A miR Image of Stem Cells and Their Lineages - Current Topics in Developmental Biology - page 179

( Andl et al ., 2006; Yi et al ., 2006 ). Temporal profiling during skin develop-
ment unveiled a myriad of miRs which are differentially expressed in the
epidermis and its notable appendage, the HF ( Yi et al ., 2006 ). Interestingly,
this included not only miRs such as miR-100, miR-125, and let-7, which
are conserved throughout the animal kingdom, but also several vertebrate-
specific miRs such as miR-203 and miR-205. As more and more species
were analyzed for tissue-specific expression of miRs, it became evident that
these miRs are characteristic of the vertebrate skin epithelium.
Complete ablation of Dicer in all mouse tissues results in the arrest of
development by embryonic day 7.5 (E7.5) ( Bernstein et al ., 2003 ). Epider-
mal stratification does not take place until E13.5 ! E16.5, and HFs form in
waves from E14.5 ! P0 ( Schmidt-Ullrich and Paus, 2005 ). Thus to study
Dicer function in skin, several groups have generated Dicer conditional KO
(cKO) mice by using a floxed Dicer allele and a Cre recombinase transgene
driven by a skin epithelial-specific keratin-14 (K14) promoter ( Andl et al .,
2006; Yi et al ., 2006 ). Like its coexpressed partner K5 , K14 becomes
strongly active in embryonic skin progenitor cells by E15 ( Byrne et al .,

1994; Vassar et al ., 1989 ). As such, the K14-Cre-mediated Dicer ablation
depletes Dicer and miRs in all skin lineages.
Because the loss of mature miRs is secondary to the ablation of Dicer and
the relatively long half-life of miRs, mature miRs were not completely
depleted until E17.5 ( Yi et al ., 2006 ) or birth ( Andl et al ., 2006 ) depending
most likely upon strain-specific differences. However, more than 100 miRs
were lost by then, and yet the cKO pups initially appeared normal in size
and appearance, and the epidermis, HFs, and SGs were correctly specified.
Thus, unlike well-established master regulatory circuits, for example, BMP,
Wnt, and Notch signaling pathways, the miR pathway did not seem to be
required for lineage specification during skin development.
Closer inspection revealed that the epidermis generated the expected
architectural and morphological signs of differentiation ( Yi et al ., 2006 ). By
contrast, developing Dicer- null HFs evaginated upward and arrested within
the epidermis, rather than invaginating inward into the dermis ( Andl et al .,
2006; Yi et al ., 2006 )( Fig. 7.3 ). Strikingly, the evaginating HFs attracted the
DP into the epidermis, thereby maintaining the mesenchymal-epithelial
association typically requisite to execute the program of terminal differentia-
tion. However, only concentric rings of matrix and IRS cells surrounded the
basement membrane around the DP, with no traces of hair shaft formation.
Exactly, how miR-deficiency-induced dysregulation in epithelial gene
expression might cause these gross abnormalities remains unclear. However,
even when Dicer was ablated after the HFs have formed, they subsequently
degenerated, leaving behind only cyst-like structures, and interestingly no
bulge compartment ( Andl et al ., 2006 ). Thus, the arrest in HFs cannot
simply be due to the architectural constraints associated with evagination,
but rather must reflect perturbations in the differentiation program itself.