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Cytokine Biology Dept., The Forsyth Institute, and Department of Craniofacial and Developmental Biology, Harvard School of Dental Medicine, 140 The Fenway, Boston, MA 02115; mlevin{at}forsyth.org
CONTROVERSY
The consistent asymmetry of organs such as the heart, viscera, and brain raises profound questions in developmental and cell biology. It is also of high biomedical significance, because several human syndromes affect the right-left axis. Significant progress in our understanding of the molecular genetic basis of right-left patterning has recently been made, but the crucial details of the origin of asymmetry remain unknown. In particular, the roles of cilia and motor proteins have been hotly debated in the field. The dominant model stems from work on rodent embryos, but it is controversial because numerous observations in other species suggest a different mechanism for the initiation of asymmetry. The following review outlines the current state of the field and proposes an alternative to the currently popular cilia model.— Olav Alvares, Editor
The bilaterally symmetric body plan of vertebrates features several consistent asymmetries in the placement, structure, and function of organs such as the heart, intestine, and brain. Deviations from the normal pattern result in situs inversus, isomerisms, or heterotaxia (independent randomization), which have significant clinical implications. The invariance of the left-right (LR) asymmetry of normal morphology, neuronal function, and phenotype of several syndromes raises fascinating and fundamental questions in cell, developmental, evolutionary, and neurobiology. While a pathway of asymmetrically expressed signaling factors has been well-characterized in several model systems, very early steps in the establishment of LR asymmetry remain poorly understood. In particular, the origin of consistently oriented asymmetry is unknown. Recently, a candidate for the origins of asymmetry has been suggested: bulk transport of extracellular morphogens by rotating primary cilia during gastrulation. This model is appealing because it ‘bootstraps’ morphological asymmetry of the embryo from the intrinsic structural (molecular) chirality of motile cilia. However, conceptual and practical problems remain with this hypothesis. Indeed, the genetic data are also consistent with a different mechanism: cytoplasmic transport roles of motor proteins. This review outlines the progress and remaining questions in the field of left-right asymmetry, and focuses on an alternative model for ‘Step 1’ of asymmetry. More specifically, based on wide-ranging data on ion fluxes and motor protein function in several species, it is suggested that laterality is driven by pH/voltage gradients across the midline, which are established by chiral movement of motor proteins with respect to the cytoskeleton.
Key words. Left-right asymmetry, developmental biology, embryo, ion transport, motor proteins, cilia
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