Left–right patterning from the inside out: Widespread evidence for intracellular control

Abstract

The field of left-right (LR) patterning--the study of molecular mechanisms that yield directed morphological asymmetries in otherwise symmetrical organisms--is in disarray. On one hand is the undeniably elegant hypothesis that rotary beating of inclined cilia is the primary symmetry-breaking step: they create an asymmetric extracellular flow across the embryonic midline. On the other hand lurk many early symmetry-breaking steps that, even in some vertebrates, precede the onset of ciliary flow. We highlight an intracellular model of LR patterning where gene expression is initiated by physiological asymmetries that arise from subcellular asymmetries (e.g. motor-protein function along oriented cytoskeletal tracks). A survey of symmetry breaking in eukaryotes ranging from protists to vertebrates suggests that intracellular cytoskeletal elements are ancient and primary LR cues. Evolutionarily, quirky effectors like ciliary motion were likely added later in vertebrates. In some species (like mice), developmentally earlier cues may have been abandoned entirely. Late-developing asymmetries pose a challenge to the intracellular model, but early mid-plane determination in many groups increases its plausibility. Multiple experimental tests are possible.

Far from solved: A perspective on what we know about early mechanisms of left–right asymmetry

“…Previously, we suggested alternative interpretations of existing data and presented a different view on LR asymmetry (Levin and Nascone, 1997;Levin and Palmer, 2007), as have others (Brown and Wolpert, 1990;Bock and Marsh, 1991;Yost, 1991). Since then, while papers associating ciliary function with asymmetry continue to mount (see Basu and Brueckner, 2008, for an excellent review), several important studies now reveal additional crucial data that require a reappraisal of the field.…”

Laterality defects are influenced by timing of treatments and animal model

“…Previous discussions about the appropriateness of the mouse model to extrapolate understanding of LR mechanisms to other animals have focused on the differences between LR mutations in mouse and human (Vandenberg and Levin, 2010b; Levin, 2005), the impact of embryonic architecture (Blum et al, 2009; Gros et al, 2009), and the difficulties inherent in working with mouse embryos, which are randomized when cultured (Levin and Palmer, 2007; Fujinaga and Baden, 1991). The general assumption is that there is conservation of mechanisms across species (Levin and Palmer, 2007; Palmer, 2004; Tabin, 2006); thus, the question is whether the central importance of cilia to mouse LR asymmetry makes this animal an outlier, or whether the many examples of animals that orient the LR axis without the benefit of, or prior to the appearance of cilia, are the outliers (Vandenberg and Levin, 2010b).…”

“…The general assumption is that there is conservation of mechanisms across species (Levin and Palmer, 2007; Palmer, 2004; Tabin, 2006); thus, the question is whether the central importance of cilia to mouse LR asymmetry makes this animal an outlier, or whether the many examples of animals that orient the LR axis without the benefit of, or prior to the appearance of cilia, are the outliers (Vandenberg and Levin, 2010b). The results of this study suggest that mice are particularly vulnerable to LR randomization, to a degree that sets them apart from other animal models.…”

“…To select studies for analysis, PubMed was searched with keywords “left right asymmetry.” Additional studies were found from citation lists at the end of comprehensive review articles (Hirokawa et al, 2006; Levin, 2005; 2006; 2007; Levin and Palmer, 2007; Shiratori and Hamada, 2006). Any study that examined the effects of a genetic mutation, molecular manipulation (morpholino treatment, injection of mRNA, etc.…”

“…Treatments were categorized as having effects early in embryogenesis, i.e. during the first few cell cleavages up to blastula stages, prior to when ciliary motion has been observed (Levin and Palmer, 2007), or as having effects during neurula stages when ciliary motion has been implicated in symmetry breaking (Basu and Brueckner, 2008; McGrath and Brueckner, 2003). These two groups will be referred to as EARLY treatments and CILIA treatments, respectively.…”