cell news 2/2013
23
research news
forcing random cell movements into a functional form:
the cellular choreography of cardiac morphogenesis in fsh
salim abdelilah-seyfried
introduction
The frst historical report of an inversely positioned heart dates
back to the 15th century when the omnitalented “Renaissance
man” Leonardo da Vinci artistically recorded this morphologi-
cal rarity. His observation highlights the profound surprise that
such an unusual positioning of this organ elicited at that time.
In most of us, visceral organs such as heart, lung, liver, gut, and
spleen are stereotypically distributed within the body cavity
with the heart on the left side. Not only the position but also the
morphology of the heart is highly asymmetric with respect to
the left/right (L/R) axis [one of the three body axes in vertebra-
tes, alongside the anterior-posterior (head-to-toe) and the dor-
soventral (back-to-front) axes]. To a large extent this morpho-
logical asymmetry serves cardiac function. The left ventricular
chamber is larger and thicker and supports the main systemic
circulatory system, whereas the smaller right ventricular cham-
ber sustains only the smaller circulatory system of the lungs. Si-
milarly, the positions and distribution of major arteries and the
two atrial chambers is highly asymmetric with respect to the L/R
axis. An abnormal morphogenesis or mispositioning of the heart
endangers its effciency; during an average human lifetime, the
heart performs a truly Herculean and relentless task: beating
approximately some 2.5 billion times – and pumping an estima-
ted 190 million liters of blood through the vascular network to
support all bodily functions.
Today studies in zebrafsh and other model organisms have
shown us that this highly stereotypical L/R asymmetry of heart
morphology is the result of invariant asymmetrical development.
Two principal signaling cascades that have been conserved
through evolution - Nodal and the Bone morphogenetic protein
(Bmp) signaling pathways - are essential in establishing cardiac
laterality (Zhang and Bradley, 1996; Schilling et al., 1999; Bre-
ckenridge et al., 2001; Chocron et al., 2007; Smith et al., 2008;
Schier et al., 2009; Chen et al., 2010). Both Nodals and Bmp mo-
lecules belong to the larger transforming growth factor ß (TGFß)
superfamily of signaling molecules. These factors function by
binding to their respective type I and type II serine/threonine ki-
nase receptors, which, upon ligand binding, phosphorylate a set
of downstream receptor-regulated-Smad transcription factors.
Although Nodals and Bmps bind to different receptor complexes
and pass signals via different groups of Smad proteins, both si-
gnaling cascades require the association of the phosphorylated
(p)Smads, with a common co-Smad4 for nuclear translocation
and target gene activation. Until recently, both the potential
mode of interaction between Nodals and Bmp and the target
genes activated by these two TGFß signaling pathways during
heart development were unknown.
Over the past two decades, zebrafsh (
Danio rerio
) has become
the model organism of choice to elucidate the cellular behavi-
ors and molecular pathways that underlie early heart develop-
ment (Staudt and Stainier, 2012). Several impressive features
contribute to the popularity of this organism for such analy-
ses. First, zebrafsh embryonic development can proceed even
in the absence of a functional heart because the embryos are
so small that nutrients and oxygen can freely diffuse into the
embryo proper and sustain embryonic life for several days on
their own. Second, the zebrafsh embryo is transparent and has
an extra-uterine mode of development. This has allowed pow-
erful live imaging approaches, particularly in transgenic emb-
ryos that carry tissue- or cell type-specifc transgenic reporter
constructs. Finally, the feasibility of modifying gene functions
through genetic gain- and loss-of function approaches makes
this organism a prime candidate for the analysis of develop-
mental factors, including genes that potentially play a role in
human cardiac diseases. These properties have permitted the
collection of a larger number of mutants with defective car-
diac morphogenesis and an analysis of the respective loss-of-
function effects of candidate genes: the misguided behavior of
cardiac progenitor cells can be followed via four-dimensional
high-resolution
in vivo
microscopy. Their analysis has led to sur-
prising functional insights into the morphogenesis of the heart.
heart tube formation is the result of a process of epi-
thelial morphogenetic transformation
Zebrafsh cardiac development results from complex cell rear-
rangements involving myocardial and endocardial progenitor
cells, the two main types of cells that form the nascent heart
tube (reviewed in Staudt and Stainier, 2012). Myocardial cells
produce the outer muscular layer of the heart whereas endo-
cardial progenitor cells give rise to the specialized endothelial
