According to a press release from the Forsyth Institute, scientists studying frogs, chickens and zebrafish have identified a common molecular mechanism responsible for embryonic left/right patterning:
A team of Forsyth Institute scientists, led by Michael Levin, PhD, Director of the Forsyth Center for Regenerative and Developmental Biology, examined the molecular and genetic factors that control left/right asymmetry and identified a novel component: an ion transporter that creates strong natural voltage gradients and pH changes. The pump that normally acidifies subcellular compartments was shown to control embryonic laterality at very early stages. Their findings further challenged the previously held hypothesis that cilia (short hair-like structures on a cell) were the primary agents allowing an embryo to correctly position its internal organs along the left-right axis. Instead, their research showed a single asymmetry mechanism linking ciliary, serotonergic (serotonin is the chemical substance involved in transmitting signals between neurons), and ion flow mechanisms. The data was strengthened by the operation of this mechanism through all three vertebrates. This is important because prior data was very fragmented and different asymmetry-controlling systems appeared to be operating in frog/chick embryos vs. human/mouse/zebrafish embryos…
Dr. Levin’s team looked at molecular genetic and physiological characterization of a novel, early, biophysical event that is crucial for correct asymmetry: the flow of hydrogen ion or H+ flux. A pharmacological screen implicated the H+-pump H+-V-ATPase in Xenopus (frog) embryo asymmetry, where it directs left- and right-sided gene expression. The cell cytoskeleton is responsible for the LR-asymmetric localization of this pump during the first few cell cleavages in frog embryos. H+-flux across plasma membranes is thus asymmetric at the four- and eight-cell stages, and this asymmetry requires H+-V-ATPase activity. Artificially equalizing the asymmetry in H+ flux, by increasing or decreasing it on both sides equally, both randomized the location of the viscera without causing any other defects. To understand the mechanism of action of H+-V-ATPase, researchers isolated its two physiological functions, cytoplasmic pH and membrane voltage gradient (Vmem) regulation. Varying either pH or Vmem, independently of direct manipulation of H+-V-ATPase, caused disruptions of the normal LR pattern, suggesting important roles for both physiological parameters. V-ATPase inhibition also abolished the normal localization of serotonin at the 16-cell stage, suggesting that it helps to regulate the early flow of this important neurotransmitter. These data implicate H+-V-ATPase activity in patterning the left right axis of three different vertebrates, reveal mechanisms both upstream and downstream of its activity, and identify a novel role for this important ion transporter. Based on these observations, they proposed a detailed pH- and Vmem-dependent model of the early physiology of left/right patterning.
Illustrated above is dextrocardia: one of the left-right confusion syndromes.
The press release…
