Howard Hughes Medical Institute, Date: 2003-03-20
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
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.
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
"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
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
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.
The original news release can be found