University of Minnesota
November 2, 2010
David Zarkower and his colleagues have made fundamental discoveries in sex determination.
How cells destined to become sperm make a critical decision
By Deane Morrison
The stereotype of a commitment-shy male may not play out very often in men, but their sperm are a different story.
Cells that give rise to eggs and sperm—germ cells—must undergo a special form of cell division that commits them to their fates. But future sperm put it off much longer than future eggs do.
That much was well known. Now, University of Minnesota researchers have discovered how they manage it.
In adult males, a gene blocks the signal to switch to the radically different mode of division. This allows precursors of sperm cells to vastly increase their numbers and, thus, the numbers of sperm, which cannot divide and multiply.
"It belongs to the only gene family found to control sex determination in a wide variety of animal species," says David Zarkower, professor of genetics, cell biology, and development, who led the study.
The work may someday help boost male fertility or reduce it—i.e., in a male Pill. It is published in Developmental Cell.
The great divide
Normal humans have 23 pairs of chromosomes, each pair consisting of one chromosome inherited from the mother and the other from the father. In normal cell division (mitosis), a cell splits into two daughter cells, each of which gets a pair of each chromosome, including the sex chromosomes: X-X in females and X-Y in males.
But germ cells in a late stage of development must divide so that daughter cells get only one member of each chromosomal pair. In the case of the X-Y chromosomal pair in males, it means that the X (from a man's mother) and Y (from his father) end up in different sperm cells (see diagram). This form of cell division, called meiosis, ensures that sperm and egg each have half the usual number of chromosomes, which is restored upon fertilization.
In this greatly simplified chart, the X and Y chromosomes of the male illustrate how the two forms of cell division distribute the members of a chromosomal pair in radically different fashion. In both rows, the first figure shows a cell after its chromosomes have duplicated themselves, a necessary condition for either form of cell division. Graphic by Ranja Sem
In adult males, germ cells go through multiple rounds of mitosis, generating large numbers of new cells. With every round, the cells mature, until they are ready to undergo meiosis and turn into sperm. At any given time, a testis contains germ cells performing meiosis while neighboring cells are performing mitosis, a fundamentally different process.
"It's been an open question how males control which cells perform mitosis and which perform meiosis when they are side by side," Zarkower notes.
A master switch
A clue came when Zarkower and his U of M colleagues—postdoctoral fellow Clinton Matson, research associate Mark Murphy, and Associate Professor Vivian Bardwell—noticed that a gene they had studied for a long time, called DMRT1, was active in mouse germ cells dividing by mitosis but was "silenced" in cells after they had entered meiosis.
So they did the logical thing: Using pinpoint genetic manipulation, they disabled the DMRT1 gene in just those germ cells that were still dividing by mitosis, not even close to entering meiosis yet.
Zarkower credits Matson with figuring out what happened when DMRT1 was disabled. It turned out that by switching off DMRT1, they made the germ cells enter meiosis precociously.
Killing the messenger
Further experiments showed that among DMRT1's many effects, it kept the male germ cells from responding to retinoic acid, a form of vitamin A that acts as a messenger by signaling the cells to begin meiosis. Retinoic acid exerts its effect by activating another gene, and DMRT1 blocked both the functioning of the other gene and its activation by retinoic acid.
So what silences DMRT1 in male germ cells that are ready to enter meiosis?
"We're working on that," answers Zarkower.
He muses that someday, the ability to turn DMRT1 on and off may help, for example, a man facing chemotherapy, which often destroys male germ cells. Before treatment, doctors could remove and culture a sample of germ cells, keeping the gene turned on until they have generated lots of sperm cell precursors that could be transplanted back after chemotherapy.
And a pill that interfered specifically with the functioning of DMRT1 in germ cells could greatly reduce male fertility.
Studying the molecular basis of sexual development never loses its appeal, Zarkower says.
"It's fascinating because the two sexes look the same as embryos, yet they grow up as adults having many differences that are essential to maintaining the species," he says.
Published in 2010