Amita Sehgal

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 has been involved in the discovery of Drosophila TIM and many other important components of the Drosophila clock mechanism.[2] Sehgal has contributed greatly to 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.[1]

Amita Sehgal
Alma materDelhi University, Jawaharlal Nehru University, Cornell University
Scientific career
Fieldschronobiology
InstitutionsPerelman School of Medicine
Academic advisorsMichael Young

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.[5] After earning her master's degree, she worked in a lab studying the DNA repair process in Muscular Dystrophy.[5] She began pursuing her PhD in cell biology and genetics at Cornell University in 1983.[5] It was here, while studying a human neuronal growth factor, that her interest in science truly developed.[5] 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.[5]

Research

Timeline of selected major research contributions
  • 1994: Discovered the timeless mutation in fruit flies.
  • 1995: Cloned the timeless gene and showed the expression of the timeless gene has daily cycles.
  • 1996: Showed pulses of light degrade timeless.
  • 2000: Developed a Drosophila model for sleep.
  • 2001: Showed neurofibromin 1 plays a role in the circadian pathway in fruit flies.
  • 2006: Discovered the jetlag mutation and showed the JETLAG protein is involved in the degradation of the TIMELESS protein.
  • 2006: Showed mushroom bodies in fruit flies are important for sleep.
  • 2008: Discovered the sleepless gene in fruit flies.
  • 2014: Discovered the GABAT gene in fruit flies.
  • 2014: Discovered the redeye gene in fruit flies.

Timeless and Period

Amita Sehgal has contributed tremendously towards the understanding of the biological clock of Drosophila melanogaster[6] In 1994, Sehgal, Price, Man, and Young, through forward genetics, discovered a mutant of the gene timeless (TIM) in Drosophila melanogaster.[2] In the following year, Sehgal et al. cloned TIM through positional cloning and were able to show that TIM and PER had similar cycling levels of their mRNA and protein.[2] A yeast 2-hybrid then showed that TIM protein binds directly to PER. PER and TIM dimerize and accumulate during the day. In the evening, they enter the nucleus to inhibit the transcription of their mRNA. Phosphorylation of PER and TIM then leads to their degradation.[2] In 1996, Sehgal was involved in an experiment that showed degradation in TIM levels caused by a pulse of light that resets the molecular clock.[2] Sehgal and her team later showed dCRY is responsible for the degradation of TIM.[2]

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.[7] 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.[7] They showed that in flies, NF1 functions through the MAP kinase pathway, which is the same pathway implicated in Neurofibromatosis type 1 in humans.[7]

Jetlag

In 2006, Sehgal and her colleagues discovered a mutant fly which takes an abnormally long time to adjust to new light-dark cycles.[8] They named the underlying mutated gene jetlag (jet).[8] This gene codes for an F-box protein called JET, a ubiquitin ligase that facilitates resetting the drosophila clock.[8] Sequencing of the gene revealed two alleles of jetlag: the "c" allele (common) and the "r" allele (rare).[8] 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.[8]

Mushroom bodies

Mushroom bodies are located in the brains of Drosophila and are known to play a role in learning, memory, olfaction, and locomotion.[9] In 2006, Sehgal and her colleagues discovered that mushroom bodies also play a major role in regulating sleep in flies.[9][10] 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.[11] 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.[11]

Sleepless

In 2008, Sehgal et al. discovered the sleepless gene in fruit flies through insertional mutagenesis.[12] Mutations in the sleepless gene caused the flies to sleep 80% less than normal flies[13] and live half as long as normal flies.[14] Sehgal et al. observed flies had extreme loss of sleep when the flies completely lacked the SLEEPLESS protein. Flies with mutations which lowered the level of SLEEPLESS protein had normal levels of sleep, but when the flies were sleep-deprived, they showed abnormal recovery sleep.[13] Sehgal et al. also found increased stem cell activity within the testes of male flies with mutations in sleepless.[14] The SLEEPLESS protein activates Shaker potassium channels and inhibits nicotinic acetylcholine receptors.[15]

GABAT

Shortly after discovering the sss gene, Sehgal and colleagues used an unbiased proteomic approach and compared brain proteins between sss mutants and wild type flies.[16] They discovered that levels of a mitochondrial γ-aminobutyric acid transaminase (GABAT) are increased in sss mutant brains. sleepless mutants also have low GABA levels. Flies with GABAT mutations showed prolonged sleep time and more solid sleep. Loss of GABAT completely reversed the short sleep phenotype of the sss mutants and restores the sleep of the latter. Sehgal et al. also found GABAT is required in glia to promote wakefulness in response to loss of sleepless in a distinct set of surrounding neurons. "The findings shed light on mechanisms that may be shared between sleep disruption and some neurological disorders",[17] such as epilepsy.

Redeye

Sehgal's lab recently identified a new gene involved in the regulation of sleep in fruit flies, redeye. The redeye gene was discovered through random mutation of the fruit fly chromosome 3. Sehgal found the longer a fly is awake, the higher the level of redeye becomes in the fly.[14] Redeye levels showed changes throughout the day even when the genes which are part of the circadian clock were mutated.[14] This observation indicates redeye is controlled by factors outside of the circadian clock.[14]

Awards and positions

Positions[3][18]
  • Director of Penn Chronobiology Program-Present
  • Howard Hughes Medical Institute Investigator 1997–Present
  • John Herr Musser Professor in the Department of Neuroscience at the Perelman School of Medicine at the University of Pennsylvania-present
  • Vice Chair of the Department of Neuroscience
  • Co-Director of the Penn Medicine Neuroscience Center 2008-2014

Awards[5]
  • Outstanding Scientific Achievement Award, Sleep Research Society
  • Michael S. Brown Junior Faculty Research Award
  • Stanley Cohen Senior Faculty Research Award
  • Elected to the National Academy of Medicine (formerly Institute of Medicine) 2009
  • Elected to the American Academy of Arts and Sciences 2011
  • Elected Fellow of the American Association for the Advancement of Science 2016
  • Elected to the National Academy of Sciences, 2016[19]
gollark: Probably.
gollark: It wouldn't be hot enough to *melt* if it stopped spinning like that.
gollark: If the Earth stopped moving, its trajectory would go directly toward the Sun. This would cause it to melt.
gollark: Except the REPEALED PENUMBRAE/NX-51 site.
gollark: All locations are locations for religious discussion.

References
  1. "Circadian Rhythms and Sleep". Howard Hughes Medical Institute. May 2012. Retrieved 2015-04-09.
  2. Panda, Satchidananda; Hogenesch, John B.; Kay, Steve A. (May 16, 2002). "Circadian rhythms from flies to human". Nature. 417 (6886): 329–335. Bibcode:2002Natur.417..329P. doi:10.1038/417329a. ISSN 0028-0836. PMID 12015613.
  3. "Amita Sehgal".
  4. Sehgal, Amita; Ousley, Andrea; Hunter-Ensor, Melissa (April 19, 2002). "Control of Circadian Rhythms by a Two-Component Clock". Molecular and Cellular Neuroscience. 7 (3): 165–172. doi:10.1006/mcne.1996.0013. PMID 8726101.
  5. "Amita Sehgal, PhD". Howard Hughes Medical Institute. Retrieved March 31, 2015.
  6. "Experiments Illuminate Workings of Biological Clocks". Howard Hughes Medical Institute. Retrieved 2015-04-21.
  7. "New Pathway to Understanding Circadian Rhythms". Howard Hughes Medical Institute. September 21, 2001. Retrieved April 23, 2015.
  8. Van Gelder, Russell (November 21, 2006). "Timeless Genes and Jetlag". PNAS. 103 (47): 17583–4. Bibcode:2006PNAS..10317583V. doi:10.1073/pnas.0608751103. PMC 1693787. PMID 17101961.
  9. Vosshall, Leslie B.; Stocker, Reinhard F. (July 2007). "Molecular Architecture of Smell and Taste in Drosophila". Annual Review of Neuroscience. 30: 505–533. doi:10.1146/annurev.neuro.30.051606.094306. PMID 17506643.
  10. Allada, Ravi; Chung, Brian Y. (November 13, 2009). "Circadian Organization of Behavior and Physiology in Drosophila". Annual Review of Physiology. 72: 605–24. doi:10.1146/annurev-physiol-021909-135815. PMC 2887282. PMID 20148690.
  11. "Researchers Find the Snooze Button". Howard Hughes Medical Institute News. June 8, 2006. Retrieved April 23, 2015.
  12. Cirelli, Chiara (August 2009). "The genetic and molecular regulation of sleep: from fruit flies to humans". Nature Reviews Neuroscience. 10 (8): 549–560. doi:10.1038/nrn2683. ISSN 1471-003X. PMC 2767184. PMID 19617891.
  13. "Research News: Fruit Fly Study Yields a Gene Required for Peaceful Slumber | Howard Hughes Medical Institute (HHMI)". Retrieved 2015-04-09.
  14. "HHMI Bulletin Spring 2014: Around the Clock | Howard Hughes Medical Institute (HHMI)". Retrieved 2015-04-09.
  15. Wu, Meilin; Robinson, James E.; Joiner, William J. (Mar 17, 2014). "SLEEPLESS is a bifunctional regulator of excitability and cholinergic synaptic transmission". Current Biology. 24 (6): 621–629. doi:10.1016/j.cub.2014.02.026. ISSN 1879-0445. PMC 4059605. PMID 24613312.
  16. Chen, W-F; Maguire, S; Sowcik, M; Luo, W; Koh, K; Sehgal, A (2015). "A neuron–glia interaction involving GABA transaminase contributes to sleep loss in sleepless mutants". Molecular Psychiatry. 20 (2): 240–251. doi:10.1038/mp.2014.11. PMC 4168011. PMID 24637426.
  17. "www.sciencedaily.com/releases/2014/04/140401142127.htm". www.sciencedaily.com. Retrieved 2016-05-09.
  18. Johnson, Greg (ed.). "Amita Sehgal". Penn Current. Archived from the original on September 8, 2015. Retrieved April 8, 2015.
  19. 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.
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