Zika virus (ZIKV), a single stranded (+) RNA in the Flaviviridae family, has been identified as the etiologic agent of congenital Zika virus syndrome (cZVS). Viral infection is responsible for the recent increase in the number of children born with microcephaly and cortical malformations in Brazil and Colombia. Consequently, ZIKV has been classified as new TORCH agent. Our data, along with observations by others, demonstrate that ZIKV infection induces severe alterations in the cytoskeleton of cells, in particular the collapse of the signature vimentin basal project of the radial glial progenitors, within the developing mouse brain. We hypothesize that understanding the mechanisms by which ZV infection causes deformations in the cytoskeleton leading to congenital neurological dysfunction will facilitate greater understanding of cZVS and may identify new causes of autosomal-recessive microcephaly. We propose that retrograde trafficking along actin microfilaments is necessary to assemble and maintain the vimentin intermediate filaments required for migration of postmitotic neurons into the developing cortex. Furthermore, we postulate that identification of the virus specific proteins responsible and the mechanism by which they deregulate the cytoskeleton will provide insight into how ZIKV replication alters radial glia morphology, and if the reduced complexity of the cortex associated with cZVS results from premature delamination of the post-mitotic neuronal, precocious neuronal differentiation and disruption of other required developmental processes. The goal of this proposal is to use both genetics and biochemistry to determine if ZIKV deregulates postmitotic neuron migration into the developing neocortex by impairing retrograde trafficking along the actin microfilament needed to establish and maintain dynamics and integrity of the vimentin intermediate filament cytoskeleton. Identification viral proteins that distort the cytoskeleton, and determining their mechanisms of action, will enrich our understanding of how ZIKV infection induces cortical malformations.
Congenital Zika virus syndrome (cZVS) comprises a variety of neurodevelopmental defects including microcephaly, lissencephaly, and other cortical malformations of the brain. Our published data suggests that virus infection induced cytoskeletal deformations, particularly collapse of the vimentin intermediate filaments, may lead to neurodevelopmental pathologies associated with cZVS. We propose to investigate if retrograde trafficking along actin microfilaments is necessary to assemble and maintain the vimentin intermediate filaments required for directed migration of postmitotic neurons into the developing cortex, and describe mechanisms by which viral proteins induce severe disruption of brain development.
