DEVELOPMENT AND STEM CELLS
RESEARCH REPORT 3879
Development 138, 3879-3884 (2011) doi:10.1242/dev.069336
© 2011. Published by The Company of Biologists Ltd
Germ line differentiation factor Bag of Marbles is a
regulator of hematopoietic progenitor maintenance during
Drosophila hematopoiesis
Tsuyoshi Tokusumi, Yumiko Tokusumi, Dawn W. Hopkins, Douglas A. Shoue, Lauren Corona and
Robert A. Schulz*
SUMMARY
Bag of Marbles (Bam) is a stem cell differentiation factor in the Drosophila germ line. Here, we demonstrate that Bam has a
crucial function in the lymph gland, the tissue that orchestrates the second phase of Drosophila hematopoiesis. In bam mutant
larvae, depletion of hematopoietic progenitors is observed, coupled with prodigious production of differentiated hemocytes.
Conversely, forced expression of Bam in the lymph gland results in expansion of prohemocytes and substantial reduction of
differentiated blood cells. These findings identify Bam as a regulatory protein that promotes blood cell precursor maintenance
and prevents hemocyte differentiation during larval hematopoiesis. Cell-specific knockdown of bam function via RNAi expression
revealed that Bam activity is required cell-autonomously in hematopoietic progenitors for their maintenance. microRNA-7 (mir-7)
mutant lymph glands present with phenotypes identical to those seen in bam-null animals and mutants double-heterozygous for
bam and mir-7 reveal that the two cooperate to maintain the hematopoietic progenitor population. By contrast, analysis of yan
mutant lymph glands revealed that this transcriptional regulator promotes blood cell differentiation and the loss of prohemocyte
maintenance. Expression of Bam or mir-7 in hematopoietic progenitors leads to a reduction of Yan protein. Together, these
results demonstrate that Bam and mir-7 antagonize the differentiation-promoting function of Yan to maintain the stem-like
hematopoietic progenitor state during hematopoiesis.
INTRODUCTION
The discovery of a stem cell-like hematopoietic progenitor niche
within the lymph glands of Drosophila larvae represents a
significant contribution of this model system to the study of blood
cell formation (Krzemien et al., 2007; Mandal et al., 2007). During
the third instar, each anterior lymph gland becomes organized into
three distinct regions (Jung et al., 2005). The medullary zone is
populated by undifferentiated hematopoietic progenitors that
express components of the Hedgehog (Hh) and JAK/STAT
signaling pathways. At a peripheral position, the cortical zone is
populated by differentiated plasmatocytes and crystal cells that are
derived from the blood cell precursors present within the medullary
zone. With certain altered genetic conditions or as a result of wasp
parasitization, an additional group of hemocytes called
lamellocytes appear in the cortical zone, probably generated owing
to plasmatocyte plasticity (Markus et al., 2009; Tokusumi et al.,
2009a; Honti et al., 2010; Stofanko et al., 2010).
The third lymph gland domain is the posterior signaling center
(PSC), a region of 30-40 cells that does not give rise to differentiated
blood cells (Jung et al., 2005). The PSC is formed as a result of the
specification function of Antennapedia (Antp) and is maintained by
the functions of Collier (Knot – FlyBase) and Wingless (Crozatier et
al., 2004; Mandal et al., 2007; Sinenko et al., 2009). Cells of the PSC
uniquely express the Hh and Serrate signaling proteins (Lebestky et
al., 2003; Mandal et al., 2007), with Hh expression being positively
Department of Biological Sciences, University of Notre Dame, 147 Galvin Life Science
Building, Notre Dame, IN 46556, USA.
*Author for correspondence ([email protected])
Accepted 2 July 2011
regulated by the GATA factor Serpent (Tokusumi et al., 2010).
Recent lineage analyses have demonstrated the existence of a fourth
lymph gland region: a border zone located between the medullary
and cortical zones, which harbors intermediate hematopoietic
progenitors that are primed to initiate a blood cell differentiation
program (Krzemien et al., 2010).
Elegant studies have demonstrated that the PSC serves as a
hematopoietic progenitor niche within the lymph gland and that
this functional domain is essential for preserving normal hemocyte
homeostasis (Krzemien et al., 2007; Mandal et al., 2007).
Specifically, communication between PSC cells and hemocyte
precursors is essential for the maintenance of the progenitor
population and the prevention of these cells from becoming
abnormally programmed to differentiate into mature blood cells.
Key aspects of this regulatory network include Hh expression in
PSC cells, coupled with the non-autonomous activation of the Hh
signaling pathway in hematopoietic progenitors. Additionally, the
PSC plays a role in triggering the activation of the JAK/STAT
pathway within prohemocytes. With the disruption of any of these
events, the precursor population is lost owing to the premature
differentiation of hemocytes (Krzemien et al., 2007; Mandal et al.,
2007; Tokusumi et al., 2010).
Although important progress has been made towards an
understanding of hematopoietic progenitor-niche cell interactions,
there remains a paucity of information on events that control blood
cell precursor maintenance versus programmed lineage
differentiation. Intriguingly, we discovered that the bag of marbles
(bam) gene is transcriptionally active in this hematopoietic tissue.
Bam has been characterized as a key regulatory component of the
germ line as its normal function is to direct germ cells towards
spermatocyte or cystoblast differentiation (McKearin and Spradling,
DEVELOPMENT
KEY WORDS: Bam, Drosophila, Hematopoiesis, mir-7, Yan
3880 RESEARCH REPORT
Development 138 (18)
1990; McKearin and Ohlstein, 1995). Recent studies have
demonstrated that Bam and its partner Bgcn form a complex that
works via a translational repression mechanism to balance stem cell
self-renewal versus cystoblast differentiation (Li, Y. et al., 2009;
Shen et al., 2009; Kim et al., 2010). Here, we investigate the
expression and requirement of Bam in the lymph gland and
demonstrate that it functions, not as a blood cell differentiation factor,
but as a positive regulator of hematopoietic progenitor maintenance.
Bam works with microRNA-7 (mir-7) to negatively attenuate the
lymph gland function of Yan (Aop – FlyBase), a transcription factor
previously shown to be a hemocyte differentiation-promoting protein
(Zetervall et al., 2004). Our findings illuminate a novel mechanism
for the control of hematopoietic progenitor maintenance during the
final phase of Drosophila hematopoiesis.
Lymph glands were processed and immunostained as previously described
(Tokusumi et al., 2010). The following primary antibodies were used to
determine protein expression in dissected tissues: mouse anti-Yan (1:100,
Developmental Studies Hybridoma Bank); rabbit anti--Gal (1:1000, ICN);
mouse anti--Gal (1:500, Promega); mouse anti-Bam (McKearin and
Ohlstein, 1995) (1:10, D. McKearin and Developmental Studies Hybridoma
Bank); P1 antibody (Vilmos et al., 2004) (1:100, I. Ando); mouse anti-Antp
(1:100, Developmental Studies Hybridoma Bank). Immunostained samples
were analyzed with a Nikon A1R laser scanning confocal microscope.
MATERIALS AND METHODS
Microarray analysis
Drosophila strains
RNA prepared from 300 lymph glands dissected from four-day-old wildtype larvae was analyzed on GeneChip Drosophila Genome 2.0 arrays.
Tissue immunostaining
RESULTS AND DISCUSSION
Bam expression and function in cells of the lymph
gland hematopoietic organ
Through a microarray analysis of mRNAs present in lymph glands
dissected from third-instar larvae, we determined that bam was
transcriptionally active in this tissue that hosts the final phase of
Fig. 1. Bam expression and function during hematopoiesis. (A)Immunostaining of wild-type (wt) Drosophila lymph glands with an anti-Bam
antibody. (B)dome-lacZ serves as a marker of prohemocytes in wild-type lymph glands. (C)Reduction of dome-lacZ-positive prohemocytes in lymph
glands from bam86 larvae. (D)P1 antibody detects plasmatocytes in lymph glands from wild-type larvae. (E)Increased numbers of plasmatocytes in
lymph glands dissected from bam86 larvae. (F)Expression of BcF6-GFP marks crystal cells (present), whereas activity of MSNF9-mCherry marks
lamellocytes (absent) in wild-type lymph glands. (G)Increased crystal cells and induced lamellocytes in lymph glands from bam86 larvae.
(H)Immunostaining with P1 antibody and domeGal4-driven UAS-2XEYFP expression in control lymph glands. (I)Forced expression of the UASbamGFP transgene by domeGal4 results in expansion of the medullary zone and reduction of plasmatocytes. CZ, cortical zone; MZ, medullary zone.
DEVELOPMENT
Lines obtained from the Bloomington Drosophila Stock Center (Indiana
University, IN, USA) were: w1118, bam86, yan1, UAS-2XEGFP, UAS2XEYFP, UAS-mCD8::GFP and UAS-yan. TepIVGal4 (Avet-Rochex et al.,
2010; Tokusumi et al., 2010) was obtained from the Drosophila Genetic
Resource Center in Kyoto, Japan. The UAS-bam RNAi strains 10422R-1
and 10422R-2 were obtained from the National Institute of Genetics in
Mishima, Japan; HMS00029 was obtained from Harvard Medical School.
We also used strains provided by various colleagues: dome-lacZ
(domeMESO) (Hombria et al., 2005) (N. Fossett); domeGal4 (Bourbon et
al., 2002) (C. Evans); UAS-bamGFP (Chen and McKearin, 2003) (D.
McKearin); mir-71, UAS-mir-7 and mir-7 enhancer-GFP (Li and Carthew,
2005; Li, X. et al., 2009) (R. Carthew); and eaterGal4, hhF4f-GFP and
MSNF9mo-mCherry (Tokusumi et al., 2009a; Tokusumi et al., 2009b;
Tokusumi et al., 2010).
Drosophila hematopoiesis. The immunostaining of wild-type
lymph glands with an anti-Bam antibody revealed that the protein
is expressed in dome-lacZ- and TepIVGal4>UAS-mCD8::GFPpositive hematopoietic progenitors located within the medullary
zone (Fig. 1A, data not shown). This finding suggested that Bam
might play a key role in regulating blood cell homeostasis within
the lymph gland.
Under normal conditions, there exists a balance between the
quiescent prohemocyte population and the production of
plasmatocytes and crystal cells (Fig. 1B,D,F,H). As animals
homozygous null for bam are viable, we assayed lymph glands
from bam86/bam86 larvae to monitor the status of prohemocyte
maintenance versus hemocyte differentiation. bam mutant lymph
glands showed a diminution of dome-lacZ-marked hematopoietic
progenitors from the medullary zone (Fig. 1C), coupled with an
overproduction of P1-positive plasmatocytes (Fig. 1E) and
BcF6-GFP-marked crystal cells (Fig. 1G). Whereas lamellocytes
are rarely observed in lymph glands of wild-type larvae, these
MSNF9mCherry-expressing cells were induced in considerable
numbers in the bam mutant tissue (Fig. 1G). Thus, the absence
of bam function resulted in an appreciable loss of hematopoietic
progenitors and the copious production of differentiated
hemocytes. Conversely, forced expression of Bam culminated in
an expansion of blood cell precursors throughout the lymph
gland and the near complete absence of differentiated
plasmatocytes (Fig. 1I).
The demonstration of Bam as a regulator of blood cell
precursor maintenance implies that selective mRNA translational
control is likely to be an important regulatory mechanism in the
decision between hematopoietic progenitor maintenance versus
lineage-specific blood cell differentiation. It is noteworthy that
bgcn mutant lymph glands underwent a normal hematopoietic
process (data not shown). Thus, Bam might interact functionally
with a novel protein partner in regulating mRNA translation to
ensure an optimal blood cell homeostasis within this
hematopoietic organ.
Bam function is required cell-autonomously for
hematopoietic progenitor maintenance
To determine whether Bam is required intrinsically in blood cell
precursors to ensure their maintenance, we knocked down gene
function in prohemocytes through the generation of lymph glands
with the genotype TepIVGal4>UAS-bam RNAi. As TepIVGal4 is a
medullary zone-specific driver (Fig. 2A,D), we were able to
eliminate Bam activity precisely from the hemocyte precursor
population. Expression of bam RNAi resulted in a near-complete
loss of hematopoietic progenitors (Fig. 2B,C,E,F), coupled with an
expansion of the P1-positive plasmatocyte population (Fig. 2B,C).
We also determined that a loss of Bam activity from prohemocytes
did not affect the neighboring PSC population (Fig. 2E,F). Thus, a
major effect of eliminating bam function from hematopoietic
progenitors is a failure to maintain the blood cell precursor state
and the premature programming of precursor cells into the
plasmatocyte lineage.
Mutation of the mir-7 gene generates
hematopoietic phenotypes identical to those
observed in bam-null lymph glands
A recent study reported the presence of a mir-7 target site in the 3⬘
UTR of bam and that this sequence could be utilized to repress
Bam expression during male germ line differentiation (Pek et al.,
2009). To ensure proper stem cell lineage differentiation, a model
RESEARCH REPORT 3881
Fig. 2. Bam functions cell-autonomously in hematopoietic
progenitors. (A)TepIVGal4-driven UAS-mCD8::GFP marks blood cell
precursors whereas P1 marks plasmatocytes within a wild-type
Drosophila lymph gland. (B,C)Loss of hematopoietic progenitors and
increase in plasmatocytes due to UAS-bam RNAi expression. (D)Control
lymph gland stained for prohemocytes and Antp-expressing PSC cells.
(E,F)Hematopoietic progenitors are decreased owing to UAS-bam RNAi
expression. CZ, cortical zone; MZ, medullary zone; PSC, posterior
signaling center.
was proposed in which Maelstrom represses the expression of mir7, thus alleviating its repression of bam and allowing this
differentiation factor to function normally.
Based on this report, we decided to investigate the lymph gland
expression and function of mir-7. Initially, we determined that a
mir-7 enhancer-GFP transgene (Li, X. et al., 2009) was expressed
at low levels in cells in the proximal part of the medullary zone and
more strongly in cells of the PSC (Fig. 3A). We then postulated that
if mir-7 negative regulation of Bam function occurred in cells of
the lymph gland, then we might discern mir-7 hematopoietic
phenotypes that differed from those observed in bam mutant
animals. To the contrary, mir-7 mutant lymph glands presented
with altered blood cell populations identical to those found in bam
mutants. mir-7-null lymph glands showed a reduction in blood cell
precursors (Fig. 3B) and enhanced production of differentiated
plasmatocytes and lamellocytes (Fig. 3C). Given the similar nature
of the phenotypes, we assayed animals that were doubleheterozygous for bam- and mir-7-null alleles and observed a
significant reduction in the number of hematopoietic progenitors
(Fig. 3F). When considered together, the bam and mir-7 analyses
implicate a concerted function of the two in the maintenance of the
stem-like blood cell precursor state.
DEVELOPMENT
Bam function in hematopoiesis
3882 RESEARCH REPORT
Development 138 (18)
expression throughout the lymph gland in the expanded
prohemocyte population. The lack of mir-7 negative regulation of
Bam function indicates that this regulatory RNA can function
differentially based on its cell-specific context.
Forced expression of mir-7 in hematopoietic progenitors resulted
in an expansion of the prohemocyte population and a decrease in
the number of differentiated plasmatocytes (Fig. 3E). Notably, this
mir-7 gain-of-function condition failed to repress Bam protein
expression (Fig. 3E⬘), as would have been predicted from the prior
report of mir-7 negative regulation of bam. Rather, mir-7 induction
of supernumerary hematopoietic progenitors resulted in Bam
Conclusion
Our findings on Bam, mir-7 and Yan suggest a mechanism for the
interaction of these regulators in the control of blood cell
homeostasis (Fig. 4L). The role of Yan is to direct a quiescent
hematopoietic progenitor, through a primed intermediate progenitor
state, towards a blood cell differentiation fate as crystal cell,
plasmatocyte or lamellocyte. The final differentiation status of
these cells would be subject to the function of distinct lineagedetermining transcription factors. By contrast, Bam and mir-7
cooperate to negatively modulate yan mRNA translation in the
quiescent hematopoietic progenitor, thus maintaining the initial
prohemocyte state. Although details of this possible translational
repression remain to be parsed out, it is likely to include an as yet
DEVELOPMENT
Fig. 3. mir-7 expression and function during hematopoiesis.
(A)mir-7 enhancer-GFP transgene is expressed in the medullary zone
and PSC cells in control Drosophila lymph glands. (B)mir-7 mutant
lymph glands possess a diminished medullary zone as marked by domelacZ. (C)mir-7 mutant lymph glands present with an overproduction of
plasmatocytes (marked by P1) and lamellocytes (marked by MSNF9mCherry). (D)Immunostaining with P1 antibody and expression pattern
of TepIVGal4-driven GFP in a control lymph gland. (E)Forced expression
of mir-7 in hematopoietic progenitors results in medullary zone
expansion and plasmatocyte reduction. (E⬘)Expanded pattern of Bam
protein accumulation in a mir-7 gain-of-function lymph gland.
(F)Double-heterozygous combination of mir-71 and bam86 alleles
results in a lymph gland devoid of prohemocytes. MZ, medullary zone;
PSC, posterior signaling center.
Yan is a blood cell differentiation factor
negatively regulated by Bam and mir-7
Yan is an ETS-family protein that functions as a transcriptional
repressor (Lai and Rubin, 1992). Relevant to our analysis of the
genetic control of larval hematopoiesis, it was reported that
forced expression of Yan in lymph glands results in a robust
production of differentiated blood cells, including crystal cells
and lamellocytes (Zettervall et al., 2004). Additionally, yan
expression is subject to negative regulation by mir-7 during
photoreceptor differentiation in the eye (Li and Carthew, 2005;
Li, X. et al., 2009). Given these observations, we analyzed the
expression and function of yan during hematopoiesis while
considering our findings on the roles of bam and mir-7 in this
developmental process.
The immunostaining of hematopoietic tissues obtained from
wild-type animals with an anti-Yan antibody revealed that the
protein is expressed in cells present in a border zone located
between the medullary and cortical zones (Fig. 4A). As Yanexpressing cells did not express the hematopoietic progenitor
marker TepIVGal4>UAS-mCD8::GFP or the plasmatocyte marker
eaterGal4>UAS-GFP (Fig. 4B,C), the Yan-positive cells probably
correspond to intermediate hematopoietic progenitors that are
primed to initiate hemocyte differentiation (Krzemien et al., 2010).
The absence of Yan in cells of the cortical zone suggested that the
protein functions transiently in blood cell precursors and is
downregulated during the differentiation of mature hemocytes. The
analysis of yan mutant lymph glands revealed an enlargement of
the dome-lacZ-expressing hematopoietic progenitor pool (Fig. 4D).
By contrast, forced expression of Yan resulted in the loss of blood
cell precursors coupled with an expansion of P1-positive
plasmatocytes (Fig. 4F). These findings strengthened the notion
that Yan functions as a hemocyte differentiation factor during larval
hematopoiesis.
yan loss- and gain-of-function animals show completely
opposite phenotypes to those observed for comparably altered
mir-7 and bam larvae. We thus tested the possibility that mir-7
and Bam could function as negative regulators of Yan expression
in hematopoietic cells. In mir-7- or bam-null lymph glands, we
detected an increased level of Yan protein in a dispersed
population of progenitor cells (Fig. 4G,I). Conversely, forced
expression of mir-7 or bam in blood cell precursors resulted in a
reduction of Yan protein from the expanded prohemocyte
population (Fig. 4H,J,K).
Bam function in hematopoiesis
RESEARCH REPORT 3883
unidentified protein partner of Bam that would facilitate mir-7 and
yan mRNA packaging within an inhibitory RNA-induced silencing
complex in prohemocytes (Bartel, 2004).
Acknowledgements
We thank I. Ando, R. Carthew, C. Evans, N. Fossett, D. McKearin and various
stock centers for antibodies and Drosophila strains. This work was supported
by grants to R.A.S. from the NIH (HL071540) and the Notre Dame Initiative in
Adult Stem Cell Research. Deposited in PMC for release after 12 months.
Competing interests statement
The authors declare no competing financial interests.
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