Amphoterin-induced gene and ORF (AMIGO) is a brain-enriched transmembrane immunoglobulin (Ig) superfamily protein with six extracellular leucine-rich repeats (LRR) and a single immunoglobulin-like (Ig) domain. We report here that AMIGO is a glycosylated protein widely expressed in the central nervous system (CNS), and can be found in neurons, astrocytes as well as oligodendrocytes. In morphologically mature primary neurons, endogenous AMIGO, and transfected full length AMIGO (AMIGO-FL) are largely dendritic, while AMIGO with its LRR domain deleted (AMIGO-Ig) is predominantly axonal. In line with AMIGO's dendritic localization, siRNA-mediated silencing of AMIGO resulted in reduced dendritic growth of cortical neurons in culture. SH-SY5Y cells stably over-expressing AMIGO are more resistant to apoptosis induced by staurosporine and H(2) O(2) compared to vector controls. AMIGO therefore likely plays important roles in dendritic outgrowth during development, and could modulate the survival of developing and adult neurons.

The emergence of neurotropic Zika virus (ZIKV) raised a public health emergency of global concern. ZIKV can cross the placental barrier and infect foetal brains, resulting in microcephaly, but the pathogenesis of ZIKV is poorly understood. With recent findings reporting AXL as a type I interferon antagonist rather than an entry receptor, the exact entry mechanism remains unresolved. Here we report that cell surface sialic acid plays an important role in ZIKV infection. Removal of cell surface sialic acid by neuraminidase significantly abolished ZIKV infection in Vero cells and human induced-pluripotent stem cells-derived neural progenitor cells. Furthermore, knockout of the sialic acid biosynthesis gene encoding UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase resulted in significantly less ZIKV infection of both African and Asian lineages. Huh7 cells deficient in α2,3-linked sialic acid through knockout of ST3 β-galactoside-α2,3-sialyltransferase 4 had significantly reduced ZIKV infection. Removal of membrane-bound, un-internalized virus with pronase treatment revealed the role of sialic acid in ZIKV internalization but not attachment. Sialyllactose inhibition studies showed that there is no direct interaction between sialic acid and ZIKV, implying that sialic acid could be mediating ZIKV-receptor complex internalization. Identification of α2,3-linked sialic acid as an important host factor for ZIKV internalization provides new insight into ZIKV infection and pathogenesis.

Edited by Xiao-Fan WangProper positioning of neurons is fundamental for brain functions. However, little is known on how adult-born neurons generated in the hilar side of hippocampal dentate gyrus migrate into the granular cell layer. Because class 3 Semaphorins (Sema3) are involved in dendritic growth of these newborn neurons, we examined whether they are essential for cell positioning. We disrupted Sema3 signaling by silencing neuropilin 1 (NRP1) or 2 (NRP2), the main receptors for Sema3A and Sema3F, in neural progenitors of adult mouse dentate gyrus. Silencing of NRP2, but not NRP1, affected cell positioning of adult newborn neurons. Glycogen synthase kinase-3␤ (GSK3␤) knockdown phenocopied this NRP2 silencing-mediated cell positioning defect, but did not affect dendritic growth. Furthermore, GSK3␤ is activated upon stimulation with Sema3F, and GSK3␤ overexpression rescued the cell positioning phenotypes seen in NRP2-deficient neurons. These results point to a new role for NRP2 in the positioning of neurons during adult hippocampal neurogenesis, acting via the GSK3␤ signaling pathway.

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