Extracellular adenosine deamination primes tip organizer development in Dictyostelium

Ammonia is a morphogen in Dictyostelium and is known to arise from the catabolism of proteins and RNA. However, we show that extracellular adenosine deamination catalyzed by ‘adenosine deaminase related growth factor’ (ADGF), is a major source of ammonia, and demonstrate a direct role of ammonia in tip organizer development. The tip formed during early development in Dictyostelium functions analogously to the embryonic organizer of higher vertebrates. Dictyostelium cell lines carrying mutations in the gene adgf fail to establish an organizer, and this could be reversed by exposing the mutants to volatile ammonia. Interestingly, Klebsiella pneumoniae physically separated from the Dictyostelium adgf mutants in a partitioned dish, also rescues the mound arrest phenotype suggesting a cross-kingdom interaction that drives development. Both the substrate, adenosine and the product, ammonia regulate adgf expression, and ADGF acts downstream of the histidine kinase DhkD in regulating tip formation. Thus, the consecutive transformation of extracellular cAMP to adenosine, and adenosine to ammonia are integral steps during Dictyostelium development. Remarkably, in higher vertebrates, adgf expression is elevated during gastrulation and thus adenosine deamination may be a conserved process driving organizer development in different organisms.