Extracellular adenosine deamination primes tip organizer development in Dictyostelium

Ammonia is a morphogen in <i>Dictyostelium</i> and is known to arise from the catabolism of proteins and RNA. However, we show that extracellular adenosine deamination catalysed 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 <i>Dictyostelium</i> functions analogously to the embryonic organizer of higher vertebrates. <i>Dictyostelium</i> strains carrying mutations in the gene <i>adgf</i> fail to establish an organizer, and this could be reversed by exposing the mutants to volatile ammonia. Interestingly, <i>Klebsiella pneumoniae</i> physically separated from the <i>Dictyostelium adgf</i> mutants in a partitioned dish also rescues the mound arrest phenotype. Both the substrate, adenosine and the product, ammonia, regulate <i>adgf</i> 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 is integral steps during <i>Dictyostelium</i> development. Remarkably, in higher vertebrates, <i>adgf</i> expression is elevated during gastrulation and thus adenosine deamination may be a conserved process driving organizer development in different organisms.