The secreted molecule Jeb signals through the RTK Alk and Ras to specify the founder cells of the visceral mesoderm. H.-H. Lee 1, H. Nagaso 1, J.B. Weiss 2, M. Frasch 1. 1) Molecular, Cell and Developmental Biology, Mount Sinai School of Medicine, New York, NY; 2) Molecular Medicine and Cardiology, Oregon Health and Sciences University, Portland, OR.
The circular visceral muscles are derived from metameric primordia in the dorsal mesoderm that are defined by the expression of two essential regulators, bagpipe (bap) and biniou (bin). The cells within these primordia become subdivided into two populations: (1) A ventral row of founder cells, marked by the expression of dumbfounded (duf) and the T-box gene org-1. These founders are endowed with the full genetic program to form visceral muscle fibers. (2) Dorsally-located fusion-competent cells, which are marked by sticks and stones (sns) and need to fuse with founders to differentiate. Here we describe a novel signaling pathway controlling the subdivision of the visceral mesoderm (VM) into founders and fusion-competent cells. We show that founder cell specification requires the activities of Jelly belly (Jeb), a molecule secreted from cells abutting the VM primordia ventrally, and the receptor tyrosine kinase Alk, which is expressed in the entire VM primordia. Jeb and Alk trigger MAPK activation and expression of duf and org-1 in the presumptive founder cells. Ectopic expression of Jeb, or of constitutively active Alk and Ras, converts all cells of the VM primordia into founders. Furthermore, forced expression of activated Alk in the VM primordia of jeb mutants restores duf and org-1 expression and rescues most of the visceral muscle defects. Notch counteracts Jeb/Alk signaling, thereby contributing to the restriction of founders to the ventral margin of the VM. Altogether, these and other data suggest that Jeb acts as a spatially-restricted ligand of the RTK Alk and triggers visceral muscle founder specification via a Ras/MAPK cascade. Bap and Bin provide cellular competence to respond to these signals. A founder cell-specific enhancer of org-1 enables us to dissect the molecular integration of these signaling and transcriptional events.