Ignacio Provencio

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Ignacio Provencio (born 29 June 1965) is an American neuroscientist and the discoverer of melanopsin, [1] an opsin found in specialized photosensitive ganglion cells of the mammalian retina. Provencio served as the program committee chair of the Society for Research on Biological Rhythms from 2008 to 2010. [2]

Contents

Biography

Provencio was born in Bitburg, Germany and attended Lebanon Catholic High School in Lebanon, PA. During his undergraduate career at Swarthmore College, Provencio became interested in neuroscience while studying crayfish, cockroaches, and fireflies under Jon Copeland. [3] From 1987 to 1989 he worked as a lab technician in Steve Reppert's research laboratory at Massachusetts General Hospital, where he was introduced to the field of circadian biology. He graduated in 1987 from Swarthmore College with a B.A. in Biology and went on to earn his Ph.D. from the University of Virginia, a university with a strong network of circadian biologists, in 1996. During his postdoctoral training at Uniformed Services University, Provencio held assistant and associate professorships at Uniformed Services University, Department of Anatomy, Physiology, and Genetics where he still maintains an adjunct associate professorship. [4] Provencio is a full professor at the University of Virginia. [5]

Work

Role of melanopsin in photic responses

In 1998, Provencio discovered melanopsin as a new opsin in the photosensitive skin melanophores of the African clawed frog. [6] In 2000, he showed that melanopsin is also present in mouse, rhesus macaques, and humans, where it is only present in the eye. The unique inner retinal localization of melanopsin indicated that melanopsin was not involved in image formation. [7] Later, he demonstrated that the melanopsin pigment might be involved in entrainment of a circadian oscillator to light cycles in mammals. [8]

He found that blind mice without classical photoreceptor cells (rods and cones) still had eye-mediated responses to light. Mice with the melanopsin gene knocked out but with functional rods and cones were also able to entrain. However, when melanopsin was knocked out in blind mice without rods and cones, they exhibited “complete loss of photoentrainment of the circadian oscillator, pupillary light responses, photic suppression of arylalkylamine-N-acetyltransferase transcript, and acute suppression of locomotor activity by light.” [8] Provencio concluded that either melanopsin-containing retinal ganglion cells or outer-retinal photoreceptors (rods and cones) are sufficient to induce a response to light. However, in the absence of either rods and cones or melanopsin, melanopsin becomes necessary for photoentrainment of the circadian oscillator and for other photic responses. [8]

To further investigate the role of melanopsin in light-induced phase shifting in mammals, the Provencio lab studied the locomotor activities of melanopsin-null mice (Opn4 -/-) in response to light. [9] The Opn4 -/- mice showed similar circadian behaviors as the normal mice: they entrained to light/dark cycles and free-ran under constant darkness in a way expected from the normal mice. [9] Researchers in Provencio's lab thus concluded that melanopsin was not involved in the functioning of the master clock oscillation. [9] On the other hand, Opn4-/- mice had difficulties adjusting to new phases in response to pulses of monochromatic light. [9] The implication was that melanopsin was necessary for phase resetting but other mechanisms of light inputs might be involved in circadian entrainment as well. [9]

In 2008, the Provencio lab was able to specifically destroy melanopsin cells in the fully developed mouse retina using an immunotoxin made of an anti-melanopsin antibody conjugated to the protein saporin. [10] This resulted in lowered responsiveness to light/dark cycles; a similar characteristic was observed in gene-knockout mutants lacking rods, cones or melanopsin. Furthermore, light-induced negative masking, mediated by rods, cones and/or melanopsin cells, was missing in the mice lacking melanopsin cells. [10] Therefore, Provencio suggested that cells containing melanopsin might be required to transmit rod and/or cone information for certain non-image forming visual responses. [10]

Entrainment in blind patients

Provencio's discovery of melanopsin and its function in photoentrainment supports earlier studies showing that some blind patients can entrain to a daily light cycle. [11] Since retinal ganglion cells that express melanopsin have also been found in humans, these studies suggest that blind humans who still retain functional melanopsin cells are those who are able to entrain to daily light cycles. These studies also show that blind patients who cannot entrain and lack melanopsin cells have a significantly greater risk of suffering from circadian rhythm sleep disorders. [12] While enucleation of blind patients and babies was a common practice for cosmetic or analgesic reasons, doctors now must make a more cautious decision on whether to enucleate blind patients, especially infants, because they may still have functioning photosensitive retinal ganglion cells that express melanopsin. [13] In addition, there are now studies attempting to optimize light therapy for those with circadian rhythm sleep disorders that specifically try to stimulate melanopsin cells in blind patients. [14]

Recent studies

Provencio's research team has found that in albino mice, the amount of melanopsin protein in various retinal cells varies based on the environmental light conditions. [15] In constant light conditions, melanopsin cell number did not increase. [15] However, when these constant-light mice were exposed to light-dark schedules, there was regain of melanopsin cell number. [15] This study shows that bouts of darkness or the order of light and dark periods may control the normal development of the melanopsin system. [15]

In a 2006 study, Provencio explored the role of the protein RPE65 for photoentrainment. RPE65 is an important protein found in intrinsically photosensitive retinal ganglion cells (ipRGCs) that is necessary for regeneration of visual chromophore in rods and cones. RPE65 knockout mice (Rpe65(-/-)) showed much weaker phase shifts when compared to rodless, coneless mice, which suggested that RPE65 might have other roles. [16]

To further define the functions of RPE65, Provencio took Rpe65(-/-) mice and also eliminated rods. The technique used for this was insertion of the rdta transgene, which selectively kills rods. They found that circadian photosensitivity returned in these mice without RPE65 protein and without rods, versus mice without RPE65 protein that still had rods. [16]

Provencio also took Rpe65(-/-) mice and crossed them with melanopsin knockout mice (Opn4(-/-)). This created double RPE and melanopsin knockout mice, which resulted in abnormal photoentrainment and diurnal behavior. From these results, Provencio concluded that RPE65 is not necessary for the function of ipRGCs. However, because of the interesting restoration of circadian photosensitivity in rodless, RPE-less mice, there seems to be a mechanism by which rods can influences ipRGCs and rods may interact. [16]

See also

Related Research Articles

Free-running sleep is a rare sleep pattern whereby the sleep schedule of a person shifts later every day. It occurs as the sleep disorder non-24-hour sleep-wake disorder or artificially as part of experiments used in the study of circadian and other rhythms in biology. Study subjects are shielded from all time cues, often by a constant light protocol, by a constant dark protocol or by the use of light/dark conditions to which the organism cannot entrain such as the ultrashort protocol of one hour dark and two hours light. Also, limited amounts of food may be made available at short intervals so as to avoid entrainment to mealtimes. Subjects are thus forced to live by their internal circadian "clocks".

<span class="mw-page-title-main">Retina</span> Part of the eye

The retina is the innermost, light-sensitive layer of tissue of the eye of most vertebrates and some molluscs. The optics of the eye create a focused two-dimensional image of the visual world on the retina, which then processes that image within the retina and sends nerve impulses along the optic nerve to the visual cortex to create visual perception. The retina serves a function which is in many ways analogous to that of the film or image sensor in a camera.

<span class="mw-page-title-main">Chronobiology</span> Field of biology

Chronobiology is a field of biology that examines timing processes, including periodic (cyclic) phenomena in living organisms, such as their adaptation to solar- and lunar-related rhythms. These cycles are known as biological rhythms. Chronobiology comes from the ancient Greek χρόνος, and biology, which pertains to the study, or science, of life. The related terms chronomics and chronome have been used in some cases to describe either the molecular mechanisms involved in chronobiological phenomena or the more quantitative aspects of chronobiology, particularly where comparison of cycles between organisms is required.

<span class="mw-page-title-main">Photoreceptor cell</span> Type of neuroepithelial cell

A photoreceptor cell is a specialized type of neuroepithelial cell found in the retina that is capable of visual phototransduction. The great biological importance of photoreceptors is that they convert light into signals that can stimulate biological processes. To be more specific, photoreceptor proteins in the cell absorb photons, triggering a change in the cell's membrane potential.

<span class="mw-page-title-main">Cone cell</span> Photoreceptor cells responsible for color vision made to function in bright light

Cone cells, or cones, are photoreceptor cells in the retinas of vertebrate eyes including the human eye. They respond differently to light of different wavelengths, and the combination of their responses is responsible for color vision. Cones function best in relatively bright light, called the photopic region, as opposed to rod cells, which work better in dim light, or the scotopic region. Cone cells are densely packed in the fovea centralis, a 0.3 mm diameter rod-free area with very thin, densely packed cones which quickly reduce in number towards the periphery of the retina. Conversely, they are absent from the optic disc, contributing to the blind spot. There are about six to seven million cones in a human eye, with the highest concentration being towards the macula.

<span class="mw-page-title-main">Retinal</span> Chemical compound

Retinal is a polyene chromophore. Retinal, bound to proteins called opsins, is the chemical basis of visual phototransduction, the light-detection stage of visual perception (vision).

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

Melanopsin is a type of photopigment belonging to a larger family of light-sensitive retinal proteins called opsins and encoded by the gene Opn4. In the mammalian retina, there are two additional categories of opsins, both involved in the formation of visual images: rhodopsin and photopsin in the rod and cone photoreceptor cells, respectively.

<span class="mw-page-title-main">Giant retinal ganglion cells</span>

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Intrinsically photosensitive retinal ganglion cells (ipRGCs), also called photosensitive retinal ganglion cells (pRGC), or melanopsin-containing retinal ganglion cells (mRGCs), are a type of neuron in the retina of the mammalian eye. The presence of ipRGCs was first suspected in 1927 when rodless, coneless mice still responded to a light stimulus through pupil constriction, This implied that rods and cones are not the only light-sensitive neurons in the retina. Yet research on these cells did not advance until the 1980s. Recent research has shown that these retinal ganglion cells, unlike other retinal ganglion cells, are intrinsically photosensitive due to the presence of melanopsin, a light-sensitive protein. Therefore they constitute a third class of photoreceptors, in addition to rod and cone cells.

<span class="mw-page-title-main">Retinohypothalamic tract</span> Neural pathway involved with circadian rhythms

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References

  1. ↑ Provencio, Ignacio; Jiang, Guisen; De Grip, Willem J.; Hayes, William Pär; Rollag, Mark D. (1998). "Melanopsin: an opsin in melanophores, brain, and eye". Proceedings of the National Academy of Sciences. 95 (1): 340–5. Bibcode:1998PNAS...95..340P. doi: 10.1073/pnas.95.1.340 . PMC   18217 . PMID   9419377.
  2. ↑ "The Society for Research on Biological Rhythms". Society for Research on Biological Rhythms. Archived from the original on 22 March 2011. Retrieved 9 April 2011.
  3. ↑ Scientific American May 2011. . April 20, 2011.
  4. ↑ Provencio, Ignacio. "UVA Vision Research Group Directory". University of Virginia, Department of Ophthalmology. Retrieved 9 April 2011.
  5. ↑ "Ignacio Provencio". University of Virginia. Retrieved May 2, 2009.
  6. ↑ Provencio, I; Jiang, G; De Grip, WJ; Hayes, WP; Rollag, MD (1998). "Melanopsin: An opsin in melanophores, brain, and eye". Proc. Natl. Acad. Sci. USA. 95 (1): 340–5. Bibcode:1998PNAS...95..340P. doi: 10.1073/pnas.95.1.340 . PMC   18217 . PMID   9419377.
  7. ↑ Provencio, I; Rodriguez, IR; Jiang, G; Hayes, WP; Moreira, EF; Rollag, MD (2000). "A novel human opsin in the inner retina". The Journal of Neuroscience. 20 (2): 600–5. doi: 10.1523/jneurosci.20-02-00600.2000 . PMC   6772411 . PMID   10632589.
  8. 1 2 3 Panda, S.; Provencio, I; Tu, DC; Pires, SS; Rollag, MD; Castrucci, AM; Pletcher, MT; Sato, TK; et al. (2003). "Melanopsin is Required for Non-Image-Forming Photic Responses in Blind Mice". Science. 301 (5632): 525–7. Bibcode:2003Sci...301..525P. doi:10.1126/science.1086179. PMID   12829787. S2CID   37600812.
  9. 1 2 3 4 5 Panda, S.; Sato, TK; Castrucci, AM; Rollag, MD; Degrip, WJ; Hogenesch, JB; Provencio, I; Kay, SA (2002). "Melanopsin (Opn4) Requirement for Normal Light-Induced Circadian Phase Shifting". Science. 298 (5601): 2213–6. Bibcode:2002Sci...298.2213P. doi:10.1126/science.1076848. PMID   12481141. S2CID   20602808.
  10. 1 2 3 Göz, Didem; Studholme, Keith; Lappi, Douglas A.; Rollag, Mark D.; Provencio, Ignacio; Morin, Lawrence P. (2008). Greene, Ernest (ed.). "Targeted Destruction of Photosensitive Retinal Ganglion Cells with a Saporin Conjugate Alters the Effects of Light on Mouse Circadian Rhythms". PLOS ONE. 3 (9): e3153. Bibcode:2008PLoSO...3.3153G. doi: 10.1371/journal.pone.0003153 . PMC   2519834 . PMID   18773079.
  11. ↑ Czeisler, Charles A.; Shanahan, Theresa L.; Klerman, Elizabeth B.; Martens, Heinz; Brotman, Daniel J.; Emens, Jonathan S.; Klein, Torsten; Rizzo, Joseph F. (1995). "Suppression of Melatonin Secretion in Some Blind Patients by Exposure to Bright Light". New England Journal of Medicine. 332 (1): 6–11. doi:10.1056/NEJM199501053320102. PMID   7990870.
  12. ↑ "Circadian Rhythm Sleep Disorder (formerly Sleep-Wake Schedule Disorder)". Armenian Medical Network. Retrieved April 19, 2011.
  13. ↑ Baruch El-Ad MD. "Non-24-hour sleep-wake syndrome". Medlink Neurology. Retrieved April 19, 2011.
  14. ↑ Gooley, J. J.; Rajaratnam, S. M. W.; Brainard, G. C.; Kronauer, R. E.; Czeisler, C. A.; Lockley, S. W. (2010). "Spectral Responses of the Human Circadian System Depend on the Irradiance and Duration of Exposure to Light". Science Translational Medicine. 2 (31): 31ra33. doi:10.1126/scitranslmed.3000741. PMC   4414925 . PMID   20463367.
  15. 1 2 3 4 Gonzalez-Menendez, I.; Contreras, F.; Cernuda-Cernuda, R.; Provencio, I.; Garcia-Fernandez, J. M. (2010). "Postnatal Development and Functional Adaptations of the Melanopsin Photoreceptive System in the Albino Mouse Retina". Investigative Ophthalmology & Visual Science. 51 (9): 4840–4847. doi:10.1167/iovs.10-5253. PMC   2941179 . PMID   20435589.
  16. 1 2 3 Doyle, S. E.; Castrucci, A. M.; McCall, M.; Provencio, I.; Menaker, M. (2006). "Nonvisual light responses in the Rpe65 knockout mouse: Rod loss restores sensitivity to the melanopsin system". Proceedings of the National Academy of Sciences. 103 (27): 10432–10437. doi: 10.1073/pnas.0600934103 . PMC   1502475 . PMID   16788070.
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