Biology Reference
In-Depth Information
progress has been made in deciphering miR expression patterns and func-
tions in embryonic development, differentiation, maintenance of stem cells,
and human diseases (reviewed by
Ambros, 2004; Bartel, 2009
). The exis-
tence of a hitherto unappreciated dimension of gene regulation mediated by
miRs led to an explosion of new studies, which have not only provided new
insights into our understanding of developmental and stem cell biology but
also pointed to new directions for therapeutic applications of stem cells.
In this review, we consider the most recent progress toward understand-
ing the biological role of miRs in mammalian skin development and in
various adult stem cells. Because of the significant interest in this topic,
many excellent reviews have been published in recent years and we also
refer our readers to these chapters for a comprehensive view of the field
(
Gangaraju and Lin, 2009; Ivey and Srivastava, 2010; Martinez and
Gregory, 2010
).
2. The Discovery of miRs and Their Roles
in Caenorhabditis elegans
The founding members of the miR family, namely,
lin-4
and
let-7
,
were originally identified as heterochronic genes that govern developmental
transitions in the nematode
C. elegans
(
Lee
et al
., 1993; Pasquinelli
et al
.,
2000; Reinhart
et al
., 2000; Wightman
et al
., 1993
). In those early studies,
lin-4
and
let-7
were both found to negatively regulate the translation of
master regulators of differentiation such as lin-14, lin-28, and lin-41.
Intriguingly, these proteins were found not only to maintain an early
developmental lineage but also then be downregulated as the animal transi-
tions to a later lineage. Thus for example, lin-4 functions in downregulating
lin-14 and lin-28 through the first larval stage (L1), while let-7 down-
regulates hbl-1 and lin-41 when the animal develops from the fourth larval
stage (L4) to the adult stage (
Lee
et al
., 1993; Reinhart
et al
., 2000
).
The negative regulatory networks involving lin-4, let-7, and their
mRNA targets provided the basis for the paradigm, whereby miRs help
deplete protein production by mRNAs that were inherited from an earlier
stage in the lineage, but which impair progression to the next step. In doing
so, miRs facilitate a precise, robust transition through the developmental
program. Indeed, in many of the recent investigations which we discuss in
the chapter, and which are aimed at exploring miR regulation of mamma-
lian stem cell lineages and development, miRs appear to act in accordance
to such model.
Although lin-4 was identified in 1993, it took the subsequent discovery of
let-7 in 2000 and the rapid realization that it is highly conserved before miRs
began to attract broader interest from the scientific community. A decade
