Org-1-Dependent Lineage Reprogramming Generates the Ventral Longitudinal Musculature of the Drosophila Heart

Only few examples of transdifferentiation, which denotes the conversion of one differentiated cell type to another [1], are known to occur during normal development, and more often, it is associated with regeneration processes [2-7]. With respect to muscles, dedifferentiation/redifferentiation processes have been documented during post-traumatic muscle regeneration in blastema of newts as well as during myocardial regeneration [8, 9]. As shown herein, the ventral longitudinal muscles of the adult Drosophila heart arise from specific larval alary muscles in a process that represents the first known example of syncytial muscle transdifferentiation via dedifferentiation into mononucleate myoblasts during normal development. We demonstrate that this unique process depends on the reinitiation of a transcriptional program previously employed for embryonic alary muscle development, in which the factors Org-1 (Drosophila Tbx1) and Tailup (Drosophila Islet1) are key components. During metamorphosis, the action of these factors is combined with cell-autonomous inputs from the ecdysone steroid and the Hox gene Ultrabithorax, which provide temporal and spatial specificity to the transdifferentiation events. Following muscle dedifferentiation, inductive cues, particularly from the remodeling heart tube, are required for the redifferentiation of myoblasts into ventral longitudinal muscles. Our results provide new insights into mechanisms of lineage commitment and cell-fate plasticity during development.