TheDrosophilamuscle LIM protein, Mlp84B, cooperates with D-titin to maintain muscle structural integrity

Abstract

Muscle LIM protein (MLP) is a cytoskeletal LIM-only protein expressed in striated muscle. Mutations in human MLP are associated with cardiomyopathy; however, the molecular mechanism by which MLP functions is not established. A Drosophila MLP homolog, mlp84B, displays many of the same features as the vertebrate protein, illustrating the utility of the fly for the study of MLP function. Animals lacking Mlp84B develop into larvae with a morphologically intact musculature, but the mutants arrest during pupation with impaired muscle function. Mlp84B displays muscle-specific expression and is a component of the Z-disc and nucleus. Preventing nuclear retention of Mlp84B does not affect its function, indicating that Mlp84B site of action is likely to be at the Z-disc. Within the Z-disc, Mlp84B is colocalized with the N-terminus of D-titin, a protein crucial for sarcomere organization and stretch mechanics. The mlp84B mutants phenotypically resemble weak D-titin mutants. Furthermore, reducing D-titin activity in the mlp84B background leads to pronounced enhancement of the mlp84B muscle defects and loss of muscle structural integrity. The genetic interactions between mlp84B and D-titin reveal a role for Mlp84B in maintaining muscle structural integrity that was not obvious from analysis of the mlp84B mutants themselves, and suggest Mlp84B and D-titin cooperate to stabilize muscle sarcomeres.

Sexual transfer of the steroid hormone 20E induces the postmating switch in Anopheles gambiae

“…Among up-regulated transcripts (n = 137) were a considerable number of genes associated with tissue structure, including the cytoskeleton genes Actin5C, Actincytosk, and β-tubulin I and an adducin-like protein important for cytoskeleton network assembly (37). Changes in the atrial musculature were indicated through induction of Mlp84B, which functions in muscle differentiation (38), and two myosins. Functional enrichment analysis (Table S1) identified the proteasome pathway as significantly up-regulated, whereas downregulated genes (n = 119) were overrepresented by membranespanning tetraspanins, with potential roles in intracellular signaling, cellular motility, and hemocyte cell-cell interactions (Fig.…”

Novel Regulators of Planar Cell Polarity: A Genetic Analysis in Drosophila

“…Scaffolding proteins encoded by CG11146, with SH3/SH2 domains, CG1019 (Muscle LIM protein, Mlp), a LIM domain-containing protein (Clark et al 2007) and CG13388 (a kinase anchoring protein, Akap200) (Jackson and Berg 2002) were also isolated. Finally, proteins of unknown molecular nature encoded by CG15730, which is the fly ortholog of Mks1 (Meckel-Gruber syndrome 1), a gene mutated in human cilliary disease, and CG10068, which has been associated with cytokinesis in a cell-based genome-wide screen (Echard et al 2004) round out the molecular features of the new PCP regulators (see Discussion for more details).…”

Molecular mechanisms of mechanosensing in muscle development

“…MLP in vertebrates also initiates a stretchregulated downstream response, a hypertrophic program that leads to an increase in the number of sarcomeres, likely through its ability to translocate from the Z-disk to the nucleus, where it associates with muscle-specific transcriptional activators (Arber et al, 1994;Knöll et al, 2002). In contrast, Drosophila Mlp(s) display some transient nuclear localization, but with no proven nuclear function, because an Mlp84B transgene carrying a nuclear export signal can fully rescue the pupal lethality of mlp84B mutants (Stronach et al, 1996;Clark et al, 2007).…”

“…1). The Drosophila MLP family is encoded by two genes, mlp60A and mlp84B, and their protein products are both detected at the periphery of Z-disks and at myotendinous junctions (Stronach et al, 1996;Clark et al, 2007). Interestingly, despite its early localization, Mlp84B depletion results in late muscle defects observed just before pupation.…”

“…Interestingly, despite its early localization, Mlp84B depletion results in late muscle defects observed just before pupation. However, the onset and severity of phenotypes is enhanced when the activity of Drosophila D-titin is reduced in the mlp84B background, indicating that Mlp84B maintains sarcomeric structural integrity in cooperation with Dtitin (Clark et al, 2007). In the Drosophila heart, Mlp84B acts as a stress sensor, which, when disrupted, causes diastolic interval prolongation, heart rhythm abnormalities, and reduced lifespan, while showing no obvious structural phenotypes (Mery et al, 2008).…”