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NEUROBIOLOGY 'Baby Bells' Carry Molecular Dialogue Critical to Fertility
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Much like a complex society, the human body
relies on different communication systems, such as nerve transmission,
hormones, and gap junctions.
Gap junctions? While the basic function of the
former two systems are familiar even to the casual observer, gap
junctions for decades have not revealed their raison d'être.
Consequently, these ubiquitous channels linking neighboring cells
have long remained obscure.
Not any longer. In one of the first glimpses
at what gap junctions actually do--and how they may cause disease—researchers
led by David Paul, associate professor of neurobiology at HMS, demonstrate
that they are crucial to female fertility, at least in mice. In
the February 6 Nature, the scientists report that mice engineered
to lack the gene for one such channel never produce mature eggs
because the nurturing cells in the ovarian follicles cannot communicate
properly with the oocytes they shelter.
Filling in the Gaps
Co-author Daniel Goodenough, Takeda Professor of Cell Biology
at HMS, first isolated gap junctions biochemically and named their
protein subunits connexins. These proteins assemble into tiny tubes
in the cell membrane, connect to a similar tube in a neighbor's
membrane, and so create a pore through which small molecules can
pass from cell to cell.
Gap junctions are everywhere, occurring in all
multicellular organisms from sponges on up. In mammals, cells of
almost every tissue make them at some point during development.
Researchers suspect that gap junctions are the
Baby Bells of the body's communication systems, serving as local
distributors of information coming in via long-distance carriers
like hormones. In the ovaries, for example, hormones convey messages
from the brain, but not all ovarian cells have the necessary receptors.
Those that do may use gap junctions to forward the information to
their neighbors, says Paul.
At the same time, gap junctions are thought to
create private communication networks. If only certain cells are
supposed to hear an incoming message, gap junctions linking only
the targeted recipients would enable limited distribution, says
first author Alexander Simon, a research fellow in Paul's lab.
But solid experimental proof for these scenarios
is missing, in part because it is difficult to identify individual
signals passing through the pores. Indeed, Paul says a 30-year-old
hypothesis, namely that gap junctions somehow control the development
and size of an organism, still awaits testing. "That is what we
hoped the knockout mice would do--give us better answers about what
the specific functions are," says Paul.
The mice obliged. Females unable to form certain
types of gap junctions—those made from connexin37—turned
out infertile because communication between the oocyte and its surrounding
cells is jammed. During each normal menstrual cycle, an immature
follicle, consisting of an oocyte embedded in a single layer of
nurturing cells, begins to mature. Spurred by hormones, the oocyte
grows larger, and the nurturing cells divide to form a multilayered
coat. After ovulation, the remaining follicle turns into the corpus
luteum, a gland that secretes progesterone to support a possible
pregnancy.
In the knockout mice all this goes awry. The
follicle never reaches its proper size because the nurturing cells
do not divide enough. The egg never matures, either, and ultimately
dies. In another instance of poor communication between nurturing
cells and oocyte, the follicle behaves as if nothing is amiss, proceeding
to become a corpus luteum even though the egg has not ovulated.
Paul suspects that a back-and-forth of different
signals coordinates the sequential steps that eventually yield a
mature egg, but the nature of these signals is still mysterious.
Moreover, gap junctions are not the only means of communication
at play in the follicle's development. Growth factors and hormones
are also known to be involved, and sorting out the respective roles
of each will require more research, Simon adds.
The finding may have implications for female
infertility in humans, possibly helping to explain the pathophysiology
of certain cases. In some women suffering from a syndrome called
spontaneous premature ovarian failure, the follicles turn into corpora
lutea before the oocyte is ready, similar to what happens in the
knockout mice. "That rings a bell," says Paul, but he adds that
more research is needed to explore this link, and systematic studies
of the underlying causes of human infertility are difficult to carry
out.
As often happens in science, Paul and Simon started
this work expecting to study something completely different. The
researchers had reason to believe that depriving mice of connexin37
would cause major defects in the cardiovascular system. It didn't.
"Doing knockouts is like riding a wild horse," Paul says. "You never
know where you'll get dumped off."
—Gabrielle Strobel