Biology Reference
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discovered that miR-155 is expressed in mature B and T lymphocytes, and
that it is also significantly upregulated in a variety of lymphomas (
Eis
et al
.,
2005
). Loss-of-function studies in mice revealed that miR-155 is a critical
in vivo
regulator of specific differentiation processes in the immune response
(
Rodriguez
et al
., 2007; Thai
et al
., 2007
).
In an effort to identify miR-155 targets, upregulatedmRNAs in
miR-155
null T lymphocytes were analyzed for the presence of seed matches to
miR-155 (
Rodriguez
et al
., 2007
). Even though
65% of the upregulated
genes contained miR-155 seed matches in their 3
0
UTRs, the key miR-155
targets appeared to bemRNAs encoding cytokines, providing an explanation
for the remarkable impact and specificity of this miR on immune cell
lineages.
Another elegant study of hematopoietic-specific miRs focused on
miR-150 and provided an example of a single mRNA:miR regulatory
pair that functions critically in lymphocyte development (
Xiao
et al
.,
2007
). Like miR-155, miR-150 is primarily expressed in mature lympho-
cytes rather than the progenitor cells. By loss- and gain-of-function studies,
miR-150 was shown to regulate lymphocyte terminal differentiation (
Xiao
et al
., 2007
). Importantly, the expression of c-Myb, a key transcription
factor and the top predicted target of miR-150, inversely correlates with
that of miR-150, suggesting that miR-150 might be both necessary and
sufficient to control c-Myb expression. Interestingly, the ensuing
c-Myb
heterozygous KO mouse showed phenotypes similar to those observed in a
miR-150
transgenic mouse, lending support to the argument that miR-150
carries out its function through the accurate control of c-Myb expression
(
Xiao
et al
., 2007
).
Similar to miR-150 and miR-155, miR-223 is also expressed at a low
level in the HSCs but gradually upregulated during the differentiation
toward mature peripheral blood granulocytes (
Johnnidis
et al
., 2008
).
When genetically ablated, miR-223 KO mice have an increased population
of granulocyte progenitors. This phenotype is likely due to the derepression
of one of miR-223 direct targets,
Mef2c
, a transcription factor that promotes
proliferation of the myeloid progenitors. Remarkably, when the miR-223
KO mice were across to
Mef2c
KO mice, the loss of Mef2c was able to
repress the enhanced progenitor proliferation. This result strongly suggests
that the downregulation of Mef2c by miR-223 during granulocyte differ-
entiation is important to suppress the proliferative capacity of the differ-
entiating progenitors. It is also interesting that although Mef2c is dispensable
for the hematopoietic homeostasis, its regulation by miR-223 appears to be
critical to modulate the pool of progenitor cells during the granulocytic
differentiation.
Studies of the erythroid lineage have also revealed an inverse relationship
between miR expression and progenitor. When erythroid progenitors
begin to differentiate into red blood cells, the miR-144/miR-451 locus is
