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Araujo, S.

Publications and source records attributed to Araujo, S..

2 recordsLinked to original sources

Sequoia affects Drosophila central nervous system development by regulating axonal extension and guidance

The development of the Drosophila melanogaster central nervous system (CNS) requires both determination of neuronal cell types and the subsequent establishment of neural connectivity. Numerous studies have identified genes and molecules required for both these processes. Once neurons have differentiated, they are guided to their targets by attractive and repulsive forces and an increasing number of molecules that provide these functions have been identified. However, little is known on how molecules involved in neuronal differentiation might affect subsequent steps of axonal development such as axonal morphogenesis. The sequoia (seq) mutant was identified in a Drosophila genetic screen for defects in dendrite elaboration. Sequoia is a pan-neural nuclear protein containing two putative zinc-fingers homologous to the DNA binding domain of Tramtrack. Mutations in seq have been reported to affect the cell fate decision of external sensory organ neurons and to effect axon and dendrite morphology. Previous reports have focused mainly on the effects this mutation causes in dendritic morphogenesis in the peripheral nervous system (PNS). Amongst mutants isolated from a previous mutagenesis screen, we have identified three new alleles of sequoia, GA168, C022 and C3101 and identify the molecular lesions in two previously identified alleles, Z1241 and H156 (1). Analysis of these five alleles has revealed that seq mutations lead to several defects in nervous system development. seq mutants show defects in the spatial organization of their CNS from early developmental stages and have abnormal cell morphology, both at early and late stages of embryonic development. Mutations in seq affect motor axon outgrowth and general CNS and PNS development. The reported seq mutations reveal an important link between neuronal differentiation and axonal outgrowth and guidance and shed light on the importance of different Seq domains.

developmental biology↗

Essential role of the CCL2-CCR2 axis in Mayaro virus-induced disease

Mayaro virus (MAYV) is an emerging arbovirus member of the Togaviridae family and Alphavirus genus. MAYV infection causes an acute febrile illness accompanied by persistent polyarthralgia and myalgia. Understanding the mechanisms involved in arthritis caused by alphaviruses is necessary to develop specific therapies. In this work, we investigated the role of the CCL2/CCR2 axis in the pathogenesis of MAYV-induced disease. For this, WT C57BL/6J and CCR2-/- mice were infected with MAYV subcutaneously and evaluated for disease development. MAYV infection induced an acute inflammatory disease in WT mice. The immune response profile was characterized by an increase in the production of inflammatory mediators, such as IL-6, TNF and CCL2. Higher levels of CCL2 at the local and systemic levels, was followed by significant recruitment of CCR2+ macrophages and a cellular response orchestrated by these cells. CCR2-/- mice showed an increase in CXCL-1 levels, followed by a replacement of the macrophage inflammatory infiltrate by neutrophils. Additionally, absence of the CCR2 receptor protected mice from bone loss induced by MAYV. Accordingly, the silencing of CCL2 chemokine expression in vivo and the pharmacological blockade of CCR2 promoted a partial improvement in disease. Cell culture data support the mechanism underlying MAYVs bone pathology in which: i) MAYV infection promoted a pro-osteoclastogenic microenvironment mediated by IL-6, TNF and CCL2 and ii) migration of osteoclast precursors was dependent on the CCR2/CCL2 axis. Overall, these data contribute to the understanding of the pathophysiology of MAYV infection and to the identification future of specific therapeutic targets in MAYV-induced disease. ImportanceThis work demonstrates the role of the CCL2/CCR2 axis in MAYV-induced disease. Infection of WT C57BL/6J and CCR2-/- mice was associated with high levels of CCL2, an important chemoattractant involved in the recruitment of macrophages, the main precursor of osteoclasts. In the absence of the CCR2 receptor there is a mitigation of macrophage migration to the target organs of infection and protection of these mice against bone loss induced by MAYV infection. Much evidence has shown that host immune response factors contribute significantly to the tissue damage associated to alfavirus infections. Thus, this work highlights molecular and cellular targets involved in the pathogenesis of arthritis triggered by MAYV, and identifies novel therapeutic possibilities directed to the host inflammatory response unleashed by MAYV.

cell biology↗