how to keep Ovaries Female? Ask "FOXL2".

The eternal oppositesYin & Yang

The celebrated Male-ness transcription factor SRY, encoded by the Y-chromosome is needed for the differentiation of the indifferent gonads into Testis.

In this study, Mathias Trier, from EMBL demonstrates that in the mouse, a single factor, the forkhead transcriptional regulator, FOXL2, is required to prevent transdifferentiation of an ovary to a testis in the adult animal.

In one of their earlier studies in 2004, when they knocked out the gene in mice, females began to form ovaries, but later in development, the ovaries degenerated.

In the The current study the investigators let the mice develop ovaries normally, and then knocked down the gene once the animals reached adulthood.

Rationale behind the attempt:

1. Foxl2 is known to behave differently during development and adulthood. It regulates other genes important to organ differentiation.

2. During development, another gene, Wnt4, is expressed which is thought to be the major signal that suppresses the male program of development. After the female gonads develop, Wnt4 shuts off.

Contrarily, Foxl2's expression throughout the life of a female suggests that it is continually needed in female

physiology.

Critical Observations:

Inducible deletion of Foxl2 in adult ovarian follicles leads to immediate upregulation of testis-specific

genes including the critical SRY target gene Sox9.

Granulosa and Theca cells got reprogrammed into Sertoli- and Leydig- cell lineages

Testosterone levels were comparable to those of normal XY male littermates.

Change from ovarian cells to testicular cells didn't affect the outward physical appearance of the mice, i.e. the secondary sexual characters didnt undergo a change.

The overarching take-home-message from the work is that a fully differentiated adult organ has the potential - under conducive circumstances - to undergo radical remodeling, and undergo trans-differentiation.

And, FOXL2 and SOX9, which are gatekeepers of male- and female-ness oppose each other’s action

to ensure together the establishment and maintenance of the different female and male supporting cell types respectively.

But really, how do efficient epigenetic-changes happen in the cell in a span less than 48 hours, is a question not answered in this study.

Some questions which remain:

* Would the same phenomenon be possible in the Male as well? That is, the testis changing into an ovary.

* Female being the pre-differentiation default-sex , it is surprising that one' would need a factor to maintain "female-ness" throughout life?

* Moreover does SRY or its target genes, maintain "male-ness" in the adult male?

* And what is the role of FOXL2 in the Male?

* To change the epigenetics, phenotype, function and overall the total "identity" of a cell to another, by just 1   factor is a bit of a concern.
The most pertinent question, therefore perhaps is the following: Why  did mother-nature evolve such a "dangerous" strategy, whereby tinkering with just 1 gene, changes everything? To put it this way, what is the relevance of having a "master-player" and make a system increasingly vulnerable?

References:

Somatic Sex Reprogramming of Adult Ovaries to Testes by FOXL2 Ablation.

Cell 139, 1130–1142, December 11, 2009

N. Henriette Uhlenhaut, Susanne Jakob, Katrin Anlag, Tobias Eisenberger, Ryohei Sekido, Jana Kress, Anna-Corina Treier, Claudia Klugmann, Christian Klasen, Nadine I. Holter, Dieter Riethmacher, Gu¨ nther Schu¨ tz, Austin J. Cooney, Robin Lovell-Badge, and Mathias Treier1

 http://www.the-scientist.com/blog/display/56212/

The murine winged-helix transcription factor Foxl2 is required for granulosa cell differentiation and ovary maintenance.
Development, 131, 933-942 (2004)
Dirk Schmidt, Catherine E. Ovitt, Katrin Anlag, Sandra Fehsenfeld, Lars Gredsted, Anna-Corina Treier and Mathias Treier.

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Salute the SPERM

                     a group of sperms with a distinct Head and Tail

How are we made? How do we end up having millions of cells when we have only started with 2 of them (actually 1, after they have fused)?

Imagine this: we are totally non-existent until one among the father's millions-of sperms would have located and fused with the mother's egg (oocyte as it is called). Imagine also that the sperm and the egg are totally powerless to make us, all alone by themselves - i.e to make us, it's inevitable that they beat all odds and meet each other!

And what's even more incredible is that once they have met successfully, the destiny is sealed- they must forgo their individual entities and must now function as a whole, a new entity, which is both similar and different to each other. In other words, they must die as individuals, to make us!

The sperm is the only motile cell of the body. The only cell, which can, by virtue of its huge reserves of energy and a peculiar structure (it has a 'head' and a huge tail stcuk to its behind), undergoes a swift biochemical change (Capacitation, which I'll explain later), beats its tail frantically to generate a forward propulsive force and moves extremely rapidly in order to meet its paramour, the oocyte. The sperm, has a haploid (x) number of chromosomes (so does the oocyte), in order to give rise to a normal (2x) number upon fusion.

During Spermatogenesis, the spermatogonia (2x) undergo meiosis to form mature spermatids (x), which in the female tract, undergo this fantastic biochemical-switch called Capacitiation (which is actually a cumulative term for 2 separate events - Hyperactivation and Acrosome reaction) and is characterised with a distinct, almost-violent, whiplash movement of the tail (resembling the letter '8').

Interestingly, a huge-Calcium ion influx into the sperm, aided by the sudden high-fluidity of the it's cell-membrane is necessary and sufficient to bringing about capacitation. It has been shown experiments with Ca-channel blockers, ionophores etc, that sperm-capacitation could be blocked.

It is also evidenced by various groups, that the Capacitation-event is a result of distinct tyrosine-residue phosphorylation of several important proteins (as it turns out ser-thr phosp. play a relatively-smaller role in it). Obviously, protein kinases, mainly of the EGF-R family and also RTK and TK's of the NR type are the major culprits for bringing our this phenomenon!  Inhibition of tyr. residue phosphorylation-events by suitable inhibitors have shown the dependancy of the event on crucial catalytic-activity of the kinases. Interestingly, only some Phosphatases have been shown to play a critical role in the event. As it turns out, the sperm has a super-compact DNA (Histones are replaced by Protamines, which are more basic-proteins and therefore package the DNA even more tightly). Hence, only proteomic and not genomic actions, decide the fate of this motile-cell!!

on Plant-Behavior

Attended some really cool talks in the symposium. commemorating Darwin and 150 years of his seminal-book "the Origin Of Species". A brief on one of them......

A senior agricultural scientist, Prof. K N Ganeshaiah ( http://www.atree.org/kng.html ), from the the Univ. of Agricultural Sciences (UAS), here at Bangalore, spoke with rarely seen passion and excitement on 'Plant-Behavior' and how that has evolved over time. Although he tended to anthropomorphise plants and their responses to complex situations by comparing plant-behavior to commonly seen behavior in animals, but the similarities were quite convincing and definitely, indeed a very enlightening 45 minutes spent.
He spoke on sexual-selection - in plants, an issue rarely delved into, citing the commonly seen case of 'Vaginal-Plugging' in the plant Kleinhovia hospita, whereby the most dominant male-organ plugs the entry point to the female opening via secretion of a chemical which inhibits the growth of other competing pollen-tubes (Pollen-Tube competition). He mentioned curious cases in plants where ovules were selectively-aborted to facilitate the growth of the 'fittest' ovule.
He discussed about the normally animal-centric, parent-offspring conflict in plants, citing the example of a pea-pod, where the siblings growing in the pod compete for resources and in several documented cases there's a clear winner at the cost of others.
He concluded his lecture with comments on the upcoming and hugely controversial field of Plant-Neurobiology, and the super-quest for cognition in plants.......I always thought the field was dead after the lone efforts of Sir J C Bose......as it turns out, the pages have just been turned!!


Some References:

Sexual selection in plants: Pros and cons

Vol. 92, pp. 1247-1250, February 1995
PNAS

The quest for cognition in plant neurobiology

http://pacocalvogarzon.files.wordpress.com/2009/02/the-quest-for-cognition-in-plant-neurobiology.pdf

A general introduction to plant neurobiology can be found in:

http://131.220.103.188/ahlavacka/spn/ society/index.php.

Plant neurobiology: no brain, no gain?

TRENDS in Plant Science Vol.12 No.4

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Remembering Darwin and 'The Origin of Species'.

Genesis, the student-secretaried, science interface of my dept. MRDG (Molecular Reproduction, Development and Genetics) at the Indian Institute of Science (IISc), is organizing a 1-day symposium to commemorate 150 years of the publication of 'Origin of Species', the seminal contribution by one of the most-gifted brains of human-kind, which defines our origins and perhaps predicts our future too.......
The symposium is on the 24th of November 2009, 9:30 a.m. to 4.00 p.m.

A snippet: IISc, is a rather plural (and democratic) place to be in. Such are its expanses of 'intellectual-freedom' (which nevertheless, from time-to-time gets ill-defined, by opportunist groups), that some of us also heard a talk on 'Devolution' or de-evolution; a totally ill-defined, ill (or no) evidenced piece of 'work' proclaiming that organisms (spl. Man) was 'perfect' earlier, and has been consistently devolving!!

                                 image of the symposium-poster

The details of the symp. are noted below:

Session I (9:30-11:30)

Vidyanand Nanjundiah,
IISc, Bangalore
Where are we today?

Ashok Sahni,
Punjab University, Chandigarh
Planet Earth: An Oasis in Space

Tea break (11-1130am)

Session II (11:30-1pm)

K.N. Ganeshaiah,
UAS, Bangalore
Behaviour in Plants

Rohini BalakrishnanIISc, Bangalore
Darwin and Mind

Lunch break

Session III (2:30-4:30 pm)

Renee Borges
IISc, Bangalore
On Erasmus Darwin

S G Kulkarni,
University of Hyderabad, Hyderabad
Darwin and creativity

Concluding Remarks
High Tea

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Down but not Out -- Possible cure for Down's -Syndrome?

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Restoration of Norepinephrine-Modulated Contextual Memory in a Mouse Model of Down Syndrome

 Sci Transl Med, 18 November, 2009:
Vol. 1, Issue 7, p. 7ra17

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from Google-Images

Down's syndrome: condition caused by the trisomy of the 21st chromosome. 

A recent paper in "Science Translational Medicine" talks of a possible hope, over the horizon, for patients, after some extremely positive results with experiments on mice.

Gen/Pheno-type of the 'Down'-Mice: The Ts65Dn mouse model has a 'humanised'-trisomy (an extra, third copy of 104 genes on chromosome 16 that are homologous to genes on human chromosome 21). and is known to show abnormal responses in behavioral tests for contextual learning. They don't respond to fear conditioning. Also, when provided with material to build nests, they create shabbier homes reflecting their decreased ability to respond to new contexts.

The study: Incidentally a significant neurodegeneration takes place in the locus coeruleus (LC), an area of the brain which produces and supplies the hippocampus (and other parts of the brain), with the neurotransmitter norepinephrine, essential for learning and memory function. That finding corroborated with the fact that the LC also degenerates in humans with Down syndrome.

Since the locus coeruleus produces norepinephrine, the group then figured out how that neurotransmitter comes into play. Upon injection of the trisomy mice with l-DOPS (l-threo-3,4-dihydroxyphenylserine, or xamoterol, a β₁-adrenergic receptor partial agonist), a drug that can cross the blood-brain barrier and convert into norepinephrine, the mice significantly improved their performance in tests of both fear conditioning and nest-building, behaving more like the normal animals.

When the drug wore off, so too did the mutants' improved nest-building ability.

The LC degeneration  in the trisomy mice doesn't just affect humans with Down syndrome, it is also significantly observed in individuals with Alzheimer's disease and other types of dementia. Incidentally, as many as 25% or more people with Down syndrome go on to develop Alzheimer's-type dementia.

This link may arise via the an increased gene dosage of App, on chromosome 21, which codes for the amyloid precursor protein, and which was found to be necessary for locus coeruleus degeneration.

Hope from the study: This study shows thet even in presence of LC-degeneration, one can still rescue the function in the brain, albeit temporarily.

Surely, of course, future studies will essentially need to explore the optimum drug and dosage that can enhance the production of norepinephrine in the 'damaged' area of the brain.

________________________________________________________________________________                                                                                                                               a li'l adapted from 'The-Scientist'

Peptide-drug for Cancers!

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Direct inhibition of the NOTCH transcription factor complex

NATURE, Vol 462, 12 November 2009, 181-188.

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                                                  The Notch signaling pathway, Nature Reviews Cancer 6, 347-359 (May 2006)

what do we have here:

This group has developed a new drug that blocks Notch (and therefore its signaling) -- previously thought to be un-blockable -- that has been causally linked to leukemia and several other cancers of the lungs, ovaries, pancreas, and the gastrointestinal tract.

The problem to find a suitable drug, I guess, was the rather large number of proteins in the Notch-activating-complex, and this group has ultimately targeted the master-mind protein MAML which must bind to the complex along a long, shallow helical groove, which is created as the other pieces come together.

They developed a way to essentially "staple" a synthetic peptide into a complementary helical shape, allowing it to fit into the groove.

The researchers tested the stapled peptides on human T-cell acute lymphoblastic leukemia (T-ALL) cell lines. Additionally, mice injected with T-ALL cells and treated with the stapled peptides showed lower leukemia counts in the bone marrow and spleen than those that went untreated.

Insights / Hopes/ Doubts:

-------------------------

This paper at least, dispels despair among oncologists and organic-chemists about peptides acting as leads for drug discovery and well, hopefully this becomes a commercially viable treatment-option!

But then, obviously, blocking an omni-present signaling-system could have other side-effects.

And whether this peptide-based approach could be extended to other treatments as well, remains to be seen.

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Chewang Norphel and his "Artificial-Glaciers"

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SCIENCE, News Focus, 659-661, 30 OCTOBER, 2009, VOL 326.

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Chewang Norphel and the strategy of Artificial glaciers (from google-images)

Amazingly inspiring story!!

Remarkable idea of a retired civil-engineer from Leh (Ladakh) to overcome the problem of water scarcity during lean months.

How? He made "artificial-glaciers" and earned himself the sobriquet "Glacier-Man".

He let the 'waste'-water (flowing from taps, springs etc.) accumulate in huge tanks during winter, where it would solidify, to make huge ice-cubes or 'ice-bergs', which could later be melted for irrigation and other purposes during the summer months.

He merely observed nature and mimicked it on a large-enough scale, to bring water in the 'rain-shadow' area which recieves only as much rain as does the Sahara desert!!

Although his technology is area and altitude-specific, nevertheless, it is a win for the indomitable Human mind and spirit!

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Viral cause of Prostate-Cancer?

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XMRV is present in malignant prostatic epithelium and is associated with prostate cancer, especially

high-grade tumors.

www.pnas.org/cgi/doi/10.1073/pnas.0906922106

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                                                    The location of the Prostate gland in the human-male; google images

This rather 'surprising' paper from researchers of Columbia Univ. and Univ. of Utah, on Prostate cancer claims that the virus XMRV (Xenotropic murine leukemia virus-related virus) is associated, especially with aggressive prostate cancers and noted, rather dangerously, that "ALL individuals may be at risk" for infection.

One problem with the study though, is that it's on prostate cells and not on more 'believable' animal models.

Although it doesnt prove that prostate cancer is a viral disease, but its close association with the cancer is quite clearly shown.

Although its too early in the day, but is there a chance that prostate cancer would become a sexually transmitted diesease (like Cervical cancer probably is)?

Additionally, and importantly, can this virus be a useful and decisive marker for prostate cancer?

Only time and further studies will tell!

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ERK2 directly binds DNA !

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Profiling the Human Protein-DNA Interactome Reveals ERK2 as a Transcriptional Repressor of Interferon Signaling.

CELL, 139, 610–622, October 30, 2009.

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Surprise, Surprise!!

A new, collaborative paper (8 departments of Johns Hopkins Univ., USA played a part in it) shows that the ubiquitous MAPK member, ERK-2 directly binds to the DNA, and fuctions as a repressor of the Interferon signaling.

The workers have used a combined bioinformatics and protein microarray-based strategy to characterize the human protein-DNA interactome.

They found over three hundred, so-called, unconventional DNA-binding proteins (uDBPs, of which ERK2, acts as a transcriptional repressor for interferon gamma-induced genes.

Although the paper shows very nice EMSA's and ChIP's but, I wonder whatever happened to the concept of "protein-domains" and "motifs" for DNA-binding activity :-)!! Conventional wisdom says that a protein is "supposed" to have 'some' DNA binding motif - HLH, HTH, Zn-finger etc., but i dont know if ERK has any of the them.

But then, really, many so-called transcription factors (like "Estrogen Receptor-alpha") are known to go and sit on the Plasma-membrane when required, inspite of not having h-phobic domains in its structure, and the reason is quite unknown.

Amusing.......and interesting.......the ways of Nature !! :-).

Enjoy!!

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pushing the limit on DNA Origami : Nanoscale capped-box of DNA

Foreword :

A recent paper (May, 2009) in Nature talks about the most recent addition to the art and science of DNA-Origami.

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Introduction to the work:

A multidisciplinary team of 15 researchers have created a DNA 'strong-box' adorned with a lid. This is the newest addition to the spectacular 'art-science' of "DNA origami" - in which oligonucleotides (short strands of nucleic acid) are used to fold longer strands of DNA into complex structures.

The allure to make 3-D DNA nanostructures had been there for quite some time, and the paper successfully attempts just that.

Methodology :

Initially the researchers wrote a computer program that would determine the genetic sequences needed to make their nanoscale 3-D box. The program begins with a digital model of a very long strand of DNA. Then, in accordance with the desired shape, it selects some 250 oligonucleotides that will attach to the DNA and aid its assembly into the desired form.

The team could also make compatible locks to their strong-boxes. A short sequence attached to one side of the box would cause it to unstitch and open in the presence of another short DNA 'key' sequence.

Promising applications :

These could be potentially used as 'cages' to deliver drugs or act as nano-biosensors.

Reference citations :

1. Andersen, E. S. et al. Nature 459, 73–76 (2009).

2. Douglas, S.M., Chou, J. J. & Shih, W. M. Proc. Natl Acad. Sci. USA 104, 6644–6648 (2007).

3. Rothemund, P. W. K. Nature 440, 297–302 (2006).

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"Selfish-Sperm" : Perfect Nemesis of Embryo Development.

.....Got hold of few papers that talk about Sperms which accumulate mutations as men age. Such mutations accumulate over time and offer a survival advantage to the sperm (hence, 'Selfish-Sperm'), but ultimately harm the offspring.

Most studies focus on the female germ line (oocytes), and very few studies have been able to examine directly mutations affecting the male germ line. Using techniques developed over the last seven years, Dr.Wilkie has attempted to answer just that.

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Reference / Source citations :

Science 1 August 2003:
Vol. 301. no. 5633, pp. 643 - 646
Evidence for Selective Advantage of Pathogenic FGFR2 Mutations in the Male Germ Line
Anne Goriely, Gilean A. T. McVean, Maria Röjmyr, Björn Ingemarsson, Andrew O. M. Wilkie*


http://genome.wellcome.ac.uk/doc_WTD020833.html


Science 2003 301: 606–7
There's something curious about paternal-age effects.
Crow JF.

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The listed paper and several reports thereon point out that sperms accumulate mutations over time in several genes, but in some of them, notably, RET, FGFR2 and FGFR3, the rate at which errors are picked up is many times the normal rate of mutation in sperm.

The mutation in FGFR-2, on which the study focusses, causes several severe genetic disorders, including Apert-syndrome, which causes premature fusion of the skull bones and webbing of the fingers and toes. It occurs in around one in every 70,000 live births.

Sayf Dr. Wilkie "In around 80 cases of Apert syndrome and two related disorders, without exception the faulty gene has come from the healthy father."

On the basis of the data, the researchers conclude that the genetic mutation leading to Apert syndrome occurs rarely, but offers cells carrying it some growth advantage. One speculation is that the mutation affects the cell division cycle of the stem cells that give rise to sperm. Instead of producing equal numbers of sperms and stem cells to produce future sperm, they produce excess stem cells. These mutant cells, generating mutant sperm, gradually increase in number relative to its non-mutated, wild-type counterparts.

Largely since the mutation has no ill-effects in the testes, as men age the sperm-cells carrying the mutation become disproportionately common, increasing the likelihood that one will successfully fertilise an egg.

This is where the actual problem lies, as the paternally-contributed mutation severely impairs the ability of FGFR2 to function (which is absolutely critical) during development of the embryo.

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Google adds options to help searchers get to the point

Reference citation :

The Scientific American website.

By Larry Greenemeier in 60-Second Science Blog

( http://www.scientificamerican.com/blog/60-second-science/post.cfm?id=google-adds-options-to-help-searche-2009-05-12 )

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Google has come up with a better idea to customize ones search by adding a feature called "Search Options" in an upgrade its uber-popular search engine.
Now searchers can reorganize the result of a key word search to emphasize particular kinds of links, such as video, audio etc.

"To meet the increasing demand of mobile users, Google also introduced a novelty application called Sky Map for mobile phones running the company's Android operating system that creates a map of the night sky that changes depending upon the user's location.

Google today also introduced something called Rich Snippets, which improves upon the blurbs provided under each link. When searching for a particular restaurant, for example, Rich Snippets will pull up a restaurant review while identifying who wrote it and when it was written."
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An Essay in 'Nature' : "Is Free Will an illusion ?"

Reference citation :

Is free will an illusion?
NATURE|Vol 459|14 May 2009, 164-165

Foreword :

The essay has an interesting debate as to what constitutes Free Will and what doesnt.........and attempts to explain a very long and intriguing philosophical conundrum scientifically...... (?)

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The author Martin Heisenberg is professor emeritus in the department of biology at the University of Würzburg, Germany, and works with fruit-flies.

He initiates the debate emphasising on the dictum that response is independant of stimulus, and unicellular animals move/locomote in ways which are different from that of multicellular organisms where synchrony between parts is needed to maintian a whole, but which could be completely independant of external stimulus, a fact corroborated by the earlier appearance of motor functions as compared to sensory system during developemnt.

On the basis of his experiments on fruit-flies where they (the flies) generate 'new' actions (never known to have been performed earlier by other flies), in the face of clear adversity......the author decides to explore and explain Freedom in scientific terms.

He first defines Freedom in the words of the great German philosopher, Emmanuel Kant, as when "a person acts freely if he does of his own accord what must be done" which implies a non-deterministic, stochastic behaviour, and then goes on to argue on the basis of his belief that "we need not be conscious of our decision-making to be free" as opposed to "freedom as the ability to consciously decide how to act"......

The essay though interesting, leaves quite a bit more explaining before a point could be fully made, especially when a scientific explanation is extended for a largely metaphysical question. Maybe more intuitive experiments on fruit-flies as well as more complex beings ('higher animals') should address this philosophical conundrum clearly.

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