Dr. Denis Duboule

The Evolution and Role of Hox Genes in Limb Development

Tarchini B, Duboule D.2006. Control of Hoxd genes’ collinearity during early limb development. Dev Cell. 10(1):93-103.

Zakany J, Zacchetti G, Duboule D. 2007. Interactions between HOXD and Gli3 genes control the limb apical ectodermal ridge via Fgf10. Dev Biol. 306(2):883-93.

Question 1

Briefly tell us a bit about yourself and your career path over the years leading to your investigations of hox genes and limb development. Additionally, there are many mechanisms at work controlling limb outgrowth and specification. We would appreciate hearing from you, as an expert in this area, what your current model of the molecular mechanisms governing limb development might be. Specifically a model that integrates what is known about shh, fgfs, and gli3 signaling with hox mediated limb patterning.

Michael Barresi

Question 2

Why did the removal of the entire Hoxd gene cluster (del 1-13) only result in a small reduction to the proximal limb? What do you predict would happen if Evx2 was completely removed?

Cecilia Flores

Question 3

In your article “Control of Hoxd Genes Collinearity during Early limb Development” the time of activation for hoxd genes was shown to be a function of the relative distance from the ELCR resulting in a temporal colinearity. Why does distance from the GCR not exhibit the same temporal readout of gene expression, but rather behave along a spatial colinearity? Why is the outcome on hox gene expression from these enhancers different?

Pelmo Takza

Question 4

You mention in your paper that the interaction between anterior hox and posterior hox determine both the onset and regression of the AER. When and how does the regression of the AER happen in normal development? Isn’t the AER required continuously for complete limb development?

Trina Campbell

Question 5

Could you expand upon the idea that other signaling cascades could be controlled by the HOX/GLI3 circuitry? Is there any idea as to which downstream cascades are affected?

Elizabeth Deschene

Question 6

In your paper describing interactions between HoxD and Gli3, you state that the phenotypes observed are due to perturbation at the very early stage of limb bud development. What role do you foresee in later limb bud development of these interactions? Is there another set of genes that take over control of limb patterning?

Monica Severson

Question 7

You state that forelimb genes and mechanisms can be applied to hind limb development, but is it known why an ankle forms instead of a wrist, or a toe instead of a finger? Do these formations result because of Hoxd gene functions and/or regulation differences?

Sanna Cahn

Question 8

Can you describe the methodology performed to map the hoxd genes, and induce scanning deletions and duplications?

Elise Kang

Question 9

When Gli3 is reduced and the limb bud is anteriorized, you mention that proximal development proceeds through more “ancient pathways”. What ancient pathways are you referring too, and do you think this is a special reaction to Gli3 reduction or is common developmental mechanisms?

Sally Kirkorian

Question 10

You say that the textbook representation of Hox clusters is misleading and is the exception and not the general rule of how Hox clusters are organized. Do you think that for the sake of describing the Hox genes in a concise and less confusing way the material should still be taught this way initially and then explain the problems with it, or right from the start explain the way the genes are organized in different lineages? How do you teach the biology of hox genes?

Krista Riihimaki

Question 11

Currently in your opinion what are the most pressing questions in the field of hox gene biology and limb development? What steps is your lab taking to address those questions?

Michael Barresi