Mutations in SOX18 cause the human hypotrichosis-lymphedema-telangiectasia (HLT) syndrome. Their murine counterparts are the spontaneous ragged mutants, showing combined defects in hair follicle, blood vessel, and lymphatic vessel development. Mice null for Sox18 display only mild coat defects, suggesting a dominant-negative effect of Sox18/ragged mutations and functional redundancy between Sox18 and other Sox-F proteins. We addressed this point in zebrafish. The zebrafish homologs of Sox18 and of Sox7 are expressed in angioblasts and in the endothelial component of nascent blood vessels in embryos. Knockdown of either gene, using moderate doses of specific morpholinos, had minimal effects on vessels. In contrast, simultaneous knockdown of both genes resulted in multiple fusions between the major axial vessels. With combined use of transgenic lines and molecular markers, we could show that endothelial cells are specified, but fail to acquire a correct arteriovenous identity. Venous endothelial cell differentiation was more severely affected than arterial. Thus, sox7 and sox18 play redundant but collectively essential roles in the establishment of proper arteriovenous identity in zebrafish. Our data suggest that a defect in arteriovenous identity could be responsible for the formation of telangiectases in patients with HLT. IntroductionThe acquisition of arterial and venous identity is an early event in endothelial cell differentiation, preceding the onset of blood circulation. Pioneering work in the zebrafish has revealed that the acquisition of arterial identity is governed by a genetic network including Shh, VEGF, and Notch signaling. [1][2][3] Many aspects of this regulatory cascade are also conserved in mammals. 4 More recently, the acquisition of venous identity was shown not to occur by default but rather to be genetically controlled. The orphan nuclear receptor COUP-TFII induces venous endothelial cell differentiation by suppressing Notch signaling. 5 Although chick-quail grafting experiments point to an initial plasticity (ie, nascent endothelial cells are able to change their arteriovenous identity depending on the surrounding context), it is becoming clear that arterial and venous angioblasts segregate from the beginning of vasculogenesis. 6 The ephrin/Eph system is involved in the establishment of arteriovenous (AV) cell identity, and is important for the segregation between arteries and veins. The transmembrane ligand ephrinB2, and its cognate tyrosine kinase receptor EphB4, are exclusively expressed by arterial and venous endothelial cells, respectively, both in mouse and in zebrafish, and this molecular distinction is essential to establish a functional hierarchical vascular network. 6 Arteriovenous malformations (AVMs) are frequently induced by a loss of arterial or venous cell identity. 7 In humans, hereditary hemorrhagic telangiectasia (HHT) is a vascular dysplasia characterized by anomalous fusion of arterioles and venules, leading to telangiectases in the skin and mucocutaneous tissues and in...
Objective-Lymphangiogenesis is regulated by transcription factors and by growth factor pathways, but their interplay has not been extensively studied so far. We addressed this issue in zebrafish. Approach and Results-Mutations in the transcription factor-coding gene SOX18 and in VEGFR3 cause lymphedema, and the VEGFR3/Flt4 ligand VEGFC plays an evolutionarily conserved role in lymphangiogenesis. Here, we report a strong genetic interaction between Sox18 and VegfC in the early phases of lymphatic development in zebrafish. Knockdown of sox18 selectively impaired lymphatic sprouting from the cardinal vein and resulted in defective lymphatic thoracic duct formation. Sox18 and the related protein Sox7 play redundant roles in arteriovenous differentiation. We used a novel transgenic line that enables inducible expression of a dominant-negative mutant form of mouse Sox18 protein. Our data led us to conclude that Sox18 is crucially involved in lymphangiogenesis after arteriovenous differentiation. Combined partial knockdown of sox18 and vegfc, using subcritical doses of specific morpholinos, revealed a synergistic interaction in both venous and lymphatic sprouting from the cardinal vein and greatly impaired thoracic duct formation. Conclusions-This interaction suggests a previously unappreciated crosstalk between the growth factor and transcription factor pathways that regulate lymphangiogenesis in development and disease. (Arterioscler Thromb Vasc Biol. 2013;33:1238-1247.)
Currently available inhibitory optogenetic tools provide short and transient silencing of neurons, but they cannot provide long-lasting inhibition because of the requirement for high light intensities. Here we present an optimized blue-light-sensitive synthetic potassium channel, BLINK2, which showed good expression in neurons in three species. The channel is activated by illumination with low doses of blue light, and in our experiments it remained active over (tens of) minutes in the dark after the illumination was stopped. This activation caused long periods of inhibition of neuronal firing in ex vivo recordings of mouse neurons and impaired motor neuron response in zebrafish in vivo. As a proof-of-concept application, we demonstrated that in a freely moving rat model of neuropathic pain, the activation of a small number of BLINK2 channels caused a long-lasting (>30 min) reduction in pain sensation.
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