Rab8 GTPase differentially controls the long-, and short-range activity of the Hedgehog morphogen gradient by regulating Hedgehog apico-basal distribution

The Hedgehog (Hh) morphogen gradient is required for patterning during metazoan development, yet the mechanisms involved in Hh apical and basolateral release and how this influences short- and long-range target induction are poorly understood. We found that depletion of the GTPase Rab8 in Hh producing cells induces an imbalance between the level of apically and laterally released Hh. This leads to a non-cell autonomous differential effects on the expression of Hh target genes, namely an increase in the short-range and a concomitant decrease in the long-range. We further found that Rab8 regulates the endocytosis and apico-basal distribution of Ihog, a transmembrane protein known to bind to Hh and critical for the establishment of the Hh gradient. Our data provide new understandings of morphogen gradient formation, whereby morphogen activity is functionally distributed between apically and baso-laterally secreted pools.