Heg1 and Ccm1/2 proteins control endocardial mechanosensitivity during zebrafish valvulogenesis

Donat, Stefan; Lourenço, Marta; Paolini, Alessio; Otten, Cécile; Renz, Marc; Abdelilah‐Seyfried, Salim

doi:10.7554/elife.28939

Cited by 54 publications

(48 citation statements)

References 58 publications

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“…In the heart, Heg1 is expressed in endothelial cells and supports vascular development by stabilizing endothelial cell-cell junctions (Kleaveland et al, 2009;de Kreuk et al, 2016). Recent studies indicate that the level of Heg1 expression is controlled by increased blood flow, implicating Heg1 as a mechanosensitive downstream effector in regulating cardiac valve morphology (Donat et al, 2018). Thus, Heg1 similarly may be activated by mechanoreceptive signaling in pSNs, possibly to regulate interactions with intrafusal myofibers.…”

Section: Identification Of Molecular Markers Of Ms and Gto Afferent Pmentioning

confidence: 99%

A Role for Sensory end Organ-Derived Signals in Regulating Muscle Spindle Proprioceptor Phenotype

Schieren

Qian

et al. 2019

J. Neurosci.

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Proprioceptive feedback from Group Ia/II muscle spindle afferents and Group Ib Golgi tendon afferents is critical for the normal execution of most motor tasks, yet how these distinct proprioceptor subtypes emerge during development remains poorly understood. Using molecular genetic approaches in mice of either sex, we identified 24 transcripts that have not previously been associated with a proprioceptor identity. Combinatorial expression analyses of these markers reveal at least three molecularly distinct proprioceptor subtypes. In addition, we find that 12 of these transcripts are expressed well after proprioceptors innervate their respective sensory receptors, and expression of three of these markers, including the heart development molecule Heg1, is significantly reduced in mice that lack muscle spindles. These data reveal Heg1 as a putative marker for proprioceptive muscle spindle afferents. Moreover, they suggest that the phenotypic specialization of functionally distinct proprioceptor subtypes depends, in part, on extrinsic sensory receptor organderived signals. Sensory feedback from muscle spindle (MS) and Golgi tendon organ (GTO) sensory end organs is critical for normal motor control, but how distinct MS and GTO afferent sensory neurons emerge during development remains poorly understood. Using (bulk)transcriptome analysis of genetically identified proprioceptors, this work reveals molecular markers for distinct proprioceptor subsets, including some that appear selectively expressed in MS afferents. Detailed analysis of the expression of these transcripts provides evidence that MS/GTO afferent subtype phenotypes may, at least in part, emerge through extrinsic, sensory end organderived signals.

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Section: Identification Of Molecular Markers Of Ms and Gto Afferent Pmentioning

confidence: 99%

A Role for Sensory end Organ-Derived Signals in Regulating Muscle Spindle Proprioceptor Phenotype

Schieren

Qian

et al. 2019

J. Neurosci.

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“…Similar valvular defects were also seen with the inhibition of Notch activity [154] . Therefore, CCM proteins are involved in appropriate valve development [155] .…”

Section: Cellular Functions and Biogenesismentioning

confidence: 99%

Recent advances in cerebral cavernous malformation research

Padarti¹,

Zhang²

2018

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Cerebral cavernous malformations (CCM) are manifested by microvascular lesions characterized by leaky endothelial cells with minimal intervening parenchyma predominantly in the central nervous system predisposed to hemorrhagic stroke, resulting in focal neurological defects. Till date, three proteins are implicated in this condition: CCM1 (KRIT1), CCM2 (MGC4607), and CCM3 (PDCD10). These multi-domain proteins form a protein complex via CCM2 that function as a docking site for the CCM signaling complex, which modulates many signaling pathways. Defects in the formation of this signaling complex have been shown to affect a wide range of cellular processes including cell-cell contact stability, vascular angiogenesis, oxidative damage protection and multiple biogenic events. In this review we provide an update on recent advances in structure and function of these CCM proteins, especially focusing on the signaling cascades involved in CCM pathogenesis and the resultant CCM cellular phenotypes in the past decade.

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“…The common cardinal vein (CCV) was dissected, flatmounted in SlowFade Gold Antifade Reagent (S36936, ThermoFisher) and the endothelial cells were imaged with a Zeiss LSM 710 or LSM 780 confocal scanning microscope. Hearts were stained with anti-Alcam (1:20, ZN-8, DSHB) as previously described (Donat et al, 2018) and imaged dissected and flat mounted in SlowFade Gold Antifade Reagent or wholemount embedded in 1% low-melting agarose with a Zeiss LSM 710 or LSM 780 confocal scanning microscope.…”

Section: Zebrafish Handling and Oocyte Injectionsmentioning

confidence: 99%

The CCM1–CCM2 complex controls complementary functions of ROCK1 and ROCK2 that are required for endothelial integrity

Lisowska

Rödel

Manet

et al. 2018

Journal of Cell Science

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Endothelial integrity relies on a mechanical crosstalk between intercellular and cell-matrix interactions. This crosstalk is compromised in hemorrhagic vascular lesions of patients carrying loss-of-function mutations in cerebral cavernous malformation (CCM) genes. RhoA/ROCK-dependent cytoskeletal remodeling is central to the disease, as it causes unbalanced cell adhesion towards increased cell-extracellular matrix adhesions and destabilized cell-cell junctions. This study reveals that CCM proteins directly orchestrate ROCK1 and ROCK2 complementary roles on the mechanics of the endothelium. CCM proteins act as a scaffold, promoting ROCK2 interactions with VE-cadherin and limiting ROCK1 kinase activity. Loss of CCM1 (also known as KRIT1) produces excessive ROCK1-dependent actin stress fibers and destabilizes intercellular junctions. Silencing of ROCK1 but not ROCK2 restores the adhesive and mechanical homeostasis of CCM1 and CCM2-depleted endothelial monolayers, and rescues the cardiovascular defects of mutant zebrafish embryos. Conversely, knocking down Rock2 but not Rock1 in wild-type zebrafish embryos generates defects reminiscent of the mutant phenotypes. Our study uncovers the role of the CCM1-CCM2 complex in controlling ROCK1 and ROCK2 to preserve endothelial integrity and drive heart morphogenesis. Moreover, it solely identifies the ROCK1 isoform as a potential therapeutic target for the CCM disease.

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Heg1 and Ccm1/2 proteins control endocardial mechanosensitivity during zebrafish valvulogenesis

Cited by 54 publications

References 58 publications

A Role for Sensory end Organ-Derived Signals in Regulating Muscle Spindle Proprioceptor Phenotype

A Role for Sensory end Organ-Derived Signals in Regulating Muscle Spindle Proprioceptor Phenotype

Recent advances in cerebral cavernous malformation research

The CCM1–CCM2 complex controls complementary functions of ROCK1 and ROCK2 that are required for endothelial integrity

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