Amita Sehgal

Last updated
Amita Sehgal
Alma mater Delhi University, Jawaharlal Nehru University, Cornell University
Scientific career
Fields chronobiology
Institutions Perelman School of Medicine
Academic advisors Michael Young, Moses Chao

Amita Sehgal is a molecular biologist and chronobiologist in the Department of Neuroscience at the Perelman School of Medicine at the University of Pennsylvania. [1] Sehgal was involved in the discovery of Drosophila TIM and many other important components of the Drosophila clock mechanism. [2] Sehgal also played a pivotal role in the development of Drosophila as a model for the study of sleep. [3] [4] Her research continues to be focused on understanding the genetic basis of sleep and also how circadian systems relate to other aspects of physiology. [5]

Contents

Education and early career

Sehgal grew up in India, and earned her BSc as an undergraduate at Delhi University and her MSc at Jawaharlal Nehru University, both in New Delhi, India. [6] She began pursuing her PhD in cell biology and genetics at Cornell University in 1983. [6] It was here, while studying a human neuronal growth factor, that her interest in science truly developed. [6] In 1988, she began her Postdoctoral Fellowship at Rockefeller University in the lab of Michael Young, where she had her first exposure to the study of circadian rhythms, a field in which she has since remained. [6]

Research

Timeline of selected major research contributions

Timeless and Period

Amita Sehgal has contributed tremendously towards the understanding of the biological clock of Drosophila melanogaster. In 1994, Sehgal, Price, Man, and Young, through forward genetics, discovered a mutant of the gene timeless (TIM) in Drosophila melanogaster. [2] [7] In the following year, Sehgal and colleagues cloned TIM through positional cloning and were able to show that TIM and PER had similar cycling levels of their mRNA. [2] [8] [9] The model they proposed, which was confirmed over time, was that PER and TIM interact and accumulate during the day. In the evening, they enter the nucleus to inhibit the transcription of their mRNA. In 1996, Sehgal's laboratory showed that degradation in TIM levels caused by a pulse of light resets the circadian clock. [10] Later, they showed that specific phosphatases control stability of PER and TIM in daily cycles. [11]

Neurofibromin 1

Neurofibromin 1 (NF1) is a tumor suppressor gene known to be dis-regulated in Neurofibromatosis type 1, a disorder which causes tumors along the spine. In 2001, Sehgal and her colleagues learned that some patients with Neurofibromatosis type 1 also experience irregularities in their sleep, and so decided to investigate the circadian rhythms of flies with a nonfunctional NF1 gene. [12] They found that these flies also have disrupted circadian rhythms, and these rhythms could be restored by inserting NF1 transgenes, thus proving that NF1 is involved in the circadian pathway. They showed that in flies, NF1 functions through the MAP kinase pathway, which is the same pathway implicated in Neurofibromatosis type 1 in humans. [12]

Jetlag

In 2006, Sehgal and her colleagues discovered a mutant fly which takes an abnormally long time to adjust to new light-dark cycles. [13] They named the underlying mutated gene jetlag (jet). This gene codes for an F-box protein called JET, a ubiquitin ligase that facilitates resetting the drosophila clock. Sequencing of the gene revealed two alleles of jetlag: the "c" allele (common) and the "r" allele (rare). In the presence of CRYPTOCHROME (CRY), JET plays a major role in the degradation of TIMELESS (TIM) protein in response to light, which is necessary for the clock to entrain to external light cues.

Mushroom bodies

Mushroom bodies are located in the brains of Drosophila and are known to play a role in learning, memory, olfaction, and locomotion. [14] In 2006, Sehgal and her colleagues discovered that mushroom bodies also play a major role in regulating sleep in flies. By using a steroid called RU-486 (Mifepristone) to regulate protein kinase A (PKA), they were able to upregulate and downregulate the expression of genes in specific areas like the mushroom bodies, and found that this structure is critical for fly sleep. [15] While the specific pathway through which these mushroom bodies regulate sleep is currently unknown, it may be that they are involved in inhibiting processing of sensory information, allowing flies to fall asleep.

Sleepless

In 2008, Sehgal et al. discovered the sleepless gene in fruit flies through insertional mutagenesis. [16] Mutations in the sleepless gene caused the flies to sleep 80% less than normal flies, and live half as long as normal flies. Sehgal et al. discovered that the SLEEPLESS protein regulates the voltage-gated potassium channel, Shaker, and also nicotinic acetylcholine receptors, specifically one called redeye that they discovered through another genetic screen. [17] Sehgal et al. also found increased stem cell activity within the testes of male flies with mutations in sleepless.

Functions of sleep

All species, including humans, sleep a lot in early life. Sehgal et al discovered what keeps sleep at high levels in young fruit flies. They also found that when sleep is disrupted in early life, mating behavior is perturbed in adults. [18] Thus, sleep may be required to allow brain development for behaviors that promote survival and species propagation. In adult animals, a possible function of sleep is to promote clearance of waste. [19] Sehgal et al found that sleep promotes endocytosis through the blood brain barrier in flies. [20]

Clocks and behavior and the blood brain barrier

The blood brain barrier (BBB) protects the brain from potentially harmful molecules in the periphery, but it can also impede the delivery of drugs to the central nervous system. Sehgal et al found that permeability of the fly BBB changes over the course of the day: night cycle, so an anti-epileptic works better at a specific time of day. [21] They have also mapped circuits that link the clock to behavioral activity. [22]

Sleep and immune function

Seeking to identify molecules that induce sleep, Toda et al conducted a genetic screen of >10,000 of fruit fly strains, and found one that drives sleep. This molecule, which they named nemuri, is an anti-microbial peptide. Its expression is switched on by infection or sleep deprivation, and it promotes survival by killing bacteria and increasing sleep. [23] [24]

Awards and positions

Positions

[25]

Awards

Related Research Articles

<span class="mw-page-title-main">Circadian rhythm</span> Natural internal process that regulates the sleep-wake cycle

A circadian rhythm, or circadian cycle, is a natural oscillation that repeats roughly every 24 hours. Circadian rhythms can refer to any process that originates within an organism and responds to the environment. Circadian rhythms are regulated by a circadian clock whose primary function is to rhythmically co-ordinate biological processes so they occur at the correct time to maximise the fitness of an individual. Circadian rhythms have been widely observed in animals, plants, fungi and cyanobacteria and there is evidence that they evolved independently in each of these kingdoms of life.

A circadian clock, or circadian oscillator, is a biochemical oscillator that cycles with a stable phase and is synchronized with solar time.

<span class="mw-page-title-main">Cryptochrome</span> Class of photoreceptors in plants and animals

Cryptochromes are a class of flavoproteins found in plants and animals that are sensitive to blue light. They are involved in the circadian rhythms and the sensing of magnetic fields in a number of species. The name cryptochrome was proposed as a portmanteau combining the chromatic nature of the photoreceptor, and the cryptogamic organisms on which many blue-light studies were carried out.

<span class="mw-page-title-main">Neurofibromin 1</span> Mammalian protein found in Homo sapiens

neurofibromatosis 1 (NF1) is a gene in humans that is located on chromosome 17. NF1 codes for neurofibromin, a GTPase-activating protein that negatively regulates RAS/MAPK pathway activity by accelerating the hydrolysis of Ras-bound GTP. NF1 has a high mutation rate and mutations in NF1 can alter cellular growth control, and neural development, resulting in neurofibromatosis type 1. Symptoms of NF1 include disfiguring cutaneous neurofibromas (CNF), café au lait pigment spots, plexiform neurofibromas (PN), skeletal defects, optic nerve gliomas, life-threatening malignant peripheral nerve sheath tumors (MPNST), pheochromocytoma, attention deficits, learning deficits and other cognitive disabilities.

<span class="mw-page-title-main">CLOCK</span> Protein-coding gene in the species Homo sapiens

CLOCK is a gene encoding a basic helix-loop-helix-PAS transcription factor that is known to affect both the persistence and period of circadian rhythms.

Timeless (tim) is a gene in multiple species but is most notable for its role in Drosophila for encoding TIM, an essential protein that regulates circadian rhythm. Timeless mRNA and protein oscillate rhythmically with time as part of a transcription-translation negative feedback loop involving the period (per) gene and its protein.

Period (per) is a gene located on the X chromosome of Drosophila melanogaster. Oscillations in levels of both per transcript and its corresponding protein PER have a period of approximately 24 hours and together play a central role in the molecular mechanism of the Drosophila biological clock driving circadian rhythms in eclosion and locomotor activity. Mutations in the per gene can shorten (perS), lengthen (perL), and even abolish (per0) the period of the circadian rhythm.

<span class="mw-page-title-main">PER1</span> Protein-coding gene in the species Homo sapiens

The PER1 gene encodes the period circadian protein homolog 1 protein in humans.

In molecular biology, an oscillating gene is a gene that is expressed in a rhythmic pattern or in periodic cycles. Oscillating genes are usually circadian and can be identified by periodic changes in the state of an organism. Circadian rhythms, controlled by oscillating genes, have a period of approximately 24 hours. For example, plant leaves opening and closing at different times of the day or the sleep-wake schedule of animals can all include circadian rhythms. Other periods are also possible, such as 29.5 days resulting from circalunar rhythms or 12.4 hours resulting from circatidal rhythms. Oscillating genes include both core clock component genes and output genes. A core clock component gene is a gene necessary for to the pacemaker. However, an output oscillating gene, such as the AVP gene, is rhythmic but not necessary to the pacemaker.

Pigment dispersing factor (pdf) is a gene that encodes the protein PDF, which is part of a large family of neuropeptides. Its hormonal product, pigment dispersing hormone (PDH), was named for the diurnal pigment movement effect it has in crustacean retinal cells upon its initial discovery in the central nervous system of arthropods. The movement and aggregation of pigments in retina cells and extra-retinal cells is hypothesized to be under a split hormonal control mechanism. One hormonal set is responsible for concentrating chromatophoral pigment by responding to changes in the organism's exposure time to darkness. Another hormonal set is responsible for dispersion and responds to the light cycle. However, insect pdf genes do not function in such pigment migration since they lack the chromatophore.

<i>Cycle</i> (gene)

Cycle (cyc) is a gene in Drosophila melanogaster that encodes the CYCLE protein (CYC). The Cycle gene (cyc) is expressed in a variety of cell types in a circadian manner. It is involved in controlling both the sleep-wake cycle and circadian regulation of gene expression by promoting transcription in a negative feedback mechanism. The cyc gene is located on the left arm of chromosome 3 and codes for a transcription factor containing a basic helix-loop-helix (bHLH) domain and a PAS domain. The 2.17 kb cyc gene is divided into 5 coding exons totaling 1,625 base pairs which code for 413 aminos acid residues. Currently 19 alleles are known for cyc. Orthologs performing the same function in other species include ARNTL and ARNTL2.

Doubletime (DBT) also known as discs overgrown (DCO) is a gene that encodes the double-time protein (DBT) in fruit flies. The gene was first identified and characterized in 1998 by Michael Young and his team at Rockefeller University.

<span class="mw-page-title-main">Michael Rosbash</span> American geneticist and chronobiologist (born 1944)

Michael Morris Rosbash is an American geneticist and chronobiologist. Rosbash is a professor and researcher at Brandeis University and investigator at the Howard Hughes Medical Institute. Rosbash's research group cloned the Drosophila period gene in 1984 and proposed the Transcription Translation Negative Feedback Loop for circadian clocks in 1990. In 1998, they discovered the cycle gene, clock gene, and cryptochrome photoreceptor in Drosophila through the use of forward genetics, by first identifying the phenotype of a mutant and then determining the genetics behind the mutation. Rosbash was elected to the National Academy of Sciences in 2003. Along with Michael W. Young and Jeffrey C. Hall, he was awarded the 2017 Nobel Prize in Physiology or Medicine "for their discoveries of molecular mechanisms controlling the circadian rhythm".

<span class="mw-page-title-main">Jeffrey C. Hall</span> American geneticist and chronobiologist (born 1945)

Jeffrey Connor Hall is an American geneticist and chronobiologist. Hall is Professor Emeritus of Biology at Brandeis University and currently resides in Cambridge, Maine.

<span class="mw-page-title-main">Michael W. Young</span> American biologist and geneticist (born 1949)

Michael Warren Young is an American biologist and geneticist. He has dedicated over three decades to research studying genetically controlled patterns of sleep and wakefulness within Drosophila melanogaster.

Hitoshi Okamura is a Japanese scientist who specializes in chronobiology. He is currently a professor of Systems Biology at Kyoto University Graduate School of Pharmaceutical Sciences and the Research Director of the Japan Science Technology Institute, CREST. Okamura's research group cloned mammalian Period genes, visualized clock oscillation at the single cell level in the central clock of the SCN, and proposed a time-signal neuronal pathway to the adrenal gland. He received a Medal of Honor with Purple Ribbon in 2007 for his research and was awarded Aschoff's Ruler for his work on circadian rhythms in rodents. His lab recently revealed the effects of m6A mRNA methylation on the circadian clock, neuronal communications in jet lag, and the role of dysregulated clocks in salt-induced hypertension.

Jeffrey L. Price is an American researcher and author in the fields of circadian rhythms and molecular biology. His chronobiology work with Drosophila melanogaster has led to the discoveries of the circadian genes timeless (tim) and doubletime (dbt), and the doubletime regulators spaghetti (SPAG) and bride of doubletime (BDBT).

<i>Drosophila</i> circadian rhythm

Drosophila circadian rhythm is a daily 24-hour cycle of rest and activity in the fruit flies of the genus Drosophila. The biological process was discovered and is best understood in the species Drosophila melanogaster. Other than normal sleep-wake activity, D. melanogaster has two unique daily behaviours, namely regular vibration during the process of hatching from the pupa, and during mating. Locomotor activity is maximum at dawn and dusk, while eclosion is at dawn.

Ravi Allada is an Indian-American chronobiologist studying the circadian and homeostatic regulation of sleep primarily in the fruit fly Drosophila. He is the Edward C. Stuntz Distinguished Professor of Neuroscience and Chair of the Department of Neurobiology at Northwestern University. Working with Michael Rosbash, he positionally cloned the Drosophila Clock gene. In his laboratory at Northwestern, he discovered a conserved mechanism for circadian control of sleep-wake cycle, as well as circuit mechanisms that manage levels of sleep.

Jet or Jetlag is a gene discovered in Drosophila and other insects. They are a part of the SCF family of ubiquitin ligases that plays a huge role in the circadian pathway by controlling the degradation of TIM, a circadian regulatory protein. The gene plays an important role in resetting the circadian clock by transmitting light from CRY to TIM. Jetlag mutants have been found to impede re-entrainment due to significantly reduced ability to degrade TIM. The F-box protein of the FBXL family named FBXL15 is JET's mammalian homolog.

References

  1. ↑ "Home | Sehgal Lab | Perelman School of Medicine at the University of Pennsylvania". www.med.upenn.edu.
  2. 1 2 3 Pennsylvania scientist played role in research that won 2017 Nobel Prize https://www.pennlive.com/news/2017/10/pennsylvania_scientist_contrib.html
  3. ↑ Sehgal, Amita; Mignot, Emmanuel (July 2011). "Genetics of Sleep and Sleep Disorders". Cell. 146 (2): 194–207. doi:10.1016/j.cell.2011.07.004. PMC   3153991 . PMID   21784243.
  4. ↑ "Amita Sehgal, PHD, on Using Fruit Flies for Sleep Research". 11 July 2019.
  5. ↑ Roy, Sree (4 September 2016). "How Time Flies: Amita Sehgal, PhD | Sleep Review".
  6. 1 2 3 4 "Time, Flies". The Scientist Magazine®.
  7. ↑ Sehgal, A.; Price, J. L.; Man, B.; Young, M. W. (18 March 1994). "Loss of circadian behavioral rhythms and per RNA oscillations in the Drosophila mutant timeless". Science. 263 (5153): 1603–1606. Bibcode:1994Sci...263.1603S. doi:10.1126/science.8128246. PMID   8128246.
  8. ↑ Myers, Michael P.; Wager-Smith, Karen; Wesley, Cedric S.; Young, Michael W.; Sehgal, Amita (3 November 1995). "Positional Cloning and Sequence Analysis of the Drosophila Clock Gene, timeless". Science. 270 (5237): 805–808. Bibcode:1995Sci...270..805M. doi:10.1126/science.270.5237.805. PMID   7481771. S2CID   3211623.
  9. ↑ Sehgal, Amita; Rothenfluh-Hilfiker, Adrian; Hunter-Ensor, Melissa; Chen, Yifeng; Myers, Michael P.; Young, Michael W. (3 November 1995). "Rhythmic Expression of timeless: A Basis for Promoting Circadian Cycles in period Gene Autoregulation". Science. 270 (5237): 808–810. Bibcode:1995Sci...270..808S. doi:10.1126/science.270.5237.808. PMID   7481772. S2CID   38151127.
  10. ↑ Hunter-Ensor, Melissa; Ousley, Andrea; Sehgal, Amita (March 1996). "Regulation of the Drosophila Protein Timeless Suggests a Mechanism for Resetting the Circadian Clock by Light". Cell. 84 (5): 677–685. doi: 10.1016/S0092-8674(00)81046-6 . PMID   8625406. S2CID   15049039.
  11. ↑ Sathyanarayanan, Sriram; Zheng, Xiangzhong; Xiao, Rui; Sehgal, Amita (February 2004). "Posttranslational Regulation of Drosophila PERIOD Protein by Protein Phosphatase 2A". Cell. 116 (4): 603–615. doi: 10.1016/S0092-8674(04)00128-X . PMID   14980226. S2CID   295780.
  12. 1 2 Williams, Julie A.; Su, Henry S.; Bernards, Andre; Field, Jeffrey; Sehgal, Amita (21 September 2001). "A Circadian Output in Drosophila Mediated by Neurofibromatosis-1 and Ras/MAPK". Science. 293 (5538): 2251–2256. Bibcode:2001Sci...293.2251W. doi:10.1126/science.1063097. PMID   11567138. S2CID   23175890.
  13. ↑ Koh, Kyunghee; Zheng, Xiangzhong; Sehgal, Amita (23 June 2006). "JETLAG Resets the Drosophila Circadian Clock by Promoting Light-Induced Degradation of TIMELESS". Science. 312 (5781): 1809–1812. Bibcode:2006Sci...312.1809K. doi:10.1126/science.1124951. PMC   2767177 . PMID   16794082.
  14. ↑ Heisenberg, Martin (April 2003). "Mushroom body memoir: from maps to models". Nature Reviews Neuroscience. 4 (4): 266–275. doi:10.1038/nrn1074. PMID   12671643. S2CID   5038386.
  15. ↑ Joiner, William J.; Crocker, Amanda; White, Benjamin H.; Sehgal, Amita (June 2006). "Sleep in Drosophila is regulated by adult mushroom bodies". Nature. 441 (7094): 757–760. Bibcode:2006Natur.441..757J. doi:10.1038/nature04811. PMID   16760980. S2CID   4323353.
  16. ↑ Koh, Kyunghee; Joiner, William J.; Wu, Mark N.; Yue, Zhifeng; Smith, Corinne J.; Sehgal, Amita (18 July 2008). "Identification of SLEEPLESS, a Sleep-Promoting Factor". Science. 321 (5887): 372–376. Bibcode:2008Sci...321..372K. doi:10.1126/science.1155942. PMC   2771549 . PMID   18635795.
  17. ↑ "HHMI Bulletin Spring 2014: Around the Clock". Howard Hughes Medical Institute. Retrieved 2015-04-09.
  18. ↑ Kayser, Matthew S.; Yue, Zhifeng; Sehgal, Amita (18 April 2014). "A Critical Period of Sleep for Development of Courtship Circuitry and Behavior in Drosophila". Science. 344 (6181): 269–274. Bibcode:2014Sci...344..269K. doi:10.1126/science.1250553. PMC   4479292 . PMID   24744368.
  19. ↑ Makin, Simon (1 November 2019). "Deep Sleep Gives Your Brain a Deep Clean". Scientific American.
  20. ↑ Artiushin, Gregory; Zhang, Shirley L; Tricoire, Hervé; Sehgal, Amita (26 November 2018). "Endocytosis at the Drosophila blood–brain barrier as a function for sleep". eLife. 7: e43326. doi: 10.7554/eLife.43326 . PMC   6255390 . PMID   30475209.
  21. ↑ Zhang, Shirley L.; Yue, Zhifeng; Arnold, Denice M.; Artiushin, Gregory; Sehgal, Amita (March 2018). "A Circadian Clock in the Blood-Brain Barrier Regulates Xenobiotic Efflux". Cell. 173 (1): 130–139.e10. doi:10.1016/j.cell.2018.02.017. PMC   5866247 . PMID   29526461.
  22. ↑ Cavanaugh, Daniel J.; Geratowski, Jill D.; Wooltorton, Julian R.A.; Spaethling, Jennifer M.; Hector, Clare E.; Zheng, Xiangzhong; Johnson, Erik C.; Eberwine, James H.; Sehgal, Amita (April 2014). "Identification of a Circadian Output Circuit for Rest:Activity Rhythms in Drosophila". Cell. 157 (3): 689–701. doi:10.1016/j.cell.2014.02.024. PMC   4003459 . PMID   24766812.
  23. ↑ Toda, Hirofumi; Williams, Julie A.; Gulledge, Michael; Sehgal, Amita (1 February 2019). "A sleep-inducing gene, nemuri, links sleep and immune function in Drosophila". Science. 363 (6426): 509–515. Bibcode:2019Sci...363..509T. doi:10.1126/science.aat1650. PMC   6505470 . PMID   30705188.
  24. ↑ Lambert, Jonathan (31 January 2019). "Sick And Tired? Scientists Find Protein That Puts Flies To Sleep And Fights Infection". NPR.
  25. ↑ Johnson, Greg (ed.). "Amita Sehgal". Penn Current. Archived from the original on September 8, 2015. Retrieved April 8, 2015.
  26. ↑ National Academy of Sciences Members and Foreign Associates Elected, News from the National Academy of Sciences, National Academy of Sciences, May 3, 2016, archived from the original on May 6, 2016, retrieved 2016-05-14.
  27. ↑ "David Geffen School of Medicine at UCLA names 2020 Switzer Prize recipient". UCLA.
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