A miR Image of Stem Cells and Their Lineages - Current Topics in Developmental Biology - page 177

noncanonical miRs can bypass the requirement of Drosha/Dgcr8 ( Babiarz
et al ., 2008 ). In all cases, the liberated hairpin is then exported by Xpo5 ( Lund
et al ., 2004; Yi et al ., 2003 ) to the cytoplasm where it undergoes a second
cleavage by Dicer ( Hutvagner et al ., 2001 ). After the processing by Dicer, one
strand of the double-stranded duplex is selectively incorporated into an RISC
composed of one of the four Argonaute proteins and their associated cofactors
( Schwarz et al ., 2003 ). Given the nearly universal mechanism for miR biogen-
esis, it is possible to explore the global function of the miR pathway by
genetically deleting either the Drosha-Dgcr8 complex or the Dicer.
4. Mammalian Skin as a Model to Uncover
How miRs Regulate Stem Cell Biology
and Tissue Morphogenesis
With its easy accessibility and established genetic tools for condi-
tional targeting, the mouse skin epithelium provides an excellent system
to explore functions of miR regulatory pathways in mammalian stem cell
biology and tissue morphogenesis. The architecture of the skin is spatially
and temporally well defined. The skin epithelium is separated from the
underlying dermis by a basement membrane rich in extracellular matrix.
In the epidermis, an inner (basal) layer of progenitors periodically with-
draws from the cell cycle and commits to upward program of terminal
differentiation, involving three distinct stages: spinous, granular, and stra-
tum corneum ( Fig. 7.2 A). Transcriptional activity ceases at the transition
after the granular stage, as terminally differentiated dead squames are
sloughed from the skin surface, continually replaced by inner cells moving
outward.
By contrast, hair follicles (HFs) and their associated sebaceous glands
(SGs) are appendages of the epidermis ( Fig. 7.2 B). Hair growth is cyclical,
fueled by epithelial stem cells that reside within a niche called the bulge,
located just below the SG. At the base of the bulge is an extension of SCs
referred to as the secondary hair germ (HG). The HG maintains the
closest proximity to an essential cluster of mesenchymal cells, the dermal
papilla (DP), which undergoes stimulatory crosstalk with the stem cells.
Once activated (the telogen to anagen transition), a new HF emerges from
the HG as the DP is pushed downward. At the base of the mature HF and
in contact with the DP, matrix cells rapidly but transiently divide and then
differentiate in concentric upward cylinders of cells to form the hair shaft
at the center and the channel or inner root sheath (IRS) surrounded by
the outer root sheath (ORS). Following the anagen growth phase, most of
the lower two-thirds of the HF undergo apoptosis and the remaining
epithelial strand retracts upward with the DP to begin the cycle anew
( Fig. 7.2 C).