Dr. David A. Zarkower

Reprogramming testis to ovaries: the role of Dmrt1

Matson CK, Murphy MW, Sarver AL, Griswold MD, Bardwell VJ, and David Zarkower. 2011. DMRT1 prevents female reprogramming in the postnatal mammalian testis. Nature. 476(7358):101-4.

Supportive Articles: -N. Henriette Uhlenhaut, et.al and, Robin Lovell-Badge, and Mathias Treier. 2009. Somatic Sex Reprogramming of Adult Ovaries to Testes by FOXL2 Ablation. Cell 139:6 1132.-Susanne Jakob and Robin Lovell-Badge. 2011. Sex determination and the control of Sox9 expression in mammals. FEBS J. 2011; 278(7):1002-9

Question 1

Briefly tell us a bit about yourself, your career path over the years, and specifically what brought you to begin working on mammalian Sex Determination.

Michael Barresi

Question 2

In an adult XY male gonads, the Sry gene forms the initial signal that is needed to inhibit Wnt4 and promote the formation and secretion and up-reguation of Sox9 and therefore Fgf9. In adult XX gonads, what is the initial signal, if there is one, to promote Wnt4 gene expression to support female sex development?

Barbara Blank

Question 3

Do all cells that no longer express Dmrt1 transdifferentiate? And, if so, what regulates what type of cell the “terminally” differentiated cell will transform into (Sertoli cell, Theca cell, or oocytes)? Can any cell no longer expressing Dmrt1 transform into a Sertoli Cell, or does it have to start out as a specific type of “terminally” differentiated cell?

Clare Landefeld

Question 4

When discussing the feminized male germ cells that express MATER and ZP2, it is stated that the nucleus morphology had changed to resemble that of an oocyte. Is it known how old the spermatozoa cells were? Do mature sperm exhibit the flexibility to make such a drastic change or only early stages of spermatozoans?

Emily Frontiere

Question 5

“Loss of Dmrt1 in fetal Sertoli cells (SCDmrt1KO) but not in fetal germ cells (GCDmrt1KO) induced FOXL2 expression (Fig. 1d–f). … This result indicates that both somatic cells and germ cells are feminized in mutant gonads.” Is the latter result surprising, given the former? This would suggest that even without the promotion of female specific signal, in the absence of Dmrt1 (thus the absence of Sox9 and Sox8) the germ cells default to the female program. This is, of course, not unreasonable but what is the significance of induced FOXL2 expression in somatic but not germ cells? Is FOXL2 expression required in these somatic cells in order for Sertoli cells to transdifferentiate? Are Sertoli/GC interactions required to “feminize” GCs?

Brittany Edens

Question 6

You also talked about how the germ cells were “arrested” at the meiotic prophase when there was a loss of DMRT1 (at p28). What do you propose is happening at that point that allows the germ cells to overcome loss of DMRT1 and remain to inhibit FOXL2 expression?

Bushra Anis

Question 7

It’s been suggested that Nr5a2 is the antagonistic mechanism of FOXL2 to turn off expression of DMRT1. How was this conclusion made? What is the antagonistic mechanism of DMRT1 to turn off expression of FOXL2? (Matson, DMRT1 prevents female reprogramming)

Chelsea Moriarty

Question 8

When you deleted the DMRT1 from the…

Student’s Name

Question 9

Can you share with us examples of individuals you have encountered who have reached a dead end in terms of treatment and prognosis? And exactly which of the current developments in stem cell research you think may help them?

Dan McCune

Question 10

There is discussion about there being a biological determinant in homosexuality. Do you believe that it is possible that a Dmrt1 could be involved or that Fgf9 and Wnt4 are not completely inhibiting each other?

Robyn Cyr

Question 11

What are your licensed candidates?

Michael Barresi

Question 12

Are DMRT1 levels different in individuals that are XXY, which have both female and male parts? Do both DMRT1 and Foxl2 work together in such individuals?

Gianna Teague

Question 13

When you think about the field of sex determination, what do you think are the most pressing questions and how is your lab contributing to that?

Michael Barresi