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J.-N. Chen and M. C. Fishman
7.4 Cardiac Laterality
Organs must fit within an overall body plan. For example, physical
juxtaposition of the heart with other neighboring organs depends upon it
having a certain shape, as does its proper and functional connectivity
with veins and arteries. One element of this proper configuration is due
to cardiac looping, the rightward bending of the ventricle. Abnormal
looping is often associated with severe congenital cardiac diseases in
humans (for review see Goldstein et al. 1998). It is not simply looping
which must be correct, but looping in the context of laterality decisions
made by other organs. In fact, complete reversal of organ positions, situs
inversus, does not usually cause significant abnormalities. However,
discordant organ laterality, heterotaxy, often results in severe defects
(Goldstein et al. 1998).
Recently, a few genes involved in left-right patterning have been
identified. Genetic or embryological manipulation of such gene activities often leads to randomization of cardiac looping (for review see
Ramsdell and Yost 1998). Interestingly, with few exceptions, most of the
molecules are not asymmetrically expressed in the organs themselves. It
is quite possible that these genes provide embryonic signals which guide
organ laterality, but are not the responding molecules within the organs.
Which genes does the heart use to interpret or respond to the embryonic
left-right signals? There are two good candidates for such a role. The
gene pitx2 is a vertebrate bicoid homologue, which is asymmetrically
expressed in the heart and the gut in mouse, chicken, and frog embryos.
Experimental manipulation of pitx2 gene activity in the frog and chick
embryos causes randomization of organ laterality (Logan et al. 1998;
Piedra et al. 1998; Ryan et al. 1998; Yoshioka et al. 1998). BMP4 is
asymmetrically expressed in the zebrafish primitive heart tube, soon
after the bilateral primordia fuse at the midline. This asymmetry is
disrupted in the zebrafish laterality mutants (see below). Furthermore,
experimental disruption of BMP4 signaling in the heart results in randomization of cardiac looping (Chen et al. 1997).
A genome-wide survey for genes establishing organ laterality is of
interest as the first step toward genetic dissection of this pathway.
Cardiac looping has classically been utilized as the first evidence of
left-right asymmetry in vertebrates. However, it is difficult to screen for
cardiac laterality mutations using cardiac looping as the only assay. A
J.-N. Chen and M. C. Fishman
7.4 Cardiac Laterality
Organs must fit within an overall body plan. For example, physical
juxtaposition of the heart with other neighboring organs depends upon it
having a certain shape, as does its proper and functional connectivity
with veins and arteries. One element of this proper configuration is due
to cardiac looping, the rightward bending of the ventricle. Abnormal
looping is often associated with severe congenital cardiac diseases in
humans (for review see Goldstein et al. 1998). It is not simply looping
which must be correct, but looping in the context of laterality decisions
made by other organs. In fact, complete reversal of organ positions, situs
inversus, does not usually cause significant abnormalities. However,
discordant organ laterality, heterotaxy, often results in severe defects
(Goldstein et al. 1998).
Recently, a few genes involved in left-right patterning have been
identified. Genetic or embryological manipulation of such gene activities often leads to randomization of cardiac looping (for review see
Ramsdell and Yost 1998). Interestingly, with few exceptions, most of the
molecules are not asymmetrically expressed in the organs themselves. It
is quite possible that these genes provide embryonic signals which guide
organ laterality, but are not the responding molecules within the organs.
Which genes does the heart use to interpret or respond to the embryonic
left-right signals? There are two good candidates for such a role. The
gene pitx2 is a vertebrate bicoid homologue, which is asymmetrically
expressed in the heart and the gut in mouse, chicken, and frog embryos.
Experimental manipulation of pitx2 gene activity in the frog and chick
embryos causes randomization of organ laterality (Logan et al. 1998;
Piedra et al. 1998; Ryan et al. 1998; Yoshioka et al. 1998). BMP4 is
asymmetrically expressed in the zebrafish primitive heart tube, soon
after the bilateral primordia fuse at the midline. This asymmetry is
disrupted in the zebrafish laterality mutants (see below). Furthermore,
experimental disruption of BMP4 signaling in the heart results in randomization of cardiac looping (Chen et al. 1997).
A genome-wide survey for genes establishing organ laterality is of
interest as the first step toward genetic dissection of this pathway.
Cardiac looping has classically been utilized as the first evidence of
left-right asymmetry in vertebrates. However, it is difficult to screen for
cardiac laterality mutations using cardiac looping as the only assay. A