Frazzled (Fra) is a chemoattractive guidance receptor regulating the cytoskeletal dynamics underlying growth cone steering at the Drosophila embryonic midline. Here, by genetically evaluating the role of Rho GTPases in Fra signaling in vivo, we uncover a Rho-dependent pathway apparently regulating conventional myosin II activity. Midline crossing errors induced by expressing activated Cdc42(v12) or Rac(v12) are suppressed by a heterozygous loss of fra(4) signaling but, in a Fra(wt) gain-of-function condition, no interaction is detected. In contrast, the frequency of crossovers is enhanced approximately 5-fold when Fra(wt) is co-expressed with activated Rho(v14) and this interaction specifically requires the cytoplasmic P3 motif of Fra. Expression of Rho(v14) and activated MLCK (ctMLCK) synergistically increase ectopic crossovers and both require phosphorylation of the regulatory light chain (Sqh) of myosin II. Abelson tyrosine kinase may also help regulate myosin II activity. Heterozygous abl(4) abolishes the midline crossing errors induced by ctMLCK alone or in combination with Fra(wt); suppression of Rho(v14) crossovers is not observed. Interestingly, an interaction between Fra and an activated Abl (Bcr-Abl) also specifically requires the P3 motif. Therefore, the P3 motif of Frazzled appears to initiate Rho and Abl dependent signals to directly or indirectly regulate myosin II activity in growth cones.
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