23 DECEMBER 2016 • VOL 354 ISSUE 6319 1533 SCIENCE sciencemag.org
By Yung Chih Lai and Cheng-Ming Chuong
The integument forms the interface between an organism and its envi- ronment. It serves diverse functions uch as communication, endothermy, defense, and flight. During vertebrate volution, various integumentary organs, including hairs, feathers, glands, and
teeth, have evolved to help animals adapt
to evolving environmental changes (1) (see
the first figure). These ectodermal organs
form through epithelial-dermal interactions. Classic tissue recombination experiments have demonstrated that the dermis
specifies the organ phenotypes within a
developmental time window (2). Yet the
underlying mechanisms remain unclear. On
page 1551 of this issue, Lu et al. (3) reveal
the specific molecular mechanism whereby
an epithelial placode can be guided to form
either a hair follicle for its architecture or a
sweat gland for its secretory function.
It is instructive to consider nature’s way
of integumentary organ design—the “tao”
of this process. Periodic patterning has
evolved as an effective integument organization principle (4) (see the second figure).
This is achieved by partitioning the integument into numerous elements (e.g., on average, >30,000 hair follicles in a mouse).
Each element contains its own stem cells
and undergoes cyclic regeneration, thus allowing it to regenerate after wear or injury.
Further, each element can be independently
controlled by modulating the stem cells to
form different appendage types under different physiological or hormone conditions
(e.g., rooster or hen feathers) and in different body regions (e.g., downy feathers become flight, tail, or contour feathers) (5).
Collectively, this is an effective way to build
complex yet adaptable integuments.
Stem cells enable a hair or feather follicle
to undergo cyclic renewal, and each cycle
is composed of growing and resting phases.
The length of the hair filament is a function
of the duration of the growth phase, which
is regulated by fibroblast growth factor 5
(FGF5) (6). This mechanism enables closely
related species to quickly adapt to cold or
warm environments. Yet this is a quantitative change. What about qualitative changes
that alter organ functions?
Lu et al. demonstrate how hair follicle
and sweat gland fates can be switched. In
mice, sweat glands are confined to the paw
regions, and the dorsal skin can only form
hair follicles. Transciptome profiling suggested distinctly different amounts of several
bone morphogenetic proteins (BMPs), WNT
proteins, and FGF proteins in regions producing hair follicles versus those producing
sweat glands. Previous experiments already
showed that suppressing BMP signaling
could convert sweat glands in mouse paws
into hairs (7). Here, the authors used inducible and tissue-specific transgenic mouse and
lentivirus technology to perturb morphogen
signaling levels at different times and in different locations. Suppressing BMP signaling
caused placodes in the ventral foot to switch
fates to form hairs, whereas increasing BMP
signaling guided placodes on the dorsal skin
to switch fates toward sweat glands.
BMP works in a circuit with WNT, FGF,
and sonic hedgehog (SHH), and the authors
show that BMP signaling in the dermis
differentially elevates WNT expression to
higher levels in the ventral foot than in the
dorsal skin. In WNT-responsive dermal cells,
the expression of several FGFs are highly
up-regulated in the ventral foot relative to
the dorsal skin. Ectopic FGF18 increased
expression of the glandular marker K18, decreased expression of the hair follicle marker
K17, and caused hair loss in the dorsal skin.
Furthermore, ectopic expression of FGF18,
BMP4, and BMP5 in the dorsal epidermis induced Engrailed-1 expression in the ventral
foot but not in the dorsal epithelium, and
caused a more glandular fate. SHH is highly
expressed in the hair relative to sweat gland
placodes. Increasing SHH signaling in the
ventral foot epidermis induced or repressed
the expression of hair-specific markers and
gland-specific markers, respectively. Thus,
Lu et al. identify a molecular circuit in the
ventral foot that works synergistically to
form sweat glands.
One of the critical events in the evolu-
tion of early humans is the expansion of
Integrative Stem Cell Center, China Medical University Hospital,
China Medical University, Taichung, Taiwan; Department of
Pathology, Keck School of Medicine, University of Southern
California, Los Angeles, CA, USA; and Research Center for
Developmental Biology and Regenerative Medicine, National
Taiwan University, Taipei, Taiwan. Email: firstname.lastname@example.org
EVOLUTION AND DEVELOPMENT
The “tao” of integuments
Hair follicle and sweat gland fates can be switched by
morphogens at specific skin regions or developmental stages
For filter-feeding animals such as baleen whales,
modification of the integument blocks tooth
formation in the mouth cavity to permit hair bundles
to form instead.
Evo-devo of integuments
A prototype animal with diverse forms of