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Cilia and the Oviduct

Author: Aashir Awan, PhD

In a previous article, there was a discussion on the role of primary cilia in ovarian cancers with specific context to the hedgehog signal transduction system.  The article helped to highlight not only the role that this organelle plays in ovarian cancer tumorigenesis but also hints at perhaps a mechanistic explanation at the molecular level (Egeberg et al., 2012).  In this review, we focus on primary cilia and some of the signal transduction pathways it helps to coordinate within the oviduct.  Motile cilia are probably better known in their roles  aiding in the movement of the oocyte.  But, in the last few years, research has been undertaken to study the sensory role of the cilium in the female reproductive system.  As such, Drs. Christensen and Stefan Teilmann (University of Copenhagen) undertook a few studies to show the importance of three different signal transduction systems that are being coordinated by the cilium in this particular tissue.

Fig2Their first paper demonstrated that progesterone receptor was localized to the cilia on the epithelial layer of cells surrounding the oviduct and specifically to the lower half of the ciliary length which can be seen in the immunofluorescence analysis of the progesterone receptor profile in the left hand-side figure (Teilmann et al., 2006).  Furthermore, the expression of this receptor is markedly increased upon exposure to gonadotrophin hormones indicating that there is a feedback loop that is sensitive to hormonal regulation.  Previously, it had been shown that progesterone regulates the activity of the outer dynein arms of the cilium through specific effector molecules (Fliegauf et al., 2005).  Thus, the progesterone released upon ovulation would be thought to directly affect the ciliated epiethlium in order to help facilitate the movement of the oocyte through the oviduct thereby highlighting the important role of the cilium (and the signal transduction pathway) to the overall physiology of the female reproductive system.  This work has recently been reproduced by Dr. Larrson’s group in Sweden (Bylander et al., 2013).

Fig1

The Christensen group continued further studies by localizing the angipoeiten receptors, Tie-1 and Tie-2, to the primary cilia of the ovarian surface epithelial as well as the oviduct as seen in the figure on right showing an immunoflourescent micrograph of the infundibulum (Teilmann and Christensen 2005).  Since the expression of their agonist, Ang1, increases during ovulation (Hazzard et al., 1999), both these receptors are thought to play a role in vascularization of the tissue surrounding the developing follicles.  Also, using this  reasoning, the paper argues that the Ang/Tie signaling axis plays an important and general role by serving as an anti-apoptotic system to maintain a dedifferentiated phenotype of both endothelial cells.

Fig3

Finally, Dr. Christensen’s group also demonstrated a unique localization of polycystins 1 and 2 to the primary cilia of ovarian granulose cells (Teilmann et al., 2005).  These calcium cation channels have been shown to sense the flow of urine in the kidney in monitoring general homeostasis and whose mutations have been shown to cause polycystic kidney disesase (Pazour et al.,2002; Yoder et al., 2002).  As with the progesterone receptor, there is a marked effect on polycystins concentration upon gonadrotrophin stimulation as clearly seen on the left-hand side figure (the arrow show ciliary localization of the polycystin 2 receptor; also, note the dramatic increase in polycystin 2 immunofluorescence in the infundibulum).  Further, the Ca2+ permeable cation channel, TRP vaniloid 4 (TRPV4) was found to be localized to the motile cilia in specific subpopulation of epithelial cells within the ampulla and isthmus.  Thus, the localization of these receptors  indicates that the primary cilia would again be involved in a sensory role perhaps by affecting the differentiation and maturation of the emerging oocyte and in relaying physiological information upon ovulatation to the epithelial cells of the surrounding oviduct.

One can imagine that these are probably only a partial list of the important receptor molecules localized thus far to the  cilia that exist within the female reproductive system.  Since more and more receptor molecules are being found within the relatively small confines of this organelle, one can hypothesize that perhaps the signal transduction mechanism between different receptor molecules is ocurring within the cilium itself perhaps even independent of what may be occurring in the cell body. Since reproductive and fertility issues remain a problem in the medical field, it behooves us to continue research into the overall contributions of  this organelle within the female reproductive system.

REFERENCES

Bylander ALind KGoksör MBillig HLarsson DJ. 2013 The classical progesterone receptor mediates the rapid reduction of fallopian tube ciliary beat frequency by progesterone. Reprod Biol Endocrinol. 11:33.

Egeberg DLLethan MManguso RSchneider LAwan AJørgensen TSByskov AGPedersen LBChristensen ST. 2012 Primary cilia and aberrant cell signaling in epithelial ovarian cancer. Cilia. 1:15.

Fliegauf MOlbrich HHorvath JWildhaber JHZariwala MAKennedy MKnowles MROmran H. 2005 Mislocalization of DNAH5 and DNAH9 in respiratory cells from patients with primary ciliary dyskinesia. Am J Respir Crit Care Med. 171:1343-1349.

Hazzard TMMolskness TAChaffin CLStouffer RL. 1999 Vascular endothelial growth factor (VEGF) and angiopoietin regulation by gonadotrophin and steroids in macaque granulosa cells during the peri-ovulatory interval. Mol Hum Reprod. 5:1115-1121.

Pazour GJ, San Agustin JT, Follit JA, Rosenbaum JL, Witman GB.20002 Polycystin-2 localizes to kidney cilia and the ciliary level is elevated in orpk mice with polycystic kidney disease. Curr Biol. 12:R378-R380.

Teilmann SC, Christensen ST. 2005 Localization of the angiopoietin receptors Tie-1 and Tie-2 on the primary cilia in the femalereproductive organs. Cell Biol Int.29:340-346.

Teilmann SCByskov AGPedersen PAWheatley DNPazour GJChristensen ST. 2005 Localization of transient receptor potential ion channels in primary and motile cilia of the female murine reproductive organs. Mol Reprod Dev. 71:444-452.

Teilmann SCClement CAThorup JByskov AGChristensen ST. 2006 Expression and localization of the progesterone receptor in mouse and human reproductive organs. J Endocrinol. 191:525-535.

Yoder BKHou XGuay-Woodford LM. 2002 The polycystic kidney disease proteins, polycystin-1, polycystin-2, polaris, and cystin, are co-localized in renal cilia. J Am Soc Nephrol. 13:2508-2516.

 

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Author/Curator: Aviral Vatsa PhD, MBBS

Nitric oxide (NO) is of extreme biological interest due to its wide range of physiological functions in almost all the human systems. For long it has been of vital interest to chemists, environmental scientists, metallurgists and other domains. It is only recently that the world of biology has discovered the ubiquitous presence of this small molecule in human body and the scientific exploration of its effects has grown ever since. It was only in 1980s that three different groups demonstrated that NO is indeed produced by mammalian cells and that NO has specific biological roles in the human body. These studies highlighted the role of NO in cardiovascular, nervous and immune systems. In cardiovascular system NO was shown to cause relaxation of vascular smooth muscle cells causing vasodilatation, in nervous system NO acts as a signalling molecule and in immune system it is used against pathogens by the phagocytosis cells. These pioneering studies opened the path of investigation of role of NO in biology. In 1998, three scientists, Robert F Furchgott, Louis J Ignarro, and Ferid Murad, were awarded Nobel Prize for their discoveries concerning ‘nitric oxide as a signalling molecule’.

Since then hundreds and thousands of publications have appeared in the scientific literature. These studies have attributed a wide range of biological functions to NO. A few important examples are:

  • toxic free radical causing injury to proteins, lipids and DNA
  • mediator of synaptic plasticity
  • intercellular neuronal signalling molecule
  • pro and anti inflammatory molecule
  • role in cell degeneration and ischaemia-reperfusion injury
  • role in atherosclerosis and inherited motor disorders
  • role in bone remodelling

The above list is by no means exhaustive, but it gives an idea about the ubiquitous involvement of NO in human systems.

Since NO has been implicated in various disease states, it has also been a prime target to achieve therapeutic benefits. Efforts are ongoing to investigate the therapeutic potential of NO in cardiovascular diseases, sepsis and shock, respiratory ailments, neuronal disease and bone conditions…just to name a few.

Although a lot of progress has happened in our understanding of this small molecule since its discovery, but still there are many challenges that the researchers face today while investigating NO. These are primarily because NO is metabolised very quickly (<5 sec) and it can difuse freely across cellular membranes owing to its chemical structure. This is the precise reason why it can act as a potent signaling molecule across systems in the first place. New techniques are appearing to delineate the role of NO at sub-cellular level and have promising potential to aid NO research in the future.

In the future posts on this topic I will strive to cover different aspects of NO physiology and its role in various disease conditions, techniques for NO detection, signaling mechanism etc.

Sources:

1. The nature of endothelium-derived vascular relaxant factor

Nature 308, 645 – 647 (12 April 1984); doi:10.1038/308645a0

T. M. Griffith, D. H. Edwards, M. J. Lewis, A. C. Newby & A. H. Henderson

2. Nitric oxide: physiology, pathophysiology, and pharmacology.

Pharmacological Rev June 1991 43:109-142

S Moncada, R M Palmer, and E A Higgs

3. Introduction to EDRF research.

J Cardiovasc Pharmacol.1993;22 Suppl 7:S1-2.

Furchgott RF

4. http://www.nobelprize.org/nobel_prizes/medicine/laureates/1998/illpres/

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