Mutation for microcephaly: Zika virus infections in humans have been known since 1947. Microcephaly and neuropathologies associated with Zika have only been reported recently, most prevalently in the Americas. Yuan et al. investigated recent stable mutations in the virus genome and engineered them into a low-virulence ancestral strain (see the Perspective by Screaton and Mongkolsapaya). A single amino acid substitution (serine to asparagine, S139N) in the viral precursor membrane protein exacerbated symptoms in pregnant mice. The reverse mutation (N139S) was less virulent. The S139N mutation arose in 2013 in French Polynesia before the virus jumped to Brazil in 2015. In vitro, this amino acid change made the virus more infectious for mouse and human neural progenitor cells and promoted apoptosis. The terrible sequelae of infection during pregnancy could thus be the result of a simple viral mutation. Science , this issue p. 933 ; see also p. 863

Neuronal apoptotic death induced by nerve growth factor (NGF) deprivation is reported to be in part mediated through a pathway that includes Rac1 and Cdc42, mitogen-activated protein kinase kinases 4 and 7 (MKK4 and -7), c-Jun N-terminal kinases (JNKs), and c-Jun. However, additional components of the pathway remain to be defined. We show here that members of the mixed-lineage kinase (MLK) family (including MLK1, MLK2, MLK3, and dual leucine zipper kinase [DLK]) are expressed in neuronal cells and are likely to act between Rac1/Cdc42 and MKK4 and -7 in death signaling. Overexpression of MLKs effectively induces apoptotic death of cultured neuronal PC12 cells and sympathetic neurons, while expression of dominant-negative forms of MLKs suppresses death evoked by NGF deprivation or expression of activated forms of Rac1 and Cdc42. CEP-1347 (KT7515), which blocks neuronal death caused by NGF deprivation and a variety of additional apoptotic stimuli and which selectively inhibits the activities of MLKs, effectively protects neuronal PC12 cells from death induced by overexpression of MLK family members. In addition, NGF deprivation or UV irradiation leads to an increase in both level and phosphorylation of endogenous DLK. These observations support a role for MLKs in the neuronal death mechanism. With respect to ordering the death pathway, dominant-negative forms of MKK4 and -7 and c-Jun are protective against death induced by MLK overexpression, placing MLKs upstream of these kinases. Additional findings place the MLKs upstream of mitochondrial cytochromec release and caspase activation.