From viruses to people, observed a perceptive geneticist, "everythingthat lives is merely DNA's way of making more DNA."
In humans, this drive to survive exists on two levels _ individual andspecies.
From a newborn's first gulp to an end-of-life death rattle, the need tobreathe impels the demand for air. Without it, life fades out in amatter of minutes.
Without water, survival is measured in days; without food, in weeks.
Those are the basic instincts that keep every individual alive. Whatkeeps the species going, from one generation to the next, is the sexualcompulsion, piston of procreation.
Until recent times, when a couple failed to conceive a child, all blamefell on the female, denounced as "barren." Nowadays, of course, thatreproach is unisex, with infertility recognized in both genders.
By recent statistics, as many as 8.5 percent of married couples in theU.S. cannot bear children. "In 40 percent of these, the male partner isinfertile," reproductive endocrinologist Janet Hall told BioWorldToday.
"Of the female 60 percent, 20 to 25 percent are due to tubal[anatomical] difficulties, and a similar proportion to hormonalproblems of ovulation" said Hall, who is at Massachusetts GeneralHospital in Boston.
By and large, the reasons for infertility are either anatomical orhormonal. And among the latter, one of the rarer causes is adeficiency in the woman of luteinizing hormone (LH).
The condition is readily diagnosable, said molecular endocrinologistJeffrey Millbrandt, of Washington University School of Medicine, inSt. Louis. "You can measure LH levels in a blood sample at anyhospital," he told BioWorld Today, "but there is no good therapy forLH deficiency."
He explained why: "LH levels are modulated during the menstrualcycle, marked by the monthly `LH surge' that releases the ovum fromthe follicle in the ovary. It would be very difficult to recapitulate thatvariability by injecting exogenous hormone, for example."
Millbrandt is senior author of a paper in today's Science titled:"Luteinizing hormone deficiency and female infertility in micelacking the transcription factor NGFI-A."
NGFI-A (nerve growth factor-induced) promotes the synthesis ofluteinizing hormone, a critical component in the gonadal cascade ofconception. It belongs to a family of DNA transcription factorsknown as immediate-early genes. "That means," Millbrandt said,"that they are rapidly induced _ within minutes _ by variousextracellular stimuli in the environment.
Honchoing Ups And Downs Of LH
"That would make sense," he pointed out. "You need something likethat to give a cyclical expression pattern of LH. Something has got tobe changing to show a rhythmic pattern of hormonal synthesis andrelease."
Originally, he and his colleagues studied this family of transcriptionfactors "for their implication in a variety of cellular processes, fromtransformation in cancer to apoptosis to differentiation. That's howwe initially discovered these genes many years ago."
Then, when the team began to make knockout animals to study theirbiological relevance, they found, "to our surprise, that these proteinshad little role in the nervous system, where they were initially thoughtto be important, and we didn't see any increased cancer levels in ourknockout animals.
"What we did find," he recalled, "was this dramatic femaleinfertility."
Their paper in Science reports the fate of knockout mice in whichthey had generated a targeted disruption of the immediate-earlyNGFI-A gene. This rendered the animals unable to secrete luteinizinghormone, which normally proceeds from its synthesis in the pituitarygland down to the ovaries and testes.
Test matings of the engineered progeny revealed that females lackingthe NGFI-A gene were infertile, whereas males proved fertile. Thiscorrelated with an absence of LH synthesis in females, but onlypartial deficiency of the hormone in males. The team traced this maledowner to atrophy of the Leydig cells in the testes. These interstitialcells are a primary target of LH.
However, their paper reported, "the amount of LH, though decreasedin NGFI-A-/- males, was adequate for spermatogenesis and malefertility."
Since completing these female-infertility experiments late last year,Millbrandt and his co-authors have determined that another memberof the transcription factor family, which they call NGFI-C, has anopposite effect; it plays a role in making male mice infertile.
"We have another paper we're getting ready to submit now," he said."It looks like it's the converse. The males are infertile, but thefemales quite fertile. It's an interesting juxtaposition of the two,because the proteins themselves are very nearly identical instructure."
Double-Cross The Knockouts
He continued: "Believe it or not, we're doing some crosses betweenthe two knockout animals. Crossing a mouse with male infertilitywith an infertile female, we get double knockouts.
"This double mating," he observed, "takes something like eightmonths to accomplish. We're excited to see what those mice aregoing to look like."
He now is gearing up for the next phase in this research project,"beginning to gather some families and some patients, and looking atmutations in these two genes, one for male infertility, the other forfemale infertility."
Millbrandt concluded: "To talk about familial infertility sounds likean oxymoron. The reason it wouldn't be totally nonsensical is that theopposite sex is fertile, even though they have these mutations. So itcould be carried on to the germline."
Biochemist William Miller at North Carolina State University inRaleigh is acquainted with Millbrandt's work. His own field isregulation of reproductive hormones in the pituitary.
"There's a larger issue here," Miller told BioWorld Today. "Peoplehave started to measure luteinizing hormone and follicle-stimulatinghormone in the circulation. And that was a major breakthrough interms of understanding how the ovary and the testis were regulated.LH and FSH are the direct regulators of the reproductive system.
"And the NGFI-A," he went on, "is a regulator of one of thoseregulators, basically, of LH. In that sense," Miller concluded, "thatopens up an entirely new field of reproductive biology. It's reallylooking at the regulators of the regulators." n
-- David N. Leff Science Editor >TX
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