Biology Reference
In-Depth Information
exhibiting a reduction in their repopulating capacity despite appearing in
increased numbers in the bone marrow (
Ergen and Goodell, 2010
). Con-
sistent with an ever-changing HSC phenotype, many of the pathways that
manage fetal HSCs are distinct from those involved in adult HSCs (
Rossi
et al
., 2008
). This suggests that the specific miRNAs relevant to HSC
biology might also change depending on the developmental stage of the
organism. While we begin to identify miRNAs that are important for HSC
function, careful consideration should be given to age-related aspects. This
may help to unravel more of the underlying causes of why HSC function
varies with age.
4.2. Lymphoid versus myeloid
As progeny hematopoietic cells differentiate away from the HSC, they
proceed down one of two general lineages: lymphoid or myeloid. Specific
deletion of Dicer in T cells (and thus a majority of miRNAs) results in
dramatic defects in the T lymphocyte lineage (
Cobb
et al
., 2005
;
Muljo
et al
., 2005
). This is characterized by a substantial reduction in the total
number of T lymphocytes with the magnitude of this decrease varying
depending on the stage of thymic development at which Dicer is removed.
Specific miRNAs involved in thymopoiesis have been identified, and
these include miRs-17-92 and miR-181a (
Li
et al
., 2007
;
Xiao
et al
.,
2008
). An important aspect of T cell development is selecting clones with
the proper antigen specificity to ensure immunity against infection while
preventing autoreactive T cells from reaching the periphery. miR-181a
functions to modulate the signaling strength of the TCR during develop-
ment and is therefore important for accurate thymic selection (
Ebert
et al
.,
2009
).
Dicer is also required for Treg development, and its absence leads to
systemic autoimmunity. In this case, miR-155 and miR-146a are impli-
cated in Treg development and function, respectively (
Lu
et al
., 2009,
2010
). Evidence points to a critical role for these miRNAs in the regulation
of Jak-Stat pathways in Tregs.
A lack of Dicer during early B cell development triggers reduced cell
survival and diminished antigen receptor diversity (
Koralov
et al
., 2008
).
miRs-17-92 and miR-150 appear to be involved in these phenotypes by
targeting Bim, Pten, and cMyb (
Koralov
et al
., 2008
;
Xiao
et al
., 2007
).
Although there is a requirement for certain miRNAs for B lymphocytes to
progress through their developmental stages, other miRNAs function as
inhibitors of B cell maturation and function, limiting B cell output. Among
these, enforced overexpression of miR-34a restricts B cells from passing
through the proB to preB cell stage of differentiation (
Rao
et al
., 2010
). This
is mediated through repression of the transcription factor FoxP1.
