March 20, 2003
Researchers Identify Signals that Cause Hair Follicles to Sprout
The delicate interplay of two chemical signals coaxes stem cells
into becoming hair follicles, according to new research by scientists
at the Howard Hughes Medical Institute at The Rockefeller
University.
The research has implications for understanding hair growth and
hair-follicle development, and it may also help explain how diverse
structures, such as teeth and lungs, are formed or how some forms of
skin cancer develop.
“These studies raise the possibility that drugs to activate these natural factors could promote hair follicle growth.”
Elaine Fuchs
In an article published in the March 20, 2003, issue of the journal
Nature, researchers led by HHMI investigator Elaine
Fuchs at The Rockefeller University discovered that two signaling
molecules, Wnt and noggin, influence immature stem cells to begin the
process of forming hair follicles.
According to Fuchs, studies in her laboratory and others revealed
the possible involvement of Wnt and other proteins in the signal
transduction pathways that trigger hair-follicle formation. In previous
studies, Fuchs and her colleagues produced an abnormally furry mouse
with high numbers of hair follicles by genetically altering the animals
to produce a stabilized form of a protein called beta-catenin. They
also knew that beta-catenin was affected by the Wnt protein. Among the
other proteins they implicated in hair-follicle formation was
“lymphoid enhancer-binding factor 1” (Lef1), which is part
of a transcription complex that controls gene activity.
“One of the aspects that scientists have been trying to
understand in development of hair follicles, tooth buds, mammary glands
and lungs is how these various transduction pathways work
together,” said Fuchs.
The researchers also had evidence that a second mechanism, involving
a signaling molecule called bone morphogenetic protein (BMP), is also
required for creating epithelial buds — pockets in the skin that are
the precursors of hair follicles.
Through experiments using mouse skin cell cultures and skin from
embryonic mice with various genes knocked out, the researchers showed
that Wnt stabilizes beta-catenin and increases its concentrations in
the target stem cell. In concert, noggin inhibits BMP, leading to
production of Lef1. In addition, beta-catenin activates Lef1, which in
turn downregulates the gene for the protein E-cadherin. E-cadherin is
important in cell adhesion. Reduced levels of E-cadherin trigger
reduction of cell adhesion structures, called adherens junctions, a
process important in initiating formation of the epithelial bud.
“Unlike the earlier experiments, in which we genetically
altered the animals, in these experiments, we have altered the stem
cells using external factors that the skin normally makes,” said
Fuchs. “And in doing so, we have been able to elicit the initial
responses that occur in the development of the hair follicles.
“The other important advance is that we now understand how Wnt
and inhibition of the BMP signaling pathway work together by regulating
this transcription factor complex. The discovery provides insights into
how signals simultaneously operate together to activate a particular
event, in this case, a transcription factor.”
The findings also hint at how different kinds of cells interact to
produce epithelial buds, said Fuchs. “These signals are probably
coming from different cells within the skin,” said Fuchs.
“The Wnt pathway is likely coming from adjacent epithelial cells,
and the noggin pathway from mesenchymal cells. But, they're working
together on a single skin stem cell to produce an activated
transcription factor.” Mesenchymal cells are unspecialized cells
in embryonic skin from which the dermis will develop.
“How these signal transduction pathways are merging was not
understood before, and we now have a much clearer picture of why they
need to be there at the same place and time in the developing
skin,” said Fuchs.
According to Fuchs, the findings also have implications for
understanding how some forms of skin cancer arise. “Our studies
suggest that too much or too little E-cadherin can be a bad
thing,” she said. “Just the right amount of E-cadherin is
needed to loosen the adhesion of the stem cells in the epithelium, to
allow them to remodel and grow downward to form the hair follicle.
What's interesting is researchers have found reduced levels of adherens
junctions in squamous cell carcinomas of the skin. So, we think our
findings may be relevant, because they suggest that if the E-cadherin
levels are reduced too much, there can still be a downgrowth of the
skin, but one that's deregulated. The early stages of hair follicle
morphogenesis resemble, to some extent, what happens in the development
of a tumor mass.”
The studies in Fuchs's laboratory seek to understand fundamental
aspects of hair follicle formation, which could eventually suggest new
ways to restore or inhibit hair growth. “These studies raise the
possibility that drugs to activate these natural factors could promote
hair follicle growth in wanted places, and inhibitory drugs could
prevent hair growth in unwanted places,” she said.
Among the next steps in the research, said Fuchs, is to understand
how the newly discovered machinery involved in epithelial bud formation
links to the later steps that causes mature hair-producing follicles to
sprout.
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