(Philadelphia,
PA) - The difference between a group of 'blank' stem
cells and a developing fetus is a complex series of
biochemical reactions that transform stem cells into
specific types of body tissue. In this week's issue
of Science, researchers at the University of Pennsylvania
Medical Center report how the enzyme QSulf1 fits into
this biochemical clockwork, helping cells respond to
one of the many chemical signals that surround them.
"It is a problem at the heart of basic biology
- how one cell becomes muscle while an adjacent cell
turns to bone," said Charles P. Emerson, PhD, Joseph
P. Leidy Professor of Biology and Chair of Penn's Department
of Cell and Developmental Biology. "For all we
know of stem cells and the molecules involved in cell
differentiation, we know very little about how these
processes physically work."
As an embryo develops, different molecular signals instruct
cells to produce proteins that will transform the cell
into a particular tissue type, such as bone or muscle.
QSulf1 functions in progenitor cells, slightly more
advanced forms of stem cells that have fewer potential
career paths.
According to the researchers, QSulf1 represents a new
class of enzymes whose main function is to modify an
important signaling co-factor, called heparan sulfate
proteoglycans (HSPG). It is a small yet important step
in a chain of reactions involved in allowing a cell
to respond to a specific molecular signal, Wnt, and
transforming the cell into muscle, instead of skin or
bone.
"It is not enough to know what proteins are involved
in embryonic development, we must understand how they
work in order to eventually understand how to fix them
when they fail," said Emerson.
Based on their findings, the researchers propose that
Qsulf1 is released onto the surface
of specific embryonic cells where it snips off a specific
sulfur-containing chemical group (called a sulfate group)
that projects from a specific part of the HSPG molecule.
As a result, Wnt signaling molecules, which are bound
to HSPGs on surface of cells, are released, allowing
Wnts to activate regulatory genes that give career instructions.
In this study, the researchers show that QSulf1 allows
embryonic cells to express a muscle master regulatory
gene called MyoD, which then instructs these cells to
become muscle progenitor cells instead of a skin or
bone progenitor cells.
These findings are not only of interest to researchers
in the fields of cell biology and developmental diseases,
but also highlights how much remains to be learned about
complex workings of the developing embryo.
Emerson and his colleagues first identified QSulf1 as
they studied bird embryos for genes whose expression
is controlled by Shh, a molecule of known importance
in developmental processes. Interestingly, the QSulf1
gene remains essentially unchanged within the genomes
of worms, flies, mice, and humans.
"Evolution has seen fit to keep this protein around
a long time," said Emerson. "What we see is
the emerging picture of a fundamental player in the
embryonic development of many types of organisms."
Understanding the mechanisms of stem cell specification
will unlock potential new technologies for the repair
of organs and tissues damaged by disease and trauma.
"If we are going to use stem cells to treat developmental
disorders, there is still a great deal that basic biology
must tell us," said Emerson. "We are only
now beginning to understand how the body builds tissues."
The research was funded by the National Institutes of
Health and the Royal Society and Welcome Trust.
Other Penn scientists who participated in the study
are Marcus K. Gustafsson; Weitao Sun; Xingbin Ai, PhD,
and David M. Standiford, PhD. Gurtej K. Dhoot, PhD,
of the Royal Veterinary College, University of London,
also collaborated in the research.
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