RESEARCH ARTICLE SUMMARY
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CELL FATE DECISIONS
Spatiotemporal antagonism in
mesenchymal-epithelial signaling in
sweat versus hair fate decision
Catherine P. Lu, Lisa Polak, Brice E. Keyes, Elaine Fuchs*
INTRODUCTION: Across the vertebrate kingdom, epithelial appendages—including mammary, sweat, and salivary glands; hair follicles
(HFs); teeth; scales; and feathers—begin to form
during embryogenesis when WNT signaling instructs progenitors within the epithelial sheet to
organize into morphologically similar placodes.
Most animals restrict these epidermal appendages to distinct body regions. This paradigm
shifted late in mammalian evolution; the dual presence of HFs
and eccrine sweat glands (SwGs)
in the skin is a recent acquisition of primates.
Classical tissue recombination experiments from the 1960s
revealed that mesenchyme directs the divergent downstream
events that determine appendage specification and patterning. Relatively little is known
about the specific spatiotemporal
cross-talk and molecular mechanisms that underlie epithelial
fate specification in response to
mesenchymal signals. Elucidating the epithelial-mesenchymal
cross-talk involved in regional
skin appendage specification is
integral to understanding how
humans have adjusted these
mechanisms to endow them
with a greater capacity than
that of their hairy cousins to
live in diverse environments.
RATIONALE: The acquisition of SwGs and
their importance in thermoregulation and water
balance are underscored by human patients who
suffer from the life-threatening condition of
lacking SwGs, either from loss in severe burns
or from genetic disorders. Conversely, a gain-of-function variant that elevates SwG numbers
has been expanding among the Southeast Asian
population, where excessive SwGs are desirable.
By elucidating the underlying mechanisms that
distinguish humans from other mammals in
their ability to make both glands and follicles
over their body skin, our findings could pave
the way for future therapeutic advances in skin
regeneration with dual appendages.
RESULTS: Using mouse as a model, we ex-
plored the differences between the back skin
mesenchyme, which is only competent to spec-
ify HFs, and the foot skin mesenchyme, which
can only make SwGs. Using genome-wide analy-
ses and functional studies, we discovered that
just after the formation of morphologically sim-
ilar epidermal buds, appendage choice is de-
termined through regional skin differences in
mesenchymal expression of bone morphogenetic
proteins (BMPs). Probing into mechanisms, we
showed that when BMPs are elevated in foot skin
mesenchyme, BMP signaling is activated in both
dermis and epidermis. This triggers a cascade of
downstream signaling events. WNT signaling is
elevated in the dermis and reduced in the epider-
mis. Mesenchymal fibroblast growth factors (FGFs)
appear and affect the overlying epithelium.
These converging pathways lead to suppression
of sonic hedgehog (SHH) in the epithelium.
This BMP:SHH antagonism within the ep-
ithelial bud specifies SwG fate and prevents
HF fate. Moreover, by manipulating gene ex-
pression in vivo at specific developmental
stages, we demonstrated that this signaling
circuitry acts only within a narrow window
of time during mouse em-
bryogenesis. Thus, when
SHH is ectopically expres-
sed in foot skin epitheli-
um during the permissive
phase, HF-specific gene ex-
pression is up-regulated
in the epithelial bud, whereas SHH signaling in
the mesenchyme stimulates expression of BMP
antagonists, further suppressing local BMP
signaling and blocking SwG fate. In human
skins, this antagonistic interplay of BMP:SHH
signaling occurs temporally, in addition to
spatially. The first bud waves are specified as
HFs, and then a tipping in the balance of
BMP:SHH signaling results in the last waves
of buds becoming SwGs.
CONCLUSION: Our findings revealed a differential impact of
BMP signaling on appendage fate
specification that has ancient roots
and occurs repeatedly throughout
vertebrate evolution. In the evolutionary developmental biology view
of BMP signaling and fate specification of integument, chicken scales
and mammalian SwGs require BMP
signaling to specify their fate, whereas
feathers and HFs must suppress it.
Our discovery of BMP-SHH antagonism in bud fate choice uncovered
additional evolutionary parallels,
this time between two even more
distantly related epidermal appendages, the mammalian SwG and
the fly wing. Our studies provide
new insights into how elevated
mesenchymal BMP signaling triggers a self-perpetuating molecular
cascade that culminates in silencing of SHH signaling to suppress
one appendage fate and specify
another. In most mammals, the BMP:SHH
antagonism is regulated spatially. Humans,
however, have evolved to regulate it temporally, endowing them with greater ability
to run marathons and survive in extreme
climates.▪
BMP-SHH antagonism specifies SwG versus HF fate. To specify SwGs,
mesenchymal-derived BMPs and FGFs signal to epithelial buds and suppress
epithelially derived SHH production. Conversely, hair follicles are specified
when mesenchymal BMP signaling is inhibited, permitting SHH production.
This antagonism is spatially restricted in most mammals but temporally
regulated in humans, permitting the presence of HFs (pink), SwGs (purple),
or both HFs and SwGs (pink with purple droplet) throughout our body skin.
The list of author affiliations is available in the full article online.
*Corresponding author. Email: fuchslb@rockefeller.edu
Cite this article as C. P. Lu et al., Science 354, aah6102 (2016).
DOI: 10.1126/science.aah6102
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at http://dx.doi.
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science.aah6102
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