Question

In mice describe the major signaling pathways, mechanisms and roles of genes that give rise to left-right asymmetry in vertebrates. b) Describe how some major organs are affected by L-R asymmetry

Answer 1

From an evolutionary perspective, the progression from bilateral symmetry to global, handed asymmetry required that important changes be made on at least three distinct levels of the organization. These could have arisen in three sequential steps, although other equally plausible evolutionary scenarios can also be envisioned. The first step—the evolution of individual organ asymmetries—would have provided an initial level of complexity over the ancestral state of simple bilateral symmetry. The next step—the development of globally coordinated asymmetry—would have required the evolution of an additional level of regulation to ensure that all of the developing organ systems adopted consistent L/R orientations relative to each other. The final stage—characterized by global, handed asymmetry—would have required the innovation of an initial biasing mechanism to consistently orient the L/R axis with reference to the other two primary axes of the body.

Developmentally, the failure to properly pattern the L/R axis at any of these three levels of organization results in distinct classes of laterality defects. The first, known as isomerism results from a failure to achieve L/R asymmetry at the level of individual organs (examples include left and right atrial isomerism, left and right pulmonary isomerism, midline liver, etc.). A second condition, known as heterotaxia, describes a situation where one or more of the individual organ systems develops with reversed L/R polarity (i.e., right-sided stomach, left-sided liver, intestinal malrotation, etc.), and results from a failure to properly coordinate the asymmetric development of multiple organ systems. Finally, the failure to properly align the L/R axis with the other two body axes produces a condition known as situs inversus, characterized by a complete inversion of the global L/R axis

The mechanisms underlying L/R determination have fascinated biologists for decades, but not until recently have researchers been able to link specific gene functions to particular processes during the development of the L/R axis. The existence of mouse and zebrafish mutants, and inherited human syndromes with distinct laterality defects, had suggested that the process of L/R determination is under genetic control. This expectation has been confirmed by the recent identification of several genes that display striking, site-specific patterns of expression in the early embryo. Surgical manipulations in chick and frog embryos have further helped to define the roles that specific embryonic structures play during the process of L/R determination.

Breaking Symmetry

Conceptually, perhaps the most challenging question in the field of L/R asymmetry is to understand how the early bilateral symmetry of the embryo is broken such that the L/R axis becomes consistently oriented with respect to the anteroposterior (A/P) and dorsoventral (D/V) axes, the other two primary axes of the embryo. To achieve this end, the embryo must integrate information concerning the relative orientations of the A/P and D/V axes, which are established at an earlier stage in development, and use this information to produce an initial difference or “bias” between cells on either side of the embryonic midline. While various theoretical models have been put forward to explain how this initial symmetry-breaking event might occur (see, for

) have recently provided us with the first experimentally deduced model of L/R axis determination in vertebrates. Interestingly, this model is entirely consistent with a previously observed correlation between situs abnormalities and ciliary dysfunction in humans (

Afzelius 1976

). The breakthrough came from analyzing a specialized cluster of monocilia present on the ventral surface of the mouse node, the mammalian equivalent of the early embryonic organizer region identified through classical transplantation studies in Xenopus. This monocilia, which project into the extraembryonic space surrounding the egg cylinder, exhibit a novel type of vortical motion that generates an apparent leftward flow of extraembryonic fluid in the node region (

). This so-called “nodal flow” has been proposed to function as the initiating event in the formation of the L/R axis by causing an initial L/R difference in the relative distribution of one or more extracellular inducers , thus triggering the activation of distinct signaling pathways on the left and right sides of the embryo (reviewed by

)

The claim that a particular genetic pathway has been conserved during evolution has become a staple attached to many developmental biology studies in the last two decades, a trend fueled by exciting advances in the synthesis of developmental and evolutionary biology. However, as it often happens, the devil is in the details. What is conserved and what is divergent in the mechanisms that control L/R asymmetry among vertebrates

The advances outlined above have allowed researchers to put forward a model that partially explains how L/R positional information is generated and interpreted in the early embryo. Generally speaking, the statement that the overall mechanisms of L/R patterning are conserved among vertebrates appears to hold true. However, it is still not clear to what degree the initial steps of L/R determination are shared among the different vertebrate classes. If, on one the hand, distinct mechanisms of symmetry-breaking do actually exist, it may be possible to relate these differences in relatively straightforward and intuitive ways to the very different modes of early development seen among vertebrates. Alternatively, as we have argued here, the basic mechanism underlying the process of symmetry-breaking—namely, the activity of nodal cilia—may, in fact, be common to all vertebrates, with the apparent differences described thus far simply reflecting variations in the relative timing of node cilia function. Resolving this fundamental question will clearly be an important target of future studies in the field.