Carla Green

Last updated
Carla Green
Born (1962-05-14) May 14, 1962 (age 61)
Cheyenne, Wyoming
NationalityAmerican
Alma materSouthwest Missouri State University
EmployerUniversity of Texas Southwestern Medical Center
Known forWork on circadian rhythms in both Xenopus and mammals.

Carla Beth Green (born 1962) is an American neurobiologist and chronobiologist. She is a professor in the Department of Neuroscience and a Distinguished Scholar in Neuroscience at the University of Texas Southwestern Medical Center. [1] She is the former president of the Society for Research on Biological Rhythms (SRBR), [2] as well as a satellite member of the International Institute for Integrative Sleep Medicine at the University of Tsukuba in Japan. [3]

Contents

Her research involves the circadian clock and how it controls rhythmic processes within the cell using molecular mechanisms. The general focus of the Green Lab is to understand the molecular mechanism of the mammalian circadian clock and how it mediates rhythmicity within the physiology, biochemistry, and behavior of an organism. Her lab currently has three main projects: identifying targets and mechanisms of expression regulation of the Nocturnin gene; identifying the mechanism of metabolic control of Nocturnin knockout lean mice; and defining structural components of the repressor protein Cryptochrome and how regulation of the nuclear entry of the protein contributes to circadian period length.

Green has formal training in cell biology, biochemistry, and molecular biology, which has given her a broad skill set to further expand her areas of study such as genomics, proteomics, structural biology, and metabolic studies over the course of her career.

Aside from her scientific focuses, she also contributes to the greater science community. At the June 23–28, 2019 Gordon Research Conference, “Clocks in Model Organisms: Circadian Networks, Physiology and Health,” she is organizing the “GRC Power Hour,” a panel designed to promote diversity and inclusion for women and minorities in the STEM field as well as encourage the professional growth of all members from all communities by providing a space for discussion and mentorship. [4]

Background

Green was born in Cheyenne, Wyoming on May 14, 1962. After spending some time in Wyoming with her mother during her early years, Green's family moved frequently—first to Denver, Colorado; then to Saint Paul, Minnesota; and finally to Springfield, Missouri when she was in first grade. She remained in Springfield throughout her adolescence before attending Southwest Missouri State University, where she graduated in 1984 with a bachelor's degree in biology. Remaining at Southwest Missouri State, she also received her master's degree in biology in 1986. After receiving her master's, Green left Springfield to attend the University of Kansas Medical Center in Kansas City, where she received her Ph.D. in Biochemistry and Molecular Biology working with Simon Kwok. From 1991-1996, she was a Postdoctoral Fellow with Joseph Besharse in the Department of Anatomy and Cell Biology at the University of Kansas Medical Center, where she worked on the molecular mechanisms of circadian rhythmicity in the retinal photoreceptors of Xenopus laevis . In 1997 she joined the faculty in the Department of Biology at the University of Virginia, continuing her work on circadian rhythms in both Xenopus and mammals. More specifically, she studied the molecular and cellular mechanisms that comprise and regulate the circadian oscillator in vertebrates.

Green was first exposed to chronobiology when she was a graduate student at the University of Kansas Medical Center. At the time, she had not been working on the subject, but heard a seminar by Joseph Besharse, who had just been recruited to the University as the new Chair of Cell Biology in 1989. She had been finishing up her Ph.D. degree and was looking for postdoctoral positions in Kansas City. When Green heard about the novel field of circadian clocks, this intrigued her. Besharse had been speaking about his work on the endogenous clock in the retinas of Xenopus. In those days, nothing was known about the molecular mechanism of circadian clocks in any system. She had been trained as a biochemist and molecular biologist, and thought that this field would be a perfect place to use her skills to work on such a fascinating biological anomaly. Besharse hired her as a postdoctoral student in his lab and she has been studying circadian clocks ever since.

Green is married to Joseph Takahashi, who is the current chair of the Department of Neuroscience at the University of Texas Southwestern Medical Center.

Career

Positions held

Research

Green is currently a principal investigator in the Department of Neuroscience at the University of Texas Southwestern Medical Center. Her lab studies the molecular mechanism of circadian rhythms in mammals, with a specific interest in the regulatory mechanisms that modulate translational and post-transcriptional processes. The Green Lab is currently focused on understanding the circadian function of Nocturnin, the circadian regulation of metabolism, and the circadian structure and function of Cryptochrome’s core components.

Nocturnin

A major focus in the Green lab has been on a protein encoded by the Nocturnin gene, named for its high-level nighttime expression. Nocturnin is a deadenylase thought to be involved in the degradation of mRNA polyA tails, suggesting that it plays a role in post-transcriptional stability and regulation of circadian gene expression, which is most beneficial to the metabolism and ultimately, survival of an organism. [5]

In 1996, Green discovered nocturnin (Noc) in the retinal photoreceptors of Xenopus laevis, where Noc mRNA displayed rhythmic expression in an isolated Xenopus eye in light/dark and constant conditions. They isolated this gene by using a high stringency differential display screen for rhythmic genes in the Xenopus retina. In 2001, Green found Noc homologues in other species such as mice with a high degree coding sequence similarity. Since expanding these studies into mice, they have shown that mouse Nocturnin mRNA is also rhythmic and expressed in many circadian clock-containing tissues. Interestingly, Green's group has shown that though Noc is not directly involved in regulating the master clock gene expression, it is required for oscillator output functions thereby contributing to circadian physiology. [6]

The rhythmic expression of nocturnin (Noc) is seen throughout the body, notably in tissues crucial for metabolism like the liver and intestine. In 2011, Green, Douris, and others were able to show differing Noc phenotypes have emerged implicating involvement of this gene in osteogenesis, lipogenesis, and adipogenesis. [7]

Her lab's current research focuses on identifying Nocturnin's circadian-relevant mRNA targets and understanding how it goes about regulating their expression. [8]

Post-transcriptional control of circadian rhythms

In 2011, Green's lab concluded that transcriptional and post-transcriptional processes are necessary to generate robust circadian rhythms of mRNA expression, but understandings of circadian post-transcriptional mechanisms lag far behind understandings of clock regulation at the transcriptional level. This was found to be due to the lack of well-developed methodologies to find post-transcriptionally regulated genes on a large scale. The authors believe that development of such methods is likely to lead to the discovery of many more genes and mechanisms that are under post-transcriptional control. [9]

Green's findings are cited in more recent developments on post-transcriptional control of the mammalian circadian clock. Recent findings in 2016 inspired by Green's research contribute to post-transcriptional control of human circadian systems in relation to chronomedicine and sleep disorders. [10]

Cryptochrome

Green's lab has focused heavily on a class of proteins known as cryptochromes, which are blue light receptor proteins found in both plants and animals. Cryptochrome proteins are essential for the proper functioning of the circadian clock in insects and mammals, and for proper development in plants. [11] Cryptoproteins regulate the circadian clocks of plants, insects, and mammals in different ways. Green has worked extensively with an amphibian, the African clawed frog (or Xenopus laevis), as well as mammalian CRY1 and CRY2, to try and uncover the mysteries of these essential transcriptional repressors. [12]

Green's research on cryptochromes began in 2003, when she and colleagues investigated the role of cryptochrome in suppressing the activation of other circadian clock genes such as CLOCK and BMAL1. They revealed that the deletion of Cryptochrome's C-terminal domain resulted in proteins unable to suppress activation of these genes. This result indicates that the C-terminal is not the domain of suppression of CLOCK/BMAL1, but is essential only for nuclear localization. [13] [14]

Green has also studied the relationship between the suprachiasmatic nucleus and peripheral circadian oscillators, in which cryptochrome plays a key role. The regulatory region of Cry1, for instance, contains a response region for the Glucocorticoid hormone , such that input of this hormone can activate transcription of Cry1. In Cry1/Cry2 null mice, regular feeding at 24 hour intervals can induce circadian expression of many transcripts, especially those related to metabolism. This shows how peripheral oscillators can bypass the usual circadian feedback loops of the central oscillator. [15]

More recently, in 2018, Green contributed to the discovery of a new co-factor which mediates regulation through direct interaction with CLOCK and BMAL1. This study provides a model for the evolutionary mechanism by which the structure of cryptochromes, and thus clock regulatory mechanisms, varies. [16]

Awards and honors

Related Research Articles

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.

The repressilator is a genetic regulatory network consisting of at least one feedback loop with at least three genes, each expressing a protein that represses the next gene in the loop. In biological research, repressilators have been used to build cellular models and understand cell function. There are both artificial and naturally-occurring repressilators. Recently, the naturally-occurring repressilator clock gene circuit in Arabidopsis thaliana and mammalian systems have been studied.

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">ARNTL2</span> Protein-coding gene in humans

Aryl hydrocarbon receptor nuclear translocator-like 2, also known as Arntl2, Mop9, Bmal2, or Clif, is a gene.

<span class="mw-page-title-main">Period circadian protein homolog 1</span> Protein-coding gene in the species Homo sapiens

Period circadian protein homolog 1 is a protein in humans that is encoded by the PER1 gene.

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.

Steven M. Reppert is an American neuroscientist known for his contributions to the fields of chronobiology and neuroethology. His research has focused primarily on the physiological, cellular, and molecular basis of circadian rhythms in mammals and more recently on the navigational mechanisms of migratory monarch butterflies. He was the Higgins Family Professor of Neuroscience at the University of Massachusetts Medical School from 2001 to 2017, and from 2001 to 2013 was the founding chair of the Department of Neurobiology. Reppert stepped down as chair in 2014. He is currently distinguished professor emeritus of neurobiology.

<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.

Steve A. Kay is a British-born chronobiologist who mainly works in the United States. Dr. Kay has pioneered methods to monitor daily gene expression in real time and characterized circadian gene expression in plants, flies and mammals. In 2014, Steve Kay celebrated 25 years of successful chronobiology research at the Kaylab 25 Symposium, joined by over one hundred researchers with whom he had collaborated with or mentored. Dr. Kay, a member of the National Academy of Sciences, U.S.A., briefly served as president of The Scripps Research Institute. and is currently a professor at the University of Southern California. He also served on the Life Sciences jury for the Infosys Prize in 2011.

Paul Hardin is an American scientist in the field of chronobiology and a pioneering researcher in the understanding of circadian clocks in flies and mammals. Hardin currently serves as a distinguished professor in the biology department at Texas A&M University. He is best known for his discovery of circadian oscillations in the mRNA of the clock gene Period (per), the importance of the E-Box in per activation, the interlocked feedback loops that control rhythms in activator gene transcription, and the circadian regulation of olfaction in Drosophila melanogaster. Born in a suburb of Chicago, Matteson, Illinois, Hardin currently resides in College Station, Texas, with his wife and three children.

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

Nocturnin is a human hydrolase enzyme that is involved in metabolism and its expression is controlled by the rhythmic circadian clock. It is encoded by the NOCT gene located on chromosome 4. Nocturnin contains a c-terminal structural domain of the Endonuclease/Exonuclease/phosphatase family. A study in January 2019, demonstrated that NADP+ and NADPH are the direct targets of Nocturnin.

Transcription-translation feedback loop (TTFL) is a cellular model for explaining circadian rhythms in behavior and physiology. Widely conserved across species, the TTFL is auto-regulatory, in which transcription of clock genes is regulated by their own protein products.

Jay Dunlap is an American chronobiologist and photobiologist who has made significant contributions to the field of chronobiology by investigating the underlying mechanisms of circadian systems in Neurospora, a fungus commonly used as a model organism in biology, and in mice and mammalian cell culture models. Major contributions by Jay Dunlap include his work investigating the role of frq and wc clock genes in circadian rhythmicity, and his leadership in coordinating the whole genome knockout collection for Neurospora. He is currently the Nathan Smith Professor of Molecular and Systems Biology at the Geisel School of Medicine at Dartmouth. He and his colleague Jennifer Loros have mentored numerous students and postdoctoral fellows, many of whom presently hold positions at various academic institutions.

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<span class="mw-page-title-main">Christine Merlin</span>

Christine Merlin is a French chronobiologist and an associate professor of biology at Texas A&M University. Merlin's research focuses on the underlying genetics of the monarch butterfly circadian clock and explores how circadian rhythms modulate monarch behavior and navigation.

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Charles J. Weitz is a chronobiologist and neurobiologist whose work primarily focuses on studying the molecular biology and genetics of circadian clocks.

References

  1. 1 2 3 4 5 6 "Carla Green, Ph.D. - Faculty Profile - UT Southwestern". profiles.utsouthwestern.edu. Retrieved 2019-04-11.
  2. ↑ "Board of Directors | SRBR: Society for Research on Biological Rhythms" . Retrieved 2019-04-11.
  3. ↑ "Carla Green | Member". International Institute for Integrative Sleep Medicine, University of Tsukuba. Retrieved 2019-04-11.
  4. ↑ "2019 Chronobiology Conference GRC". www.grc.org. Retrieved 2019-04-11.
  5. ↑ "UVA • MRMI - Green, Carla". www.virginia.edu. Retrieved 2019-04-25.
  6. ↑ Hardeland, Rüdiger (10 October 2014). "Melatonin, Noncoding RNAs, Messenger RNA Stability and Epigenetics—Evidence, Hints, Gaps and Perspectives". International Journal of Molecular Sciences. 15 (10): 18221–18252. doi: 10.3390/ijms151018221 . PMC   4227213 . PMID   25310649.
  7. ↑ Udoh, Uduak; Valcin, Jennifer; Gamble, Karen; Bailey, Shannon (14 October 2015). "The Molecular Circadian Clock and Alcohol-Induced Liver Injury". Biomolecules. 5 (4): 2504–2537. doi: 10.3390/biom5042504 . PMC   4693245 . PMID   26473939.
  8. ↑ "Carla Green Lab - UT Southwestern". www.utsouthwestern.edu. Retrieved 2019-04-25.
  9. ↑ Kojima, S.; Shingle, D. L.; Green, C. B. (17 January 2011). "Post-transcriptional control of circadian rhythms". Journal of Cell Science. 124 (3): 311–320. doi:10.1242/jcs.065771. PMC   3021995 . PMID   21242310.
  10. ↑ Preußner, Marco; Heyd, Florian (23 April 2016). "Post-transcriptional control of the mammalian circadian clock: implications for health and disease". Pflügers Archiv: European Journal of Physiology. 468 (6): 983–991. doi:10.1007/s00424-016-1820-y. PMC   4893061 . PMID   27108448.
  11. ↑ Brautigam, C. A.; Smith, B. S.; Ma, Z.; Palnitkar, M.; Tomchick, D. R.; Machius, M.; Deisenhofer, J. (6 August 2004). "Structure of the photolyase-like domain of cryptochrome 1 from Arabidopsis thaliana". Proceedings of the National Academy of Sciences. 101 (33): 12142–12147. Bibcode:2004PNAS..10112142B. doi: 10.1073/pnas.0404851101 . PMC   514401 . PMID   15299148.
  12. ↑ McCarthy, E. V.; Baggs, J. E.; Geskes, J. M.; Hogenesch, J. B.; Green, C. B. (17 August 2009). "Generation of a Novel Allelic Series of Cryptochrome Mutants via Mutagenesis Reveals Residues Involved in Protein-Protein Interaction and CRY2-Specific Repression". Molecular and Cellular Biology. 29 (20): 5465–5476. doi:10.1128/MCB.00641-09. PMC   2756885 . PMID   19687303.
  13. ↑ Zhu, Haisun; Conte, Francesca; Green, Carla B. (September 2003). "Nuclear Localization and Transcriptional Repression Are Confined to Separable Domains in the Circadian Protein CRYPTOCHROME". Current Biology. 13 (18): 1653–1658. doi: 10.1016/j.cub.2003.08.033 . PMID   13678599.
  14. ↑ Chaves, Inês; Pokorny, Richard; Byrdin, Martin; Hoang, Nathalie; Ritz, Thorsten; Brettel, Klaus; Essen, Lars-Oliver; van der Horst, Gijsbertus T. J.; Batschauer, Alfred; Ahmad, Margaret (2 June 2011). "The Cryptochromes: Blue Light Photoreceptors in Plants and Animals". Annual Review of Plant Biology. 62 (1): 335–364. doi:10.1146/annurev-arplant-042110-103759. PMID   21526969.
  15. ↑ Mohawk, Jennifer A.; Green, Carla B.; Takahashi, Joseph S. (21 July 2012). "Central and Peripheral Circadian Clocks in Mammals". Annual Review of Neuroscience. 35 (1): 445–462. doi:10.1146/annurev-neuro-060909-153128. PMC   3710582 . PMID   22483041.
  16. ↑ Rosensweig, Clark; Reynolds, Kimberly A.; Gao, Peng; Laothamatas, Isara; Shan, Yongli; Ranganathan, Rama; Takahashi, Joseph S.; Green, Carla B. (19 March 2018). "An evolutionary hotspot defines functional differences between CRYPTOCHROMES". Nature Communications. 9 (1): 1138. Bibcode:2018NatCo...9.1138R. doi:10.1038/s41467-018-03503-6. PMC   5859286 . PMID   29556064.
  17. ↑ "Awards, Biochemistry and Molecular Biology, University of Kansas Medical Center". www.kumc.edu. Retrieved 2019-04-25.
  18. ↑ "Past and Current Award Winners". American Association of Anatomists | Rockville, MD. Retrieved 2019-04-11.
  19. ↑ "Historic Fellows". American Association for the Advancement of Science. Retrieved 2019-04-25.
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