A miR Image of Stem Cells and Their Lineages - Current Topics in Developmental Biology - page 182

et al ., 2007; Yi et al ., 2008 ), rendering it an obvious first choice for exploring
the functional significance of an individual miR in the skin. In situ hybri-
dizations revealed miR-203 in the differentiating suprabasal and not the
basal progenitors of the epidermis ( Yi et al ., 2009 ), making it tempting to
speculate that the hyperproliferative epidermal phenotype observed in the
Dicer cKO skin ( Andl et al ., 2006; Yi et al ., 2006, 2008 ) might be attributable
specifically to the loss of miR-203.
Functional studies revealed miR-203's ability to unleash its potent
inhibitory powers on proliferative potential. When miR-203 was preco-
ciously expressed in the epidermal stem/progenitor cells either in vivo or
in vitro , keratinocytes exited the cell cycle and displayed significantly
reduced capacity to form colonies ( Lena et al ., 2008; Yi et al ., 2008 ).
Conversely, when epidermal cells or neonatal mice were treated with
the chemically modified antisense oligonucleotide (antagomir) against
miR-203, an increase was observed in actively dividing cells within the
suprabasal epidermal layers ( Yi et al ., 2008 ). Consistent with its function in
inhibiting cell proliferation in mammalian skin, miR-203 potently inhibited
the growth of the repairing fin when overexpressed in Zebrafish skin
( Thatcher et al ., 2008 ).
To understand how miR-203 exerts these effects, it is critical to know its
physiological targets. Although systematic and unbiased target identification
approaches are yet to be established, a few miR-203 targets have now
been documented ( Lena et al ., 2008; Yi et al ., 2008 ). The best characterized
is the transcription factor D Np63 a (also known as p73-like in human).

Over the past decade, has been extensively investigated for

its essential function in the maintenance of “stemness” in the skin and
in other stratified epithelia ( Mills et al ., 1999; Senoo et al ., 2007; Yang
et al ., 1999 ). Intriguingly and in a fashion expected of a miR's action on its
targets,

D Np63 a

D a

and miR-203 have mutually exclusive expression patterns,
opposite functions, and evolutionarily conserved regulatory relationships
( Yi et al ., 2008 ).
Importantly in the miR-203 gain- and loss-of-function studies, D Np63 a
was diminished when miR-203 was prematurely expressed basally, and
conversely,

Np63

expanded aberrantly into the suprabasal layers when
animals were treated with miR-203 antagomir ( Yi et al ., 2008 ). Although it
is not yet clear whether

D Np63 a

is the only target that mediates the
function of miR-203, this study provided an important example of miR's
ability to sharpen a developmental transition by targeting a master stem cell
regulator at the juncture at which they become induced to differentiate ( Yi
et al ., 2008 )( Fig. 7.4 A).
An additional note of intrigue is that whereas miR-203 potently
repressed epidermal stem cell proliferation, many structural markers of
terminal differentiation were not ectopically activated in the stem cells
when miR-203 was precociously expressed ( Yi et al ., 2008 ). Thus in this

D Np63 a