature sensors. In larvae, both ch organs and es neurons in the body wall react by increasing [Ca2+] after raising or lowering the temperature (Liu, 2003), suggesting that they are also capable of detecting temperature changes in the adult. Considering that two other temperature entrainment mutants, tilB and smet, very likely affect the axonemal cytoskeleton structure of the ch cilia, it is believed that perhaps dynamic properties of the ch cilia underlie temperature entrainment. The cilia in stimulated femoral ch organs of grasshoppers show active bending (i.e., not a passive reaction to the mechanical stimulus) close to the region where the cilia enters the scolopale (Moran, 1977). This ciliar bending presumably activates the ch neuron, which propagates the signal to the thoracic CNS. Interestingly, the same study showed that the femoral ch organ behaves tonically -- in other words, it keeps firing at the same rate as long as the mechanical stimulation doesn't change (Moran, 1977). This inability to adapt to an environmental stimulus is exactly what would be required for a circadian temperature receptor, because it is necessary that it tracks subtle changes in temperature over time. The current hypothesis therefore postulates the scolopale as an active unit for circadian temperature reception. Eys/Spam and Nocte are required to protect the unit from water loss at different temperatures, rendering the cilia able to react to subtle changes in temperature by actively changing its shape (perhaps by bending). The degree of ciliar bending then determines the firing frequency of the ch neuron, which is tightly coupled to the ambient temperature (Sehadova, 2009).
Both nocte alleles show similar phenotypes in regard to temperature entrainment, dendritic cap, and uncoordination phenotypes, although nocte1 always exhibits more severe defects then nocteP. This suggests that nocteP is a hypomorphic allele, a suggestion also supported by the observation that it is able to generate normally spliced transcripts in addition to aberrant ones. Evidence is also available that nocte1 is not a null allele, because (1) a truncated protein of the predicted size is detected on western blots probed with an anti-Nocte serum, and (2) driving nocte-RNAi with broadly expressed gal4 driver lines (e.g., nocte-gal4, tim-gal4) leads to adult lethality (Sehadova, 2009).
Downregulation of nocte using F-gal4 results in a severe temperature entrainment defect, confirming that this transcription unit is involved in the process. Because F-gal4 is expressed within the neurons and cilia of ch organs, this behavioral defect indicates that nocte is also expressed in ch organ neurons. Based on the potential structural defect observed in nocte mutants, the Nocte protein may be required for the proper connection between the scolopale and the dendritic cap or proper expression and distribution of temperature-entrainment-relevant gene products along the cilia. This would also explain the structural defect or nompA misexpression phenotype caused by both nocte alleles, which presumably underlies the observed temperature entrainment phenotype (Sehadova, 2009).
The findings of this study indicate that a functional clock within peripheral sensory structures important for temperature entrainment is not required. A model is therefore proposed in which ch organ neurons, which do not possess a functional clock, send temperature information to peripheral clock neurons in the thoracic CNS, or directly to the more temperature-sensitive clock neurons within the brain. A similar pathway has recently been described for sex peptide (SP) signaling, in which specific SP-receptor-expressing neurons located within the female reproductive tract signal to the CNS (Häsemeyer, 2009; Sehadova, 2009 and references therein).
For daily temperature entrainment to work, temperature signals need to be interpreted by clock neurons in a time-dependent (i.e., circadian) manner in order to result in coordinated clock protein cycling and synchronized behavior controlled by these neurons. Neuronal brain clocks totally depend on these signals to become entrained by temperature, since they cannot synchronize in culture. Because isolated brains cell-autonomously synchronize to light, these findings reveal a fundamental difference between these two entrainment pathways (Sehadova, 2009).
Circadian clocks are synchronized by both light:dark cycles and by temperature fluctuations. Although it has long been known that temperature cycles can robustly entrain Drosophila locomotor rhythms, nothing is known about the molecular mechanisms involved. This study shows that temperature cycles induce synchronized behavioral rhythms and oscillations of the clock proteins Period and Timeless in constant light, a situation that normally leads to molecular and behavioral arrhythmicity. Expression of the Drosophila clock gene period can be entrained by temperature cycles in cultured body parts and isolated brains. The phospholipase C encoded by the norpA gene contributes to thermal entrainment, suggesting that a receptor-coupled transduction cascade signals temperature changes to the circadian clock. The further genetic dissection of temperature-entrainment was initiated, and the novel Drosophila mutation nocte was isolated. nocte mutants are defective in molecular and behavioral entrainment by temperature cycles but synchronizes normally to light:dark cycles. It is concluded that temperature synchronization of the circadian clock is a tissue-autonomous process that is able to override the arrhythmia-inducing effects of constant light. These data suggest that temperature synchronization involves a cell-autonomous signal-transduction cascade from a thermal receptor to the circadian clock. This process includes the function of phospholipase C and the product specified by the novel mutation nocte (Glaser, 2005).
Although it has been known for a long time that temperature can serve as a potent Zeitgeber to entrain circadian rhythms in animals, practically nothing was known about thermal-entrainment mechanisms and, thus, about the genes and molecules involved. This study has revealed that temperature entrainment of clock-protein expression can function at the level of isolated tissues, independent of the antennal thermosensors studied with regard to Drosophila's acute thermal responsiveness described earlier (Sayeed, 1996; Zars, 2001). The situation is therefore similar to that of circadian photoreception in flies: Clock-gene-expressing tissues can be synchronized in the absence of external, image-forming photoreceptors, and this synchronization is probably mediated by the blue-light photoreceptor Cryptochrome. Similarly, these findings suggest the existence of a cell-autonomous thermoreceptor dedicated to temperature entrainment of the circadian clock. Among the candidates for such a receptor are the transient receptor potential vanilloid (TRPV) channels that have been shown to function in thermoreception in mammals and fly larvae (Glaser, 2005).
The nocte mutant was isolated in a novel screen for temperature-entrainment variants; nocte specifically affects synchronization of the circadian clock to this Zeitgeber (namely, temperature cycles). Such mutant flies are drastically impaired in molecular entrainment of Per-LUC reporter-gene rhythms as well as those of native Per and Tim expression. Behavioral rhythms can be entrained by light:dark, but not by temperature cycles, in nocte flies. Moreover, nocte flies do not affect circadian clock function as such because mutant flies are robustly rhythmic in constant darkness. The circadian clock of nocte flies is also properly temperature compensated; their free running period does not change as a function of increasing or decreasing constant ambient temperatures. These findings show that the assumed product of this gene plays a central role in, and is specific for, temperature entrainment (Glaser, 2005).
It has been shown that the norpA gene is involved in the light-entrainment pathway that ends at the brain's clock. The phospholipase C (PLC) encoded by this gene is an essential factor of the canonical photo-transduction cascade within Drosophila's external photoreceptors. Loss-of-function norpA mutations (such as norpAP24 and norpAP41, as applied in this study) disrupt this pathway and cause visual blindness -- but they also blind the eyes' contribution to circadian entrainment by light (Glaser, 2005).
In addition, norpA contributes to a temperature-sensitive splicing event at the 3' end of the per gene. Splicing of a per intron is enhanced by relatively cold temperatures, and this enhancement leads to an earlier increase of per mRNA during the daily cycle of per RNA accumulation and decline (Majercak, 1999; Majercak, 2004). Correlated with this early upswing is an advanced behavioral activity peak in cold conditions. Because both phenomena are enhanced by shortened photoperiods and suppressed by long photoperiods, it was suggested that the 3' alternative splicing event serves as a mechanism to adjust the fly's behavior to seasonal changes: More locomotion during the day in the winter, with its short photoperiods, and more behavior in the evening during the summer, to avoid the desiccation effects of midday heat (Glaser, 2005).
But are norpA and the 3'splicing mechanism also important for the more basic features of day-by-day temperature entrainment? The answer, from this analysis, is yes and no: PLC is clearly involved because norpA mutations affect both molecular and behavioral entrainment to temperature cycles. This is not true for the alternative splicing event at per's 3' end: Two types of controls (wild-type and y w) robustly synchronized their behavioral rhythms to temperature cycles in constant light and constitutively expressed roughly equal amounts of the spliced and unspliced versions of per RNA in the same LL and temperature-cycling conditions. Therefore, temporal regulation of the 3' splicing event is not necessary for entrainment to temperature cycles (Glaser, 2005).
The idea is favored that the PLC encoded by norpA has an additional role to its known functions in photo transduction and thermal regulation of splicing. It is possible that a signal-transduction cascade, similar to the visual one operating in the compound eye, is used to transduce the temperature signal to the clock. It is not known whether all clock-gene-expressing tissues also express norpA (although it is notable that norpA is expressed in adult tissues way beyond the external eyes. If not, this could explain why the temperature-entrainment defects in norpA mutants in behavior seem less severe than those of nocte. norpA's function in certain tissues could be replaced by other PLC enzymes encoded by different genes. In this respect, one of the more salient norpA mutant defects that was uncovered, that such flies cannot entrain Per-LUC rhythms to temperature cycles, suggests that the temperature-entrainment pathway involves a receptor-coupled signal-transduction cascade that includes a crucial function for PLC (Glaser, 2005).
Robust temperature-entrained reporter-gene rhythms were observed only in transgenic situations in which two-thirds or the entirety of the Per protein was fused to luciferase. These results suggest that the temperature-entrainment mechanism targets clock proteins (at least Per) and does not rely on transcriptional mechanisms. Interestingly, in Neurospora, temperature entrainment is also mainly regulated at the protein level. This supposition is also supported by the surprisingly robust Per and Tim cyclings observed in fly heads under constant light and temperature cycling conditions. These protein oscillations were severely damped in the temperature-entrainment-defective nocte mutant (Glaser, 2005).
Previous work showed that heat pulses of 37°C can induce stable molecular and behavioral phase shifts when applied during the early night but not during the late night. These heat pulses function at the posttranscriptional level because they result in rapid disappearance of Per and Tim (Edery, 1994; Sidote, 1998). Nevertheless, responsiveness of the clock to heat pulses seems to be mediated by a different mechanism, when compared with daily entrainment analyzed in the current study, because heat pulses involving elevated temperatures below 37°C (i.e., 31°C and 28°C) did not lead to significant clock-protein degradation, whereas temperature cycles applied in the current study (which were in a physiological range, 17°C to 25°C) did cause fluctuations in protein concentrations (Glaser, 2005).
A surprising finding in this study was that temperature-entrained molecular oscillations of Per-LUC and of endogenous Per and Tim proteins are robust in constant light. It was reported earlier that upon transfer to constant light and temperature, Tim protein is expressed at constitutively low levels -- probably by CRY-mediated light absorption followed by Tim:CRY interaction. Per protein continues to oscillate for about 2.5 days after transfer to LL, after which its expression levels also becomes low and constitutive. In the current experiments, Per and Tim still oscillated after 4 days in LL when temperatures were cycling, and Per-LUC luminescence oscillations continued with robust amplitude for more than 5 days. These results clearly show that temperature cycles override the arrhythmia-inducing effects of constant light and explain why circadian entrainment of behavioral and physiological rhythmicity is observed under these conditions (Glaser, 2005).
Future work will illuminate which molecules mediate temperature entrainment in addition to phospholipase C. Given the drastic and specific effects of the nocte mutation on temperature entrainment, the factor encoded by this gene will almost certainly be revealed to play a central role in this process (Glaser, 2005).
This study has shown that temperature cycles induce molecular rhythms of clock-gene expression, even in the presence of constant light, which normally results in complete molecular and behavioral arrhythmia. Synchronization was observed in isolated peripheral clock tissues and in the brain, demonstrating that the process is tissue autonomous and is responsible for the synchronized locomotor behavior under constant-light and temperature-cycling conditions. The data suggest that the mechanism functions at a posttranscriptional level involving at least the clock protein Per. Phospholipase C is likely to be involved in the signaling mechanism from the thermal receptor to the clock. The novel mutation nocte specifies a factor that is specific for thermal synchronization of the circadian clock in flies, demonstrating that this input pathway can be genetically dissected, as has been similarly shown for the light input into the circadian clock (Glaser, 2005).
Search PubMed for articles about Drosophila Nocte
Boothroyd, C. E. and Young, M. W. (2008). The in(put)s and out(put)s of the Drosophila circadian clock. Ann. N. Y. Acad. Sci. 1129: 350-357. PubMed ID: 18591494
Busza, A., Murad, A. and Emery, P. (2007). Interactions between circadian neurons control temperature synchronization of Drosophila behavior. J. Neurosci. 27: 10722-10733. PubMed ID: 17913906
Cook, B., Hardy, R. W., McConnaughey, W. B. and Zuker, C. S. (2008). Preserving cell shape under environmental stress. Nature 452: 361-364. PubMed ID: 18297055
Dubruille, R. and Emery, P. (2008). A plastic clock: how circadian rhythms respond to environmental cues in Drosophila. Mol. Neurobiol. 38: 129-145. PubMed ID: 18751931
Dunlap, J. C., Loros J. J. and DeCoursey, P. J. (2004). Chronobiolgy: Biological Timekeeping, Sinauer Associates, Inc, Sunderland, Massachusetts
Edery, I., Rutila, J. E. and Rosbash, M. (1994). Phase shifting of the circadian clock by induction of the Drosophila period protein. Science 263: 237-240. PubMed ID: 8284676
Glaser, F. T. and Stanewsky, R. (2005). Temperature synchronization of the Drosophila circadian clock. Curr. Biol. 15: 1352-1363. PubMed ID: 16085487
Glaser, F. T. and Stanewsky, R. (2007). Synchronization of the Drosophila circadian clock by temperature cycles. Cold Spring Harb. Symp. Quant. Biol. 72: 233-242. PubMed ID: 18419280
Hamada, F. N., et al. (2008). An internal thermal sensor controlling temperature preference in Drosophila. Nature 454: 217-220. PubMed ID: 18548007
Häsemeyer, M., Yapici, N., Heberlein, U. and Dickson, B. J. (2009). Sensory neurons in the Drosophila genital tract regulate female reproductive behavior. Neuron 61: 511-518. PubMed ID: 19249272
Husain, M. et al. (2006). The agrin/perlecan-related protein eyes shut is essential for epithelial lumen formation in the Drosophila retina. Dev. Cell 11: 483-493. PubMed ID: 17011488
Kernan, M. J. (2007). Mechanotransduction and auditory transduction in Drosophila. Pflugers Arch. 454: 703-720. PubMed ID: 17436012
Liu, L., et al. (2003) Identification and function of thermosensory neurons in Drosophila larvae. Nat. Neurosci. 6: 267-273. PubMed ID: 12563263
Majercak, J., Sidote, D., Hardin, P. E. and Edery, I. (1999). How a circadian clock adapts to seasonal decreases in temperature and day length. Neuron 24: 219-230. PubMed ID: 10677039
Majercak, J., Chen, W. F. and Edery, I. (2004). Splicing of the period gene 3'-terminal intron is regulated by light, circadian clock factors, and phospholipase C. Mol. Cell. Biol. 24: 3359-3372. PubMed ID: 15060157
Miyasako, Y., Umezaki, Y. and Tomioka, K. (2007). Separate sets of cerebral clock neurons are responsible for light and temperature entrainment of Drosophila circadian locomotor rhythms. J. Biol. Rhythms 22: 115-126. PubMed ID: 17440213
Moran, D. T. Varela, F. J. and Rowley, J. C. (1977). Evidence for active role of cilia in sensory transduction. Proc. Natl. Acad. Sci. 74: 793-797. PubMed ID: 265544
Picot, M., et al. (2009). A role for blind DN2 clock neurons in temperature entrainment of the Drosophila larval brain. J. Neurosci. 29: 8312-8320. PubMed ID: 19571122
Sayeed, O. and Benzer, S. (1996). Behavioral genetics of thermosensation and hygrosensation in Drosophila. Proc. Natl. Acad. Sci. 93: 6079-6084. PubMed ID: 8650222
Sehadova, H., et al. (2009). Temperature entrainment of Drosophila's circadian clock involves the gene nocte and signaling from peripheral sensory tissues to the brain. Neuron 64: 251-266. PubMed ID: 19874792
Sheeba, V., et al. (2008) The Drosophila circadian pacemaker circuit: Pas De Deux or Tarantella? Crit. Rev. Biochem. Mol. Biol. 43: 37-61. PubMed ID: 18307108
Sidote, D., Majercak, J., Parikh, V. and Edery, I. (1998). Differential effects of light and heat on the Drosophila circadian clock proteins PER and TIM, Mol. Cell. Biol. 18: 2004-2013. PubMed ID: 9528772
Zars, T. (2001). Two thermosensors in Drosophila have different behavioral functions. J. Comp. Physiol. [A] 187: 235-242. PubMed ID: 11401203
date revised: 10 May 2010
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