Chip is an essential cofactor for Apterous in the regulation of axon guidance in Drosophila

LIM-homeodomain transcription factors are expressed in subsets of neurons a nd are required for correct axon guidance and neurotransmitter identity. Th e LIM-homeodomain family member Apterous requires the LIM-binding protein C hip to execute patterned outgrowth of the Drosophila wing. To determine whe ther Chip is a general cofactor for diverse LIM-homeodomain functions in vi vo, we studied its role in the embryonic nervous system, Loss-of-function C hip mutations cause defects in neurotransmitter production that mimic apter ous and islet mutants. Chip is also required cell-autonomously by Apterous- expressing neurons for proper axon guidance, and requires both a homodimeri zation domain and a LIM interaction domain to function appropriately. Using a Chip/Apterous chimeric molecule lacking domains normally required for th eir interaction, we reconstituted the complex and rescued the axon guidance defects of apterous mutants, of Chip mutants and of embryos doubly mutant for both apterous and Chip. Our results indicate that Chip participates in a range of developmental programs controlled by LIM-homeodomain proteins an d that a tetrameric complex comprising two Apterous molecules bridged by a Chip homodimer is the functional unit through which Apterous acts during ne uronal differentiation.