Abstract
The Drosophila Alp/Enigma family protein Zasp52 localizes to myotendinous junctions and Z-discs. It is required for terminal muscle differentiation and muscle attachment. Its vertebrate ortholog ZASP/Cypher also localizes to Z-discs, interacts with α-actinin through its PDZ domain, and is involved in Z-disc maintenance. Human mutations in ZASP cause myopathies and cardiomyopathies. Here we show that Drosophila Zasp52 is one of the earliest markers of Z-disc assembly, and we use a Zasp52-GFP fusion to document myofibril assembly by live imaging. We demonstrate that Zasp52 is required for adult Z-disc stability and pupal myofibril assembly. In addition, we show that two closely related proteins, Zasp66 and the newly identified Zasp67, are also required for adult Z-disc stability and are participating with Zasp52 in Z-disc assembly resulting in more severe, synergistic myofibril defects in double mutants. Zasp52 and Zasp66 directly bind to α-actinin, and they can also form a ternary complex. Our results indicate that Alp/Enigma family members cooperate in Z-disc assembly and myofibril formation; and we propose, based on sequence analysis, a novel class of PDZ domain likely involved in α-actinin binding.
Highlights
Vertebrate muscles consist of three major types, skeletal, cardiac, and smooth muscles, which correspond in Drosophila to body wall, heart, and visceral muscle
We show by antibody stainings that Zasp52 is among the first repetitively spaced Z-disc markers in indirect flight muscle (IFM) development, indicating that Zasp52 plays a general role in Z-disc assembly
The contractile system consists of actin filaments anchored at the Z-discs, which border the sarcomere, and myosin filaments anchored at the M-line in the middle of the sarcomere
Summary
Vertebrate muscles consist of three major types, skeletal, cardiac, and smooth muscles, which correspond in Drosophila to body wall, heart, and visceral muscle. Proteins of the Alp/ Enigma family function in maintenance of Z-discs [1] and have been proposed to play an important role in myofibril assembly [2,3]. We could show that Zasp is a focal adhesion component and is required for cell spreading downstream of integrins It co-localizes with integrins at myotendinous junctions and is required for muscle attachment. It co-localizes with a-actinin to Z-discs and plays a role in embryonic Z-disc assembly [2]. Mutations of Zasp orthologs in vertebrates cause similar defects, ranging from improper formation of somites and heart in zebrafish to fragmented Z-discs in skeletal and cardiac muscles in mice [10,11]. Mutations in the human ortholog ZASP result in phenotypes of variable severity from congenital myopathy with fetal lethality to late-onset cardiomyopathy [1]
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