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Is the Early Left-Right Axis Like a Plant, a Kidney, Or a Neuron? the Integration of Physiological Signals in Embryonic Asymmetry

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Is the Early Left-Right Axis Like a Plant, a Kidney, Or a Neuron? the Integration of Physiological Signals in Embryonic Asymmetry Birth Defects Research (Part C) 78:191–223 (2006) REVIEW Is the Early Left-Right Axis like a Plant, a Kidney, or a Neuron? The Integration of Physiological Signals in Embryonic Asymmetry Michael Levin* Embryonic morphogenesis occurs along three orthogonal axes. While the Developmental noise often patterning of the anterior-posterior and dorsal-ventral axes has been results in pseudorandom character- increasingly well-characterized, the left-right (LR) axis has only relatively istics and minor stochastic devia- recently begun to be understood at the molecular level. The mechanisms tions known as fluctuating asymme- that ensure invariant LR asymmetry of the heart, viscera, and brain involve try (Klingenberg and McIntyre, fundamental aspects of cell biology, biophysics, and evolutionary biology, 1998); however, the most interest- and are important not only for basic science but also for the biomedicine of a wide range of birth defects and human genetic syndromes. The LR axis ing phenomenon is invariant (i.e., links biomolecular chirality to embryonic development and ultimately to consistently biased) differences behavior and cognition, revealing feedback loops and conserved functional between the left and right sides. For modules occurring as widely as plants and mammals. This review focuses brevity, as well as because these on the unique and fascinating physiological aspects of LR patterning in a are likely to be secondary to embry- number of vertebrate and invertebrate species, discusses several profound onic asymmetries, this review mechanistic analogies between biological regulation in diverse systems largely neglects behavioral/sensory (specifically proposing a nonciliary parallel between kidney cells and the LR asymmetries (Harnad, 1977; axis based on subcellular regulation of ion transporter targeting), high- Bisazza et al., 1998). lights the possible importance of early, highly-conserved intracellular events that are magnified to embryo-wide scales, and lays out the most important open questions about the function, evolutionary origin, and con- servation of mechanisms underlying embryonic asymmetry. Birth The Unique Fascination Defects Research (Part C) 78:191–223, 2006. VC 2006 Wiley-Liss, Inc. of the LR Axis The establishment of LR asymmetry Key words: embryogenesis; left-right asymmetry; physiology; modeling raises a number of interesting bio- logical questions. Why does asym- metry exist at all? What are the INTRODUCTION consistently asymmetric place- implications of asymmetry for the The geometrical invariance known ment of various internal organs normal structure and physiology of as symmetry is a prominent aspect such as the heart, liver, spleen, the heart, gut, and brain? Why are of developmental morphology dur- and gut, or the asymmetric devel- all normal individuals not only ing embryogenesis. Animal body- opment of paired organs (such as asymmetric, but asymmetric to the plans occur in a wide variety of sym- brain hemispheres and lungs). A same direction (i.e., why a consist- metries: spherical (e.g., volvox), fascinating atlas of such morpho- ent bias and not a 50%/50% race- radial (e.g., sea anemone), chiral logical left-right (LR) asymmetries mic population, given that individu- (e.g., snails, ciliates), bilateral (e.g., throughout the animal kingdom is als with full inversion are not obvi- housefly), and pseudobilateral (e.g., given in Neville (1976), and evolu- ously impaired)? While it is possible man). Vertebrates have a generally tionary surveys have analyzed as- to devise plausible evolutionary rea- bilaterally-symmetrical body plan, ymmetries in diverse phyla (Palmer, sons for why organisms might be but this symmetry is broken by the 1996). asymmetric in the first place (op- Michael Levin is from the Forsyth Center for Regenerative and Developmental Biology, The Forsyth Institute, and the Department of Developmental Biology, Harvard School of Dental Medicine, Boston, Massachusetts. This manuscript was written in a Forsyth Institute facility renovated with support from Research Facilities Improvement Grant Number CO6RR11244 from the National Center for Research Resources, National Institutes of Health. Grant sponsor: National Institutes of Health (NIH); Grant number: GM-06227; Grant sponsor: March of Dimes; Grant number: 6-FY04-65; Grant sponsor: NHTSA; Grant number: DTNH22-06-G-0001. *Correspondence to: Michael Levin, Department of Developmental Biology, Harvard School of Dental Medicine, 140 The Fenway, Boston, MA 02115. E-mail: [email protected] Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/bdrc.20078 VC 2006 Wiley-Liss, Inc. 192 LEVIN timal packing, fluid dynamics, maxi- feature of the world that distin- phology (Delhaas et al., 2004). This mizing surface area of tubes, etc.) guishes left from right? suggests that the gross asymmetry (Kilner et al., 2000), there is no ob- Answers to these questions of the organs is separable from the vious reason for why they should all require a detailed understanding, at chirality of subcellular components, be asymmetric to the same direc- the molecular, genetic, and bio- and also potentially explains why tion. It is, after all, much easier to chemical levels, of the formation of 50-50 racemic populations are not imagine a developmental mecha- biased asymmetry in embryos. seen: discordance between subcel- nism for generating antisymmetry lular asymmetries and large-scale (such as local amplification and Not Just Basic Biology: structures in full situs inversus indi- long-range inhibition of stochastic Asymmetry and Human viduals may sufficiently contribute biochemical differences resulting in Medicine to lower fitness in the reversed indi- a morphologically biphasic popula- viduals (over evolutionary scales) to tion), than for biasing the LR axis to Errors of LR patterning during em- explain the existence of a consistent a given direction. When, during evo- bryogenesis are relevant to the clini- and robust biasing mechanism. lution, did handed asymmetry ap- cal considerations of several fairly LR asymmetries contribute to pear, and were there true bilater- common human birth defects: syn- human physiology involving many ally-symmetrical organisms prior to dromes such as Kartagener’s and organs in addition to the heart. For the invention of oriented asymme- Ivemark’s (Winer-Muram, 1995), example, proper propulsion of the try (Cooke, 2004)? Is it connected dextrocardia, situs inversus (a com- digesta appears to depend on diges- to chirality in lower forms (such as plete mirror-image reversal of the tive tract asymmetry (Arun, 2004). snail shell coiling and chirality in sidedness of asymmetrically posi- There are also links to more subtle some plants) or even the asymme- tioned organs and asymmetric paired features of human physiology; as- try (lack of quantum parity conser- organs), heterotaxia (a loss of con- ymmetric histamine skin responses vation) in weak nuclear decay (Wu cordance where each organ makes in L versus R arms are altered in et al., 1957)? At what developmen- an independent decision as to its si- patients with left cerebral epileptic tal stages is asymmetry initiated in tus), and right or left isomerism (in focus (Meador et al., 2004), and in which the organism is completely mice, interleukin level difference in L symmetrical, for example, polysple- and R cortex corresponds to their how can the LR axis nia or asplenia). Heterotaxia and iso- paw preference (Shen et al., 2005a, merismoftenresultinserioushealth 2005b). Synergy between clinical be consistently problems for the patient (Burn, data and model systems has signifi- oriented with respect 1991). The LR asymmetry of the heart cantly contributed to the under- to the anterior- is intimately connected to its function, standing of LR patterning (Bisgrove and errors in cardiac situs represent and Yost, 2001; Zhu et al., 2006), posterior and a significant source of human heart and clinical data have suggested im- dorsal-ventral axes in disease (Kathiriya and Srivastava, portant components of the pathway. 2000). Laterality defects can arise in a One example is PA26 (sestrin), dis- the absence of any single individual (Winer-Muram, covered through the analysis of macroscopic feature 1995; Kosaki and Casey, 1998) but human laterality patients (Peeters are especially associated with mono- et al., 2003) but not yet explored in of the world that zygotic twinning (see below). model systems. Another is the inver- distinguishes left Interestingly, complete (and rare) sion of various organs long observed situs inversus totalis is not associ- in the context of human conjoined from right? ated with severe difficulties in most twins (Torgersen, 1950; Aird, 1959; patients, although it does appear to Cuniff et al., 1988; Burn, 1991; be accompanied by an estimated Winer-Muram, 1995). The discovery higher incidence of congenital heart of the spatial signals propagated by vertebrate embryos? Are the disease on the population level asymmetric gene expression in chick establishment of bilaterality, impo- (Ramsdell, 2005). This is at first embryos has allowed a partial under- sition of asymmetry, and bias of puzzling: if everything is exactly standing of laterality defects in that asymmetry with respect to the mirror-image, why should there be human conjoined twins (Kapur et al., other two axes separate events? any problem at all? All connections 1994), which appear to be induced How conserved are the molecular and structures should be preserved by crossover of LR morphogen
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