Motor protein control of ion flux is an early step in embryonic left–right asymmetry

Abstract

The invariant left-right asymmetry of animal body plans raises fascinating questions in cell, developmental, evolutionary, and neuro-biology. While intermediate mechanisms (e.g., asymmetric gene expression) have been well-characterized, very early steps remain elusive. Recent studies suggested a candidate for the origins of asymmetry: rotary movement of extracellular morphogens by cilia during gastrulation. This model is intellectually satisfying, because it bootstraps asymmetry from the intrinsic biochemical chirality of cilia. However, conceptual and practical problems remain with this hypothesis, and the genetic data is consistent with a different mechanism. Based on wide-ranging data on ion fluxes and motor protein action in a number of species, a model is proposed whereby laterality is generated much earlier, by asymmetric transport of ions, which results in pH/voltage gradients across the midline. These asymmetries are in turn generated by a new candidate for "step 1": asymmetric localization of electrogenic proteins by cytoplasmic motors.

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

“…We proposed previously that alterations in proteins with pleiotropic roles in both intracellular transport and ciliary structure/function cause LR phenotypes and ciliary defects (including kidney cysts, etc.) as parallel downstream consequences (Levin, 2003(Levin, , 2006. This model, in contrast to the model that ciliary motion causes LR asymmetry, predicts that mutations Fig.…”

“…Direct changes of viscosity in the interciliary space and reversal/rescue of nodal flow (Nonaka et al, 2002) suggest that ciliary motion can in fact control LR patterning. In contrast, the majority of studies suggesting a role for cilia in LR asymmetry have involved genetic deletions/mutations of proteins that possess nonciliary (intracellular) functions that are never tested (reviewed in Levin, 2003;Levin and Palmer, 2007); even ''ciliary'' dynein (i.e., LRD) is expressed outside of cilia, for instance in the limbs and headfolds of the developing mouse (Supp et al, 1997), and plays a role in segregation of differentially imprinted chromatids (Armakolas and Klar, 2007). Thus, the vast majority of data does not actually distinguish between ciliary function and intracellular transport or chromatid segregation models, as all three are consistent with a requirement for proteins involved in cytoskeletal assembly, motor protein function, and planar polarity.…”

Gap junctions relay FGF8‐mediated right‐sided repression of Nodal in rabbit

“…The ion flux model of symmetry breakage in frog proposed that unidirectional electrophoresis through open GJ channels resulted in asymmetric segregation of charged low molecular weight determinants and thus asymmetric gene expression (Levin et al, 2002;Levin, 2003Levin, , 2005. We have investigated whether early rabbit embryos displayed voltage or pH gradients similar to those described in Xenopus and chick (Levin et al, 2002).…”

Laterality defects are influenced by timing of treatments and animal model

“…The first is that some overlap in mechanisms has been proposed for these models. For example, LRD has been implicated as important for both models; in the cilia model, mutations in this gene are explained by their effect on extracellular fluid flow (McGrath et al, 2003; Supp et al, 1999) while in the early ion flux model, disruptions in LRD are implicated in intracellular movement of ion transporters and polarity machinery (Qiu et al, 2005; Levin, 2003). The second point is that most studies exploring the role of cilia in the process of symmetry breaking have relied on fish (zebrafish and medaka) and mice to generate data, while studies exploring earlier mechanisms typically use Xenopus and chick (Figure 1).…”