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Cilia and the Oviduct

Posted in Reproductive Biology & Bio Instrumentation, tagged angipoeiten receptor, Christensen, cilia, Cilium, Epithelium, female reproductive system, molecule, polycysin, progesterone receptor, Signal transduction, University of Copenhagen on May 22, 2013| 6 Comments »

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.

Fig2 Their 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 A, Lind K, Goksör M, Billig H, Larsson DJ. 2013 The classical progesterone receptor mediates the rapid reduction of fallopian tube ciliary beat frequency by progesterone. Reprod Biol Endocrinol. 11:33.

Egeberg DL, Lethan M, Manguso R, Schneider L, Awan A, Jørgensen TS, Byskov AG, Pedersen LB, Christensen ST. 2012 Primary cilia and aberrant cell signaling in epithelial ovarian cancer. Cilia. 1:15.

Fliegauf M, Olbrich H, Horvath J, Wildhaber JH, Zariwala MA, Kennedy M, Knowles MR, Omran 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 TM, Molskness TA, Chaffin CL, Stouffer 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 SC, Byskov AG, Pedersen PA, Wheatley DN, Pazour GJ, Christensen 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 SC, Clement CA, Thorup J, Byskov AG, Christensen ST. 2006 Expression and localization of the progesterone receptor in mouse and human reproductive organs. J Endocrinol. 191:525-535.

Yoder BK, Hou X, Guay-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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Know How We ALL, Knowingly or Unknowingly, Consume Antibiotics and How it Effects Our Health

Posted in Infectious Disease & New Antibiotic Targets, tagged Antibacterial, bacteria, Copenhagen, European Union, Salmonella, United States, University College Cork, University of Copenhagen on August 29, 2012| 3 Comments »

Curated and Reported by: Dr. Venkat S. Karra, Ph.D.

Know How We ALL Knowingly or Unknowingly Consume Antibiotics and How it Effects Our Health

Billions of microbial cells live in the guts of humans and other animals. Research on these vast bacterial populations, called microbiomes, is just getting started, but scientists already know that some microbial boarders play a crucial role in breaking down nutrients in our diet. Some have also suspected that low-dose antibiotics, given to farm animals to make them grow bigger, could work by altering the gut microbiome.

To test this hypothesis, a team led by microbiologist Martin Blaser of the New York University School of Medicine in New York City added antibiotics to the drinking water of mice that had just been weaned. The medicine—either penicillin, vancomycin, a combination of the two, or chlortetracycline—was given at doses comparable to those approved by the U.S. Food and Drug Administration as growth promoters in farm animals. After 7 weeks, the group of mice on antibiotics had significantly more fat than a control group drinking plain water, the team reports online today in Nature. “This confirms what farmers have shown for 60 years, that low-dose antibiotics cause their animals to grow bigger,” Blaser says.

Too Much Vitamin D Can Be as Unhealthy as Too Little

Posted in Biological Networks, Gene Regulation and Evolution, Disease Biology, Small Molecules in Development of Therapeutic Drugs, tagged Darshana Durup, Doctor of Philosophy, Faculty of Health, Hypovitaminosis D, Mortality rate, research, The Journal of Clinical Endocrinology and Metabolism, University of Copenhagen on May 30, 2012| Leave a Comment »

Reporter: Prabodh Kandala, PhD

Scientists know that Vitamin D deficiency is not healthy. However, new research from the University of Copenhagen now indicates that too high a level of the essential vitamin is not good either. The study is based on blood samples from 247,574 Copenhageners. The results have just been published in the reputed scientific Journal of Clinical Endocrinology and Metabolism.

Vitamin D is instrumental in helping calcium reach our bones, thus lessening the risk from falls and the risk of broken hips. Research suggests that vitamin D is also beneficial in combating cardiac disease, depression and certain types of cancers. The results from a study conducted by the Faculty of Health and Medical Sciences now support the benefits of vitamin D in terms of mortality risk. However, the research results also show higher mortality in people with too high levels of vitamin D in their bloodstream:

“We have had access to blood tests from a quarter of a million Copenhageners. We found higher mortality in people with a low level of vitamin D in their blood, but to our surprise, we also found it in people with a high level of vitamin D. We can draw a graph showing that perhaps it is harmful with too little and too much vitamin D,” explains Darshana Durup, PhD student.

If the blood contains less than 10 nanomol (nmol) of vitamin per liter of serum, mortality is 2.31 times higher. However, if the blood contains more than 140 nmol of vitamin per liter of serum, mortality is higher by a factor of 1.42. Both values are compared to 50 nmol of vitamin per liter of serum, where the scientists see the lowest mortality rate.

More studies are needed

Darshana Durup emphasises that while scientists do not know the cause of the higher mortality, she believes that the new results can be used to question the wisdom of those people who claim that you can never get too much vitamin D:

“It is important to conduct further studies in order to understand the relationship. A lot of research has been conducted on the risk of vitamin D deficiency. However, there is no scientific evidence for a ‘more is better’ argument for vitamin D, and our study does not support the argument either. We hope that our study will inspire others to study the cause of higher mortality with a high level of vitamin D,” says Darshana Durup. She adds:

“We have moved into a controversial area that stirs up strong feelings just like debates on global warming and research on nutrition. But our results are based on a quarter of a million blood tests and provide an interesting starting point for further research.”

The largest study of its kind

The study is the largest of its kind — and it was only possible to conduct it because of Denmark’s civil registration system, which is unique in the Nordic countries. The 247,574 blood samples come from the Copenhagen General Practitioners Laboratory:

“Our data material covers a wide age range. The people who participated had approached their own general practitioners for a variety of reasons and had had the vitamin D level in their bloodstream measured in that context. This means that while the study can show a possible association between mortality and a high level of vitamin D, we cannot as yet explain the higher risk,” explains Darshana Durup.

Therefore in future research project scientists would like to compare the results with information from disease registers such as the cancer register. Financial support is currently being sought for such projects.

Ref:

http://www.sciencedaily.com/releases/2012/05/120529102346.htm

http://jcem.endojournals.org/content/early/2012/05/09/jc.2012-1176