The fruit fly, Drosophila melanogaster, has a simple open
circulatory system composed of circulating blood cells
(hemocytes) and a dorsal vessel surrounded by pericardial
cells. The dorsal vessel is a contractile tube lined by a layer of
myoepithelial vascular cells called cardioblasts. The anterior
part, called the aorta, functions as a major blood vessel; the
posterior part, called the heart, pumps hemocytes through the
aorta into the body cavity. The pericardial cells flanking the
aorta and heart are excretory cells, so-called pericardial
nephrocytes. Anterior to the pericardial nephrocytes, there are
two pairs of cell clusters flanking the aorta, which comprise
the lymph and ring gland. The lymph gland is made up of
hematopoietic progenitor cells that generate all three blood cell
types in the adult. The cardioblasts, pericardial nephrocytes
and the lymph gland hematopoietic progenitors all arise from
the same cardiac mesoderm that is specified by signaling
pathways involving bone morphogenetic protein (Bmp),
Decapentaplegic (Dpp), Wingless (Wg) and fibroblast growth
factor (Fgf) (Cripps and Olson, 2002; Evans et al., 2003),
hinting at a possible link between cardiogenesis and
Several transcription factors have been shown to play key
roles in cardiogenesis and hematopoiesis in flies and
vertebrates. The Drosophila NK-type homeobox gene tinman
(tin), the earliest marker of the cardiac lineage, is initially
expressed in the entire mesoderm before becoming restricted
to the dorsal mesoderm and later to the cardiac mesoderm, in
response to ectodermal Dpp and Wg signals. After all the
cardiac cell types are specified, tin expression is extinguished
in many cardiac cell types and maintained in only a subset of
cardiac and pericardial cells (Han et al., 2002; Han and
Bodmer, 2003). In tin mutant embryos, the entire cardiogenic
region and the lymph gland fail to form (Bodmer, 1993,
Mandal et al., 2004), indicating the essential role of Tinman in
early specification of the cardiac and hematopoietic lineages.
There are several NK-type homeobox genes in vertebrates,
which are named Nkx2.3-Nkx2.10 (Evans, 1999). Nkx2.5 is
expressed in the early cardiac crescent and continues to be
expressed throughout heart development. Mouse embryos
lacking Nkx2.5 show early cardiac defects and arrested
cardiogenesis before looping morphogenesis (Lyons et al.,
1995). Furthermore, overexpression of a dominant-negative
form of Nkx2.5 in Xenopus blocks cardiogenesis (Grow and
Krieg, 1998) and mutations in Nkx2.5 cause congenital heart
disease in humans (Schott et al., 1998). As tin is no longer
expressed in hematopoietic progenitors after stage 13, its
function in hematopoiesis is limited to the early specification
of the cardiogenic mesoderm containing the progenitor cells
for the lymph gland (Mandal et al., 2004).
Members of the GATA family of zinc-finger transcription
factors play crucial roles in both cardiogenesis and
hematopoiesis in Drosophila and vertebrates. The Drosophila
GATA factor Pannier is expressed in the cardiac mesoderm as
well as the overlaying ectoderm and functions primarily in
cardiogenesis. Embryos lacking pannier (pnr) show a dramatic
reduction of cardiac progenitor cells (Gajewski et al., 1999;
Alvarez et al., 2003; Klinedinst and Bodmer, 2003). In
vertebrates, GATA4, GATA5 and GATA6 are expressed in the
The existence of hemangioblasts, which serve as common
progenitors for hematopoietic cells and cardioblasts, has
suggested a molecular link between cardiogenesis and
hematopoiesis in Drosophila. However, the molecular
mediators that might link hematopoiesis and cardiogenesis
remain unknown. Here, we show that the highly conserved
basic helix-loop-helix (bHLH) transcription factor Hand is
expressed in cardioblasts, pericardial nephrocytes and
hematopoietic progenitors. The homeodomain protein
Tinman and the GATA factors Pannier and Serpent
directly activate Hand in these cell types through a minimal
enhancer, which is necessary and sufficient to drive Hand
expression in these different cell types. Hand is activated by
Tinman and Pannier in cardioblasts and pericardial
nephrocytes, and by Serpent in hematopoietic progenitors
in the lymph gland. These findings place Hand at a nexus
of the transcriptional networks that govern cardiogenesis
and hematopoiesis, and indicate that the transcriptional
pathways involved in development of the cardiovascular,
excretory and hematopoietic systems may be more closely
related than previously appreciated.
Key words: Hand, tinman, pannier, serpent, Drosophila, Heart
development, Hematopoiesis, Lymph gland, Transcription regulation
Hand is a direct target of Tinman and GATA factors during
Drosophila cardiogenesis and hematopoiesis
Zhe Han and Eric N. Olson*
Department of Molecular Biology, University of Texas Southwestern Medical Center at Dallas, 6000 Harry Hines Boulevard, Dallas,
TX 75390, USA
*Author for correspondence (e-mail: firstname.lastname@example.org)
Accepted 12 May 2005
Development 132, 3525-3536
Published by The Company of Biologists 2005
Development and disease
cardiogenic region. Loss-of-function assays in mouse, Xenopus
and zebrafish have shown that these GATA factors are required
for myocardial differentiation and normal heart development
(Molkentin et al., 1997; Gove et al., 1997; Reiter et al., 1999).
Another Drosophila GATA factor Serpent (Srp) functions
mainly in hematopoiesis. It is expressed in all hematopoietic
progenitors formed in the head mesoderm and the lymph gland.
In serpent (srp) mutant embryos, hematopoiesis from both the
head mesoderm and the lymph gland is inhibited (Lebestky et
al., 2000; Mandal et al., 2004), indicating that Serpent plays an
essential role in hematopoietic progenitor cell specification. In
vertebrates, GATA1, GATA2 and GATA3 play fundamental
roles in various aspects of hematopoietic development (Tsai et
al., 1994; Ting et al., 1996; Ferreira et al., 2005). It is likely
that the functions of Pannier and Serpent in cardiogenesis and
hematopoiesis, respectively, reflect the highly conserved but
simplified developmental processes in Drosophila compared
Several transcription factors that are directly regulated by
Tinman and Pannier have been identified, including Mef2 and
even-skipped, through enhancer mutagenesis studies (Gajewski
et al., 1997; Gajewski et al., 1998; Nguyen and Xu, 1998; Knirr
and Frasch, 2001; Han et al., 2002). These studies have begun
to establish a transcriptional network that governs Drosophila
cardiogenesis. In this network, Tinman and Pannier function in
parallel as key cardiogenic factors at the top of the hierarchy.
Although several transcription factors, such as Lozenge (Lz)
and Glial-cells-missing (Gcm), appear to act ‘downstream’ of
Serpent, there is as yet no evidence for direct activation of these
genes by Serpent.
The Drosophila Hand gene encodes a highly conserved
basic helix-loop-helix (bHLH)
Interestingly, Hand is the only gene identified so far that is
expressed in a specific pattern in all the cardioblasts,
pericardial nephrocytes and hematopoietic progenitors in the
lymph gland (Kolsh and Paululat, 2002). The vertebrate Hand
genes have been shown to play essential roles during heart
development (Srivastava et al., 1995; Srivastava et al., 1997;
Yamagishi et al., 2001; McFadden et al., 2005). Hand genes
have also been shown to be expressed during heart
development in Xenopus, zebrafish and Ciona (Sparrow et al.,
1998; Yelon et al., 2000; Davidson and Levine, 2003). The
conserved cardiac expression patterns of Hand genes across
vast evolutionary distances suggest that these genes play
conserved roles during cardiogenesis and may be regulated by
conserved genetic pathways.
In an effort to understand the position of Hand in the genetic
networks that govern cardiogenesis and hematopoiesis, we
searched for and identified the cis-regulatory region of the
Drosophila Hand gene. We describe a minimal Hand enhancer
that completely recapitulates endogenous Hand expression in
cardioblasts, pericardial nephrocytes and lymph gland
prehemocytes. This enhancer contains consensus binding sites
for the NK factor Tinman and the GATA factors Pannier and
Serpent, which are conserved across evolutionarily divergent
Drosophila species. Mutagenesis of these consensus binding
sites shows that Hand is directly activated by Tinman and
Pannier in the heart, and by Serpent in the lymph gland.
Overexpression of Tinman, Pannier or Serpent induces ectopic
Hand in muscle progenitors, dorsal vessel and hematopoietic
progenitors, respectively, indicating that Hand is activated
separately by Tinman, Pannier and Serpent in distinct cell
types. These findings place Hand at a central position to link
the transcriptional networks that govern cardiogenesis and
Materials and methods
The following mutant stocks were used: tinEC40(Bodmer, 1993),
pnrVX6(Ramain et al., 1993), srpneo45(the Bloomington stock center).
Different Drosophila species were provided by the Tucson species
center. Overexpression of transgenes was accomplished by using the
Gal4-UAS system (Brand and Perrimon, 1993). The following fly
lines were used: twi-Gal4; 24B-Gal4 (Greig and Akam, 1993), UAS-
tin (Ranganayakulu et al., 1998), UAS-pnr (Gajewski et al., 1999),
UAS-Srp (Waltzer et al., 2002), UAS-TinEnR (Han et al., 2002),
UAS-PnrEnR (Klinedinst and Bodmer, 2003). Oregon-R was used as
the wild-type reference strain.
Generation of transgenic fly lines
The various Hand enhancer fragments (Fig. 2A) were PCR amplified
and subcloned into pC4LZ (containing the lacZ reporter gene) or
pPelican (containing the GFP reporter gene) (Barolo et al., 2000),
using SphI/XhoI or KpnI/NotI sites, respectively. The constructs were
injected according to standard procedures. Germline transformed,
transgenic flies were selected by red eye color (w+) and maintained as
homozygotes. At least four independent transgenic lines were
analyzed for each construct.
Immunohistochemistry and microscopy
Embryos from different lines were collected and stained with various
antibodies as previously described (Han et al., 2002). The following
primary antibodies were used: mouse anti-β-galactosidase 1:300
(Promega); rat anti-Eve 1:200 (from D. Kosman); rabbit anti-Tinman
1:500 (from R. Bodmer); rabbit anti-Dmef2 1:1000 (from B.
Peterson); rabbit anti-GFP 1:2000 (Abcam); and rabbit anti-Srp 1:500
(from R. Reuter). Cy2, Cy3, Cy5 or Biotin-conjugated secondary
antibodies (from Jackson Lab) were used to recognize the primary
antibodies. Images were obtained with a Zeiss LSM510-meta
confocal microscope or a Leica DMRXE compound microscope.
Electrophoretic mobility shift assays
GST-Tin and GST-Pnr fusion proteins were prepared according to
standard procedures. Complimentary oligonucleotides containing Tin
or GATA consensus site were radiolabeled using Klenow fill-in
reaction as probes. Complimentary oligonucleotides containing wild-
type consensus binding sites or binding-site mutations were used as
non-labeled competitors to compete for the binding of GST fusion
proteins in the presence of the radio-labeled probe. After 30 minutes
incubation of the protein, probe and competitor oligonucleotides at
4°C, the products were electrophoresed in 7.5% non-denaturing
polyacrylamide gels at 4°C. The sense strand DNA sequences of the
oligonucleotides used are shown as follows with consensus binding
sites in parentheses and mutated nucleotides underlined: Tin1, TTT
CCA AAA AGG (CACTTAA) TTA ATC AAA CCC; Tin2: TTT CTG
AAG CAC (CACTTAG) ACA CTT GTC TCT; Tin3, CTT TTT ATA
AAG (TCAAGTG) CTT TTG TTT CTT; Tin4/G5: ATA ATA AAC
AAA (CAATTGA) (GATA) TCT ACG CCC CAG; G1, CTC TTG
TGT TCA (TATC) TAA AAC CAG ATT; G2, GCG TCT GCG GTT
(TATC) ACT TCC GAA ATT; G3, CCA TTA GGA ATA (TATC) TAC
AAT CAA TCG; G4: CAA TCG AGT TTT (TATC) TGC GGA TTA
CAA; Tin1m, TTT CCA AAA AGG (CATCCAA) TTA ATC AAA
CCC; Tin2m, TTT CTG AAG CAC (CATCCAG) ACA CTT GTC
TCT; Tin3m, CTT TTT ATA AAG (TCGGATG) CTT TTG TTT
CTT; Tin4m, ATA ATA AAC AAA (CATCCGA) (GATA) TCT ACG
CCC CAG; G1m, CTC TTG TGT TCA (TCCC) TAA AAC CAG
Development 132 (15)Research article
3535 Drosophila cardiogenesis and hematopoiesis Development and disease
cardiogenesis and hematopoiesis in both Drosophila and
mammals (Fossett et al., 2001; Sorrentino et al., 2005). Recent
studies have shown that the Notch pathway is required for both
cardiogenic and hematopoietic progenitor specification in
Drosophila (Han and Bodmer, 2003; Mandel et al., 2004), as
well as for mammalian embryonic vascular development
(Fischer et al., 2004). It is likely that Notch also plays an
important role in mammalian hematopoiesis.
In this study, we found that Drosophila Hand is expressed
in cardioblasts, pericardial nephrocytes and pre-hemocytes,
and is directly regulated by conserved transcription factors
(NK and GATA factors) that control both cardiogenesis and
hematopoiesis. The bHLH transcription factor Hand is highly
conserved in both protein sequence and expression pattern in
almost all organisms that have a cardiovascular system. In
mammals, Hand1 is expressed at high levels in the lateral plate
mesoderm, from which the cardiogenic region and the AGM
region arise, in E9.5 mouse embryos (Firulli et al., 1998).
Functional studies of Hand1 and Hand2 using knockout mice
have demonstrated the essential role of Hand genes during
cardiogenesis (Srivastava et al., 1995; Srivastava et al., 1997;
Yamagishi et al., 2001; McFadden et al., 2005), whereas the
functional analysis of Hand genes during vertebrate
hematopoiesis has not yet been explored. It will be interesting
to determine whether mammalian Hand genes are also
regulated in the AGM region by GATA1, GATA2 and GAT3
(vertebrate orthologs to Drosophila Serpent), and whether they
play a role in mammalian hematopoiesis.
In summary, this study places Hand at a pivotal point to link
the transcriptional networks that govern cardiogenesis and
hematopoiesis, as shown in Fig. 8. As the Hand gene family
encodes highly conserved bHLH transcription factors
expressed in the cardiogenic region of widely divergent
vertebrates and probably in the AGM region in mouse, these
findings open an avenue for further exploration of the
conserved transcriptional networks that govern both
cardiogenesis and hematopoiesis, by studying the regulation
and functions of Hand genes in vertebrate model systems.
We are especially grateful to our late colleague Dr Junyoung Oh,
who initiated these studies. We thank R. Schulz, R. Bodmer, the
Bloomington stock center and the Tucson species center for fly stocks.
We also thank R. Reuter, B. Paterson and the University of Iowa
Hybridoma Bank for antibodies; Xiumin Li and Jiang Wu for
technical support; A. Diehl for graphics; and J. Page for editorial
assistance. Z.H. was supported by a post-doctorial fellowship from
The American Heart Association and E.N.O. was supported by grants
from The National Institutes of Health and from the Donald W.
Reynolds Cardiovascular Clinical Research Center, Dallas, Texas; and
from the Robert A. Welch Foundation.
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Development 132 (15)Research article