Neuron-originated Dachshund regulates tracheal tubulogenesis via Lola-Slit axis in Drosophila

Abnormal morphogenesis causes dysfunction of biological tubes and thus is associated with various diseases. However, the underlying regulatory mechanisms for biological tubulogenesis are not fully understood, especially on the cooperation among organs during embryogenesis. In this study, we unexpectedly found that mutation of dac (the ortholog of dach1 in Drosophila), which is expressed in nervous system cells but not in the trachea, causes anterior dorsal trunk (DT) breakages in Drosophila tracheal tubulogenesis. Further investigations showed that Dac interacts with the transcription factor Lola, which was also required for tracheal DT integrity. More intriguingly, we demonstrated that the expression of the secreted glycoprotein Slit was genetically regulated by Dac-Lola axis. Furthermore, we observed that loss of Slit causes DT branch breakages, copying the phenotypes of dac and lola mutations. Finally, our data proved that dac, lola, and slit orchestrate within the same genetic pathway to maintain tracheal DT integrity. In summary, our study reveals a novel Dac-Lola-Slit axis that is required for fly tracheal tubulogenesis through inter-organ communications, providing a molecular theoretical basis for the therapy of DACH1-related tubular diseases.