De Novo Formation of Oocytes

I had read a couple of reviews about all the recent ruckus in this field. I was going to write something ... but I only have so many hours in a day. Now the newest paper has now surfaced. Pure Pedantry has the details. And so I guess I'll end up writing about it anyway.

So how did this all start? Because I'm lazy (and frankly have a ton of work to do) here is what I posted on Pure Pedantry:

...the big papers came out a couple of months ago. In the first paper a bone marrow from a GFP expressing mouse was transplanted into a native mouse. The native mouse developed GFP expressing oocytes (after ovary dissection). In paper #2 a second group fused the blood systems of a GFP mouse with that of a native mouse but FAILED to see any ovulated eggs expressing GFP in the native mouse (or native eggs in the GFP mouse). So the field is in turmoil.

The newest manuscript gives support to the de novo model, but in itself is not the bulk of the evidence for this theory.

Actually Tilly's group published two papers, one in '04, one last year (not a couple of months ago). And some more ... both competing groups are here at Harvard Medical School. It's a rumble in the quad!

In the new paper, here's what they found:

Day 1 ovaries contained 7924±1564 (S.E.M.) oocytes or primordial follicles, declining on day 7 to 1987±203, with 200-800 oocytes ejected from individual ovaries on that day and day 12. Discarded oocytes and those subjacent to the surface epithelium were GCNA-positive indicating their incomplete meiotic maturation. From day 7 to 100 mean numbers of primordial follicles per ovary were not significantly depleted but declined at 200 days to 254±71. Mean numbers of all healthy follicles per ovary were not significantly different from day 7 to 100 (range 2332±349-3007±322).

That's pretty good (bolded part).

An article in the Scientist (on the contra de novo paper): No mature eggs from bone marrow

Another article in Nature on the big controversy:

Experiments published this week fuel the controversy about whether mammals are born with a fixed pool of egg cells or can make fresh eggs. The issue is divisive not just because it challenges 50 years of scientific dogma. If women could generate new eggs it would have huge implications for fertility treatments, menopause, and even cell-based therapies.

Last year, a controversial paper1 by Jonathan Tilly and his colleagues at Harvard Medical School proposed that egg cells can arise from bone marrow and other circulating cells2. But Amy Wagers, also at Harvard Medical School, and her colleagues now report that this is not the case, at least for ovulated eggs3. Some critics think the new study proves Tilly's work was flawed, but Tilly and other experts say that some aspects of egg renewal remain open questions.

Tilly's bone-marrow study drew loud criticism from others in the field, both in the press and the literature. But without experimental testing of the ideas, much of the disapproval rang hollow. Now, Wagers and her colleagues have addressed the bone-marrow hypothesis. "This is a pretty powerful denial of the idea that new eggs form and contribute to fertility," says co-author Roger Gosden of Cornell University's Weill Medical College in New York.

And in the same article, there is a hint about the paper reported in Pure Pedantry:

For now, regeneration in mice "is still an open issue", says Jeff Kerr of Monash University in Clayton, Australia. At least, "until someone comes up with some killer experiments to prove that bone marrow, or the ovary, is, or is not, the source of new oocytes". Kerr, Jock Findlay and colleagues add a piece of support for regeneration in research to be published online later this month4.

They found that the mouse strain used by Tilly and Wagers maintains a steady pool of oocyte numbers from before puberty into middle age, rather than the number declining with age as the dogma holds. Whether that is due to regeneration is unknown, says Kerr, but such a possibility would not be "completely out of left field".

So what is it? Perhaps BOTH.

Even Gosden, one of Tilly's more vocal critics, leaves the door open to the possibility of regenerative, albeit dormant, egg stem cells. "Our work suggests they do not contribute to new ovulations, but perhaps under special circumstances they could be brought back to life [in the lab dish]," he says. "I think the Tilly group might be right to some extent on that one."

Pro de novo papers:
Johnson J, Canning J, Kaneko T, Pru JK, Tilly JL.
Germline stem cells and follicular renewal in the postnatal mammalian ovary.
Nature (2004) 428:145-50

Johnson J, Bagley J, Skaznik-Wikiel M, Lee HJ, Adams GB, Niikura Y, Tschudy KS, Tilly JC, Cortes ML, Forkert R, Spitzer T, Iacomini J, Scadden DT, Tilly JL.
Oocyte generation in adult mammalian ovaries by putative germ cells in bone marrow and peripheral blood.
Cell (2005) 122:303-15.

Kerr JB, Duckett R, Myers M, Britt KL, Mladenovska T, Findlay JK.
Quantification of healthy follicles in the neonatal and adult mouse ovary: evidence for maintenance of primordial follicle supply
Reproduction (2006) 132:95-109

Contra de novo paper:
Eggan K, Jurga S, Gosden R, Min IM, Wagers AJ
Ovulated oocytes in adult mice derive from non-circulating germ cells.
Nature (2006) 441:1109-14

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