Symmetry is appealing, be it in architecture, art or facial expression, where symmetry is a key feature to finding someone attractive or not. Yet, asymmetries are widespread in nature, not as an erroneous deviation from the norm but as a way to adapt to the prevailing environmental conditions at a time. Asymmetries in many cases are actively selected for: they might well have increased the evolutionary fitness of a species. Even many single-celled organisms are built asymmetrically, such as the pear-shaped ciliate Paramecium, which may depend on its asymmetry to navigate towards the oxygen-richer surface of turbid waters, at least based on modeling. Everybody knows the lobster with its asymmetric pair of claws, the large crusher usually on the left and the smaller cutter on the right. Snail shells coil asymmetrically, as do the organs they house. Organ asymmetries are found throughout the animal kingdom, referring to asymmetric positioning, asymmetric morphology or both, with the vertebrate heart being an example for the latter. Functional asymmetries, such as that of the human brain with its localization of the language center in one hemisphere, add to the complexity of organ asymmetries and presumably played a decisive role for sociocultural evolution. The evolutionary origin of organ asymmetries may have been a longer than body length gut, which allows efficient retrieval of nutrients, and the need to stow a long gut in the body cavity in an orderly manner that ensures optimal functioning. Vertebrate organ asymmetries (situs solitus) are quite sophisticated: in humans, the apex of the asymmetrically built heart points to the left; the lung in turn, due to space restrictions, has fewer lobes on the left than on the right side (two versus three in humans), stomach and spleen are found on the left, the liver on the right, and small and large intestine coil in a chiral manner (Figure 1A). In very rare cases (1:10,000), the organ situs is inverted (situs inversus), while heterotaxia refers to another rare situation (about 1:1,000), in which subsets of organs show normal or aberrant positioning or morphology (Figure 1B). Individuals with situs solitus or situs inversus are healthy, whereas heterotaxia presents severe congenital malformations. Many human syndromes are known in which patients suffer from laterality defects, such as Katagener syndrome, in which the organ situs is inverted in one half of patients and males are sterile. Snail shells and vertebrate organs are examples of biased asymmetries with on average only one inversion in every 10,000 cases. Other asymmetries such as the coiling of the tails of piglets occur randomly with a 50:50 distribution. This primer exclusively deals with organ asymmetries in the animal kingdom, specifically with the mechanisms that ensure the development of biased asymmetries during embryogenesis.
The function of normal and defective candidate genes for human genetic diseases, which are rapidly being identified in large numbers by human geneticists and the biomedical community at large, will be best studied in relevant and predictive model organisms that allow high-speed verification, analysis of underlying developmental, cellular and molecular mechanisms, and establishment of disease models to test therapeutic options. We describe and discuss the pros and cons of the frog Xenopus, which has been extensively used to uncover developmental mechanisms in the past, but which is being underutilized as a biomedical model. We argue that Xenopus complements the more commonly used mouse and zebrafish as a time- and cost-efficient animal model to study human disease alleles and mechanisms.
Anatomical and functional asymmetries are widespread in the animal kingdom [1, 2]. In vertebrates, many visceral organs are asymmetrically placed [3]. In snails, shells and inner organs coil asymmetrically, and in Drosophila, genitalia and hindgut undergo a chiral rotation during development. The evolutionary origin of these asymmetries remains an open question [1]. Nodal signaling is widely used [4], and many, but not all, vertebrates use cilia for symmetry breaking [5]. In Drosophila, which lacks both cilia and Nodal, the unconventional myosin ID (myo1d) gene controls dextral rotation of chiral organs [6, 7]. Here, we studied the role of myo1d in left-right (LR) axis formation in Xenopus. Morpholino oligomer-mediated myo1d downregulation affected organ placement in >50% of morphant tadpoles. Induction of the left-asymmetric Nodal cascade was aberrant in >70% of cases. Expression of the flow-target gene dand5 was compromised, as was flow itself, due to shorter, fewer, and non-polarized cilia at the LR organizer. Additional phenotypes pinpointed Wnt/planar cell polarity signaling and suggested that myo1d, like in Drosophila [8], acted in the context of the planar cell polarity pathway. Indeed, convergent extension of gastrula explant cultures was inhibited in myo1d morphants, and the ATF2 reporter gene for non-canonical Wnt signaling was downregulated. Finally, genetic interference experiments demonstrated a functional interaction between the core planar cell polarity signaling gene vangl2 and myo1d in LR axis formation. Thus, our data identified myo1d as a common denominator of arthropod and chordate asymmetry, in agreement with a monophyletic origin of animal asymmetry.
Summary: Vertebrates display asymmetric arrangements of inner organs such as heart and stomach. The Nodal signaling cascade in the left lateral plate mesoderm in all cases directs asymmetric morphogenesis and placement during organogenesis. Mechanisms that lead up to left-asymmetric Nodal induction seem to differ between the vertebrates. Cilia produce a leftward extracellular fluid flow in zebrafish, medaka, mouse, rabbit, and Xenopus embryos during neurulation. In Xenopus, earlier asymmetric cues were described. Some, such as Rab11, apparently act in the zygote. Others were efficiently manipulated in ventralright cells at the four-cell stage, a lineage presumably independent of the ciliated gastrocoel roof plate (GRP) during neurulation. Here, we show that one-and fourcell manipulations of Rab11 showed equal low efficiencies of left-right disturbances. We also reevaluated the lineage of the GRP. By tracing back future ciliated cells from the gastrula to the four-cell stage, we show that ventral cells contribute to ciliated sensory cells at the border of the GRP. Knockdown of the Nodal inhibitor Coco in the ventral right lineage resulted in embryos with ectopic right-sided Nodal and Pitx2c expression. Together, these experiments support a cilia-based mechanism of symmetry breakage in the frog Xenopus. genesis 52:588-599,
Malfunctions of motile cilia cause a variety of developmental defects and diseases in humans and animal model organisms. Defects include impaired mucociliary clearance of the airways, sperm immotility, hydrocephalus and organ laterality. Here, we characterize the evolutionary conserved Cfap43 gene by loss-of-function experiments in the mouse and the frog Xenopus laevis. Cfap43 is expressed in tissues carrying motile cilia and acts as a target gene of the transcription factor FOXJ1, which is essential for the induction of motile ciliogenesis. We show that CFAP43, a protein of unknown biochemical function, localizes to the ciliary axoneme. CFAP43 is involved in the regulation of the beating frequency of tracheal cilia and loss of CFAP43 causes severe mucus accumulation in the nasal cavity. Likewise, morphant and crispant frog embryos revealed impaired function of motile cilia of the larval epidermis, a model for airway mucociliary epithelia. CFAP43 participates in the formation of flagellar axonemes during spermatogenesis as mice mutant for Cfap43 display male infertility, consistent with observations in male sterile patients. In addition, mice mutant for Cfap43 display early onset hydrocephalus. Together, these results confirm the role of CFAP43 in the male reproductive tract and pinpoint additional functions in airway epithelia mucus clearance and brain development.
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