Genetic regulation of patterned tubular branching in Drosophila

A common theme in organogenesis is the branching of epithelial tubes, for example in the lung, liver, or kidney. The later morphogenesis of these branched epithelia dictates the final form and function of the mature tissue. Epithelial branching requires the specification of branch cells, the eversion process itself, and, frequently, patterned morphogenesis to produce branches of specific shape and orientation. Using the branching of renal tubule primordia from the hindgut in Drosophila, we show that these aspects are coordinately regulated. Cell specification depends on Wnt signaling along the tubular gut and results in the spatially restricted coexpression of two transcription factors, Krüppel and Cut, in the hindgut, whose activity drives cells toward renal tubule fate. Significantly, these transcription factors also confer the competence to respond to a second signal; TGF-beta induces branching to form the four renal tubule buds. Differential activation of the TGF-beta pathway also patterns the tubules, resulting in the asymmetry in size and positioning that is characteristic of the two tubule pairs. High levels of TGF-beta promote the expression of Dorsocross1-3 and anterior tubule growth, whereas low levels allow the expression of the transcriptional repressor, Brinker, and thus promote posterior tubule identity. We show that patterning of the tubule primordium into two distinct pairs is critical for the eversion of tubule branches, as well as for their asymmetric morphogenesis.