Molecular mechanism of feather formation found
In a previous study, UW anatomy professor John F. Fallon and his team showed that Sonic hedgehog (Shh) and bone morphogenetic protein 2 (Bmp2) must be expressed in order to produce barb ridges, which are among the first structures to form in the tufted branches of the simple downy chick feather. The two proteins, which tend to play off each other in organ development, also are involved in the embryonic development of limbs, lungs, teeth and the gut.
In the current study, appearing in the Aug. 16 Proceedings of the National Academy of Sciences (PNAS Online, Aug. 8), Fallon's team and collaborators showed that during the development of barbs-filamentous structures that form the feather-the function of these two proteins interact. SHH up-regulates its own expression and that of Bmp2, and Bmp2 then signals the down-regulation of Shh expression. This dynamic signaling interaction fits a longstanding mathematical model known as an activator-inhibitor mechanism, says lead author Matthew P. Harris, Fallon's graduate student now doing a postdoctoral fellowship with Nobel Laureate Christiane Nusslein-Volhard at Max Plank Institute in Tubingen, Germany.
"In this model, the inhibitor down-regulates activator function, the activator up-regulates its own expression and the activator also increases the activity of the inhibitor," Harris says. "The model is a simple way of explaining how feather patterning is achieved."
Theoretical biologist Hans Meinhardt, also at the Max Plank Institute and a collaborator on the PNAS paper, posited the role of the activator-inhibitor model in developmental patterning in animals years ago. Through the combined efforts of Meinhardt, Richard Prum of Yale University and Scott Williamson of Cornell University, the model was placed in the context of simulations of growing feathers.
The results suggested that a simple interaction between Shh and Bmp2 is sufficient to model the creation and patterning of barbs in feather development. The team then tested whether such interactions truly exist in the developing feather. In the first steps of feather development, cells exposed to essentially the same levels of Bmp2 and Shh grow from a small bud to form a uniform ring. Shh then is expressed in specific spots along the ring, giving rise to bumps, seen microscopically as longitudinal stripes demarcating the edges of ridges in the developing barb.
"Each barb ridge grows in length by recruiting new cells, which proliferate at the growing base of the feather germ, to join the base of that barb ridge," Harris says. "The variations in the initial number of barb ridges will directly affect the shape, and consequent function, of the feather."
To test the activator-inhibitor model, Harris injected retroviruses to force the expression of either Shh or Bmp2 into the skin of six-day-old chick embryos. The virus infected only small patches of cells and allowed Harris to locally examine the effects of the treatment on barb patterning during feather development.
To assess the specific role of Bmp2 in regulating Shh expression, Harris tricked the cells into believing that Bmp2 was signaling them continuously by altering receptors in the cells. The over-expression of Bmp2 signaling via the altered receptors led to ongoing down-regulation of normal Shh expression needed to form the barbs.
Harris and colleagues used a similar experiment to test whether Shh could up-regulate its own expression during barb formation, and found that it could. Similarly, they found that regional expression of Shh led to detectable up-regulation of Bmp2 in feather buds as they first grew.
The underlying assumptions of the model were found to be true in developing feathers. These findings suggest that simple relationships between developmental genes can provide the basis for the formation of complex forms.
The researchers predict that a more complicated version of the model can be applied to the formation of more complex feathers. Termed pennaceous, these feathers occur in the duck and other birds, including adult chickens, and are not characterized as downy. The more primitive young chicken feathers, which are downy, are called plumalaceous.
"We don't have empirical evidence for this yet, but mathematical analyses lead us to believe that the addition of a third signaling factor leads to the development of the more complex pennaceous feather," Fallon says. "Our model supports paleontologic evidence that pennaceous feathers are more advanced than plumalaceous feathers."
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