A protective role for<i>Drosophila</i>Filamin in nephrocytes via Yorkie mediated hypertrophy

Koehler, Sybille; Huber, Tobias B.; Denholm, Barry

doi:10.26508/lsa.202101281

Cited by 7 publications

(4 citation statements)

References 58 publications

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“…Apart from muscles, filamin is required for a variety of processes including the formation of ring canals in the nurse cells of the ovary [ 17 ], providing mechanical protection to nephrocytes [ 53 ], promoting macrophage infiltration during development [ 54 ], coordinating axon guidance in neurons [ 55 ], positioning the nucleus in nurse cells [ 56 ], and during epithelial tumor growth [ 57 ]. Because filamin function is linked to its binding partners, which are probably tissue-specific, we expect our mutants to help interrogate filamin functions in other tissues.…”

Section: Discussionmentioning

confidence: 99%

Filamin protects myofibrils from contractile damage through changes in its mechanosensory region

Fisher,

Carriquí-Madroñal,

Mulder

et al. 2024

PLoS Genet

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Filamins are mechanosensitive actin crosslinking proteins that organize the actin cytoskeleton in a variety of shapes and tissues. In muscles, filamin crosslinks actin filaments from opposing sarcomeres, the smallest contractile units of muscles. This happens at the Z-disc, the actin-organizing center of sarcomeres. In flies and vertebrates, filamin mutations lead to fragile muscles that appear ruptured, suggesting filamin helps counteract muscle rupturing during muscle contractions by providing elastic support and/or through signaling. An elastic region at the C-terminus of filamin is called the mechanosensitive region and has been proposed to sense and counteract contractile damage. Here we use molecularly defined mutants and microscopy analysis of the Drosophila indirect flight muscles to investigate the molecular details by which filamin provides cohesion to the Z-disc. We made novel filamin mutations affecting the C-terminal region to interrogate the mechanosensitive region and detected three Z-disc phenotypes: dissociation of actin filaments, Z-disc rupture, and Z-disc enlargement. We tested a constitutively closed filamin mutant, which prevents the elastic changes in the mechanosensitive region and results in ruptured Z-discs, and a constitutively open mutant which has the opposite elastic effect on the mechanosensitive region and gives rise to enlarged Z-discs. Finally, we show that muscle contraction is required for Z-disc rupture. We propose that filamin senses myofibril damage by elastic changes in its mechanosensory region, stabilizes the Z-disc, and counteracts contractile damage at the Z-disc.

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Section: Discussionmentioning

confidence: 99%

Filamin protects myofibrils from contractile damage through changes in its mechanosensory region

Fisher,

Carriquí-Madroñal,

Mulder

et al. 2024

PLoS Genet

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“…Apart from muscles, filamin is required for a variety of processes including the formation of ring canals in the nurse cells of the ovary [13], providing mechanical protection to nephrocytes [43], promoting macrophage infiltration during development [44], coordinating axon guidance in neurons [45], positioning the nucleus in nurse cells [46], and during epithelial tumor growth [47]. Because filamin function is linked to its binding partners, which are probably tissue-specific, we expect our domains to help interrogate filamin functions in other tissues.…”

Section: Discussionmentioning

confidence: 99%

Filamin protects myofibrils from contractile damage through changes in its mechanosensory region

Fisher,

Carriquí-Madroñal,

Mulder

et al. 2023

Preprint

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Filamins are mechanosensitive actin crosslinking proteins that organize the actin cytoskeleton in a variety of shapes and tissues. In muscles, filamin crosslinks actin filaments from opposing sarcomeres, the smallest contractile units of muscles. This happens at the Z-disc, the actin-organizing center of sarcomeres. In flies and vertebrates, filamin mutations lead to fragile muscles that appear ruptured, suggesting filamin helps counteract muscle rupturing during muscle contractions either by providing elastic support or through signaling. The mechanistic details of filamin in this process are largely unknown. Here we use the indirect flight muscles of Drosophila to interrogate the molecular details by which filamin provides cohesion to the Z-disc. We made novel filamin mutations affecting the C-terminal region and detected two Z-disc phenotypes: dissociation of actin filamins and Z-disc rupture. We focused on the ruptured defect and tested a constitutively closed filamin mutant, which results in ruptured Z-discs, and a constitutively open mutant which gives rise to enlarged Z-discs. Finally, we show that muscle contraction is required for Z-disc rupture. We therefore propose that filamin senses myofibril damage by elastic changes in its mechanosensory region, which induces myofibril repair.

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“…Involvement of Drosophila filamin (cheerio) in the Hippo pathway to induce hypertrophic growth has been demonstrated [224]. However, the molecular mechanism by which cheerio controls the Hippo pathway remains unknown.…”

Section: Flna Regulates Cip Through the Hippo Pathwaymentioning

confidence: 99%

The Role of Mechanotransduction in Contact Inhibition of Locomotion and Proliferation

Nakamura

2024

IJMS

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Contact inhibition (CI) represents a crucial tumor-suppressive mechanism responsible for controlling the unbridled growth of cells, thus preventing the formation of cancerous tissues. CI can be further categorized into two distinct yet interrelated components: CI of locomotion (CIL) and CI of proliferation (CIP). These two components of CI have historically been viewed as separate processes, but emerging research suggests that they may be regulated by both distinct and shared pathways. Specifically, recent studies have indicated that both CIP and CIL utilize mechanotransduction pathways, a process that involves cells sensing and responding to mechanical forces. This review article describes the role of mechanotransduction in CI, shedding light on how mechanical forces regulate CIL and CIP. Emphasis is placed on filamin A (FLNA)-mediated mechanotransduction, elucidating how FLNA senses mechanical forces and translates them into crucial biochemical signals that regulate cell locomotion and proliferation. In addition to FLNA, trans-acting factors (TAFs), which are proteins or regulatory RNAs capable of directly or indirectly binding to specific DNA sequences in distant genes to regulate gene expression, emerge as sensitive players in both the mechanotransduction and signaling pathways of CI. This article presents methods for identifying these TAF proteins and profiling the associated changes in chromatin structure, offering valuable insights into CI and other biological functions mediated by mechanotransduction. Finally, it addresses unanswered research questions in these fields and delineates their possible future directions.

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A protective role forDrosophilaFilamin in nephrocytes via Yorkie mediated hypertrophy

Cited by 7 publications

References 58 publications

Filamin protects myofibrils from contractile damage through changes in its mechanosensory region

Filamin protects myofibrils from contractile damage through changes in its mechanosensory region

Filamin protects myofibrils from contractile damage through changes in its mechanosensory region

The Role of Mechanotransduction in Contact Inhibition of Locomotion and Proliferation

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