Biology Reference
In-Depth Information
To date, global disruption of miRNA expression in the myeloid
lineage has not been reported to be as deleterious as it is in lymphocytes.
However, removal of Dicer using a CD11b-driven Cre mouse strain
does lead to diminished osteoclast differentiation and function (
Sugatani
and Hruska, 2009
). Another study found that the development of Lan-
gerhans cells
in the skin was
impaired when Dicer was deleted in
CD11c
cells (
Kuipers
et al
., 2010
). Perhaps, this disparity between the
importance of Dicer in lymphoid versus myeloid cells is due to the innate
immune system being much older and less complex than the adaptive
branch, potentially having already evolved before miRNAs themselves
had evolved to be able to play critical roles in cellular identity and
functionality. This suggests an important general principle that miRNAs
play more of a role in recently evolved systems than in more ancient
systems. However, it is clear that in myeloid cells, the effects of some
miRNAs are balanced by opposing effects of others. By eliminating
almost all miRNAs, one might be removing both positive and negative
regulators of development leaving the system still able to function, while
gain or loss of function of one miRNA does not involve a counterbal-
ance triggering a phenotype. Such a situation is evident for miRNAs
146a and 155, which clearly oppose one another in their actions (see
below). This interpretation suggests that the role of these miRNAs might
be as buffers against excursions of the transcriptional apparatus as well as
providing fine-tuning for a system under the tension of opposing forces.
An impact on the subtypes of myeloid development has been observed
when individual miRNAs have been studied. miR-223-deficient mice
exhibit an expanded granulocytic compartment and show hyperactivation of
granulocytes during fungal infections (
Johnnidis
et al
., 2008
). Deletion of
miR-146a eventually causes an overproduction of myeloid cells of the
granulocyte-monocyte (GM) lineage (
Boldin
et al
., 2011
). Conversely, over-
expression of miR-155, miR-29a, or miR-125b in the bone marrow all
trigger a bias toward GM cell production, suggesting that these miRNAs
manage the lymphoid/myeloid balance (
Bousquet
et al
., 2010
;
Han
et al
.,
2010
;
O'Connell
et al
., 2008, 2010a
).
Megakaryocytes (which generate platelets) and red blood cells are also
part of the myeloid lineage and arise from a common megakaryocyte-
erythrocyte progenitor (MEP). Megakaryocytes have been shown to have
a distinct miRNA expression “fingerprint” initially suggesting a role for
miRNAs in directing megakaryocyte development (
Garzon
et al
., 2006
).
miR-150 was later shown to promote MEP differentiation into megakar-
yocytes through repression of cMyb (
Lu
et al
., 2008a
). Alternatively, dele-
tion of miR-451 has revealed a role for this miRNA in RBC development
(
Patrick
et al
., 2010
;
Rasmussen
et al
., 2010
). This is a good example of
specific miRNAs assisting in lineage decisions made by progenitor
populations.
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