Why the thumb of the right hand is on the left hand side

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Why the thumb of the right hand is on the left hand side

A researcher of the University of Innsbruck elucidates an important

developmental mechanism.

http://www.eurekalert.org/pub_releases/2009-05/uoi-wtt052209.php

It is the concentration of a few signaling molecules that determines the fate of

individual cells during the early development of organisms. In the renowned

journal Current Biology, a team of molecular biologists led by Pia Aanstad of

the University of Innsbruck reports that a variety of molecular mechanisms

accounts for the interpretation of the concentration of the signaling molecule

Hedgehog.

The development of an organism is a complex process to which a dozen or hundreds

of signaling molecules contribute. Some of these molecules have dozens of

functions in the fruit fly and in humans alike. One of these molecules –

Hedgehog – controls the development of, for example, the extremities, the

central nervous system, the teeth, eyes, hair, lung and the gastrointestinal

tract. " What is most remarkable: The cells are told what to do not only because

the molecule is present but also by the different concentrations of the

molecules in the tissue " , says group leader Pia Aanstad of the Institute for

Molecular Biology of the University of Innsbruck. " The concentration of Hedgehog

makes the thumb of the right hand grow on the left hand side and the thumb of

the left hand grow on the right hand side. " Thus, scientists define Hedgehog as

a morphogen – a signal that is concentration-dependent and controls the pattern

formation of an organism. A mutation in this signaling pathway induces dramatic

and embryonically lethal malformations in the early developmental stage such as

the formation of just one central eye. Defects in the Hedgehog signaling pathway

in humans are a cause for one of the most common birth defects –

holoprosencephaly. " Hedgehog genes are not new in evolution and the signaling

pathway functions in the fly, mouse, fish and in humans similarly " , says Pia

Aanstad. In her research work she focuses on the zebra danio or zebra fish. Due

to the short developmental cycle, the scientists are able to observe the

development of the small tropic fish in fast motion. " We want to better

understand how the cells process the signals of the signaling molecules and how

they react. "

Mutants do not react to high concentrations

Already during her time as a post doc in San Francisco, U.S., Pia Aanstad

discovered a mutated zebra fish whose Hedgehog signaling pathway was disrupted.

The fish showed a genetic alteration at the so-called Smoothened (Smo) protein,

which is located at the cell membrane and transfers the Hedgehog signal into the

cell. In 2005, Aanstad and her colleagues published a paper in the renowned

journal Nature, in which they showed that Smo is concentrated at cilia (cellular

projections) and also functions at the cilium. " By using high-resolution

fluorescence microscopy, we have now shown that in the new mutants a small

genetic alteration at the extracellular part of this protein inhibits

localization in the cilia and that while the cells identify the Hedgehog

signals, they interpret the concentration incorrectly " , explains Pia Aanstad.

" This is evidence for the notion that cells use various molecular mechanisms for

interpreting different Hedgehog concentrations. " This fact may also be of

importance for the diagnosis and treatment of certain cancers (basal cell

carcinoma), where the constant up-regulation of the Hedgehog signal is

responsible for uncontrolled cell growth. Aanstad published the findings

together with her colleagues from the University of California, San Francisco in

the journal Current Biology.