Biology subjects

Mihaly, J.

Publications and source records attributed to Mihaly, J..

4 recordsLinked to original sources

bioRxiv2026

Flightless I and LRRFIP work together to regulate lateral growth of the sarcomeres in Drosophila

Myofibrils are structurally highly conserved elements of the cardiac and striated muscles. The striking commonalities in their basic organization principles emerge during myofibrillogenesis when the initially formed premyofibrils grow in length and width to attain their final dimensions, characteristic of each muscle type. Although the molecular composition of the myofibrils is well known, the mechanisms governing their growth remain poorly understood, particularly those driving peripheral thickening. Here, we show that two cardiac disease associated proteins, Flightless I and LRRFIP, are required for lateral integration of the myofilaments that is essential for circumferential myofibril growth in the Drosophila flight muscle. Genetic and biochemical analysis reveal that these proteins form multimeric complexes enriched at the barbed end of the actin filaments. Furthermore, we found that the Flightless I/LRRFIP complex acts in a formin dependent manner. Together, our findings demonstrate that Flightless I and LRRFIP cooperate to promote the spatially controlled integration of peripheral actin filaments at the Z-disc, uncovering a key step in myofibril maturation.

cell biology↗

bioRxiv2021

Oxoglutarate dehydrogenase coordinates myofibril growth by maintaining amino acid homeostasis

Myofibrils are long intracellular cables specific to muscles, composed mainly of actin and myosin filaments. The actin and myosin filaments are organized into repeated units called sarcomeres, which form the myofibril cables. Muscle contraction is achieved by the simultaneous shortening of sarcomeres and for a highly coordinated contraction to occur all sarcomeres should have the same size. Muscles have evolved a variety of ways to ensure sarcomere homogeneity, one example being the controlled oligomerization of Zasp proteins that sets the diameter of the myofibril. To understand how Zasp proteins effect myofibril growth, we looked for Zasp-binding proteins at the Z-disc. We found that the E1 subunit of the oxoglutarate dehydrogenase complex is recruited to the Z-disc by Zasp52 and is required to sustain myofibril growth. By making specific mutants, we show that its enzymatic activity is important for myofibril growth, and that the other two subunits of the complex are also required for myofibril formation. Using super resolution microscopy, we revealed the overall organization of the complex at the Z-disc. Then, using metabolomic analysis, we uncovered an amino acid balance defect affecting protein synthesis, that we also confirmed by genetic tools. In summary, we show that Zasp controls the local amino acid pool responsible for myofibril growth by recruiting the OGDH complex to the Z-disc.

cell biology↗

bioRxiv2017

Formin3 regulates dendritic architecture via microtubule stabilization and is required for somatosensory nociceptive behavior

The acquisition, maintenance and modulation of dendritic architecture are critical to neuronal form, plasticity and function. Morphologically, dendritic shape impacts functional connectivity and is largely mediated by organization and dynamics of cytoskeletal fibers that provide the underlying scaffold and tracks for intracellular trafficking. Identifying molecular factors that regulate dendritic cytoskeletal architecture is therefore important in understanding mechanistic links between cytoskeletal organization and neuronal function. In a neurogenomic-driven genetic screen of cytoskeletal regulatory molecules, we identified Formin3 (Form3) as a critical regulator of cytoskeletal architecture in Drosophila nociceptive sensory neurons. Form3 is a member of the conserved Formin family of multi-functional cytoskeletal regulators and time course analyses reveal Form3 is cell-autonomously required for maintenance of complex dendritic arbors. Cytoskeletal imaging demonstrates form3 mutants exhibit a specific destabilization of the dendritic microtubule (MT) cytoskeleton, together with defective dendritic trafficking of mitochondria, satellite Golgi and the TRPA channel Painless. Biochemical studies reveal Form3 directly interacts with MTs via FH1-FH2 domains and promotes MT stabilization via acetylation. Neurologically, mutations in human Inverted Formin 2 (INF2; ortholog of form3) have been causally linked to Charcot-Marie-Tooth (CMT) disease. CMT sensory neuropathies lead to impaired peripheral sensitivity. Defects in form3 function in nociceptive neurons results in a severe impairment in noxious heat evoked behaviors. Expression of the INF2 FH1-FH2 domains rescues form3 defects in MT stabilization and nocifensive behavior revealing conserved functions in regulating the cytoskeleton and sensory behavior thereby providing novel mechanistic insights into potential etiologies of CMT sensory neuropathies.\n\nSignificance StatementMechanisms governing cytoskeletal architecture are critical in regulating neural function as aberrations are linked to a broad spectrum of neurological and neurocognitive disorders. Formins are important cytoskeletal regulators however their mechanistic roles in neuronal architecture are poorly understood. We demonstrate mutations in Drosophila formin3 lead to progressive destabilization of the dendritic microtubule cytoskeleton resulting in severely reduced arborization coupled to impaired organelle and ion channel trafficking, as well as nociceptive sensitivity. INF2 mutations are implicated in CMT sensory neuropathies, and INF2 expression can rescue microtubule and nociceptive behavioral defects in form3 mutants. While CMT sensory neuropathies have been linked to defects in axonal development and myelination, our studies connect dendritic cytoskeletal defects with peripheral insensitivity suggesting possible alternative etiological bases.

neuroscience↗

bioRxiv2017

Nitric oxide-dependent inflammation underlies Notch and PI3K/Akt oncogene cooperation

Concurrent activating mutations of the Notch and PI3K/Akt signalling pathways cooperate in the induction of aggressive cancers. Unfortunately, direct targeting of any of these aberrant pathways can result in severe side effects due to their broad physiological roles in multiple organs. Here, using an unbiased chemical in vivo screen in Drosophila we identified compounds that suppress the activity of the pro-inflammatory enzymes, nitric oxide synthase (NOS) and lipoxygenase (LOX), capable to block oncogenic Notch-PI3K/Akt cooperation without unwanted side effects. Genetic inactivation of NOS and LOX signalling components mirrors the anti-tumorigenic effect of the hit compounds. We show that NOS activity and immunosuppression associated to inflammation facilitates Notch-mediated tumorigenesis. Our study reveals an unnoticed immune inflammatory process underlying Notch-PI3K/Akt tumours and exposes NOS as a druggable target for anti-cancer therapeutic development.

cancer biology↗