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‘Dysbiosis’ of the maternal gut microbiome, in response to challenges such as infection 1 , altered diet 2 and stress 3 during pregnancy, has been increasingly associated with abnormalities in brain function and behaviour of the offspring 4 . However, it is unclear whether the maternal gut microbiome influences neurodevelopment during critical prenatal periods and in the absence of environmental challenges. Here we investigate how depletion and selective reconstitution of the maternal gut microbiome influences fetal neurodevelopment in mice. Embryos from antibiotic-treated and germ-free dams exhibited reduced brain expression of genes related to axonogenesis, deficient thalamocortical axons and impaired outgrowth of thalamic axons in response to cell-extrinsic factors. Gnotobiotic colonization of microbiome-depleted dams with a limited consortium of bacteria prevented abnormalities in fetal brain gene expression and thalamocortical axonogenesis. Metabolomic profiling revealed that the maternal microbiome regulates numerous small molecules in the maternal serum and the brains of fetal offspring. Select microbiota-dependent metabolites promoted axon outgrowth from fetal thalamic explants. Moreover, maternal supplementation with these metabolites abrogated deficiencies in fetal thalamocortical axons. Manipulation of the maternal microbiome and microbial metabolites during pregnancy yielded adult offspring with altered tactile sensitivity in two aversive somatosensory behavioural tasks, but no overt differences in many other sensorimotor behaviours. Together, our findings show that the maternal gut microbiome promotes fetal thalamocortical axonogenesis, probably through signalling by microbially modulated metabolites to neurons in the developing brain. Small molecules that arise from the maternal gut microbiome in pregnant dams promote fetal thalamocortical axonogenesis in their offspring.

Exploring the genetic basis of congenital cataracts in two families identifies a molecule, lanosterol, which prevents intracellular protein aggregation of various cataract-causing mutant crystallins, and which can reduce cataract severity and increase lens transparency in vivo in dogs. Lanosterol counters cataract formation In a study of the genetic basis of congenital cataract formation in two families, Kang Zhang and colleagues demonstrate that lanosterol, a sterol present naturally in the lens, can prevent intracellular aggregation of various cataract-causing mutant crystallin proteins. The mutations identified in the genetic study impair the function of lanosterol synthase, an enzyme for synthesizing lanosterol. In dogs with naturally occurring cataracts, the application of eye drops containing lanosterol for six weeks reduced cataract severity and increased lens transparency, suggesting that lanosterol or molecules with similar activity might provide an alternative to surgery for the management of cataracts. The human lens is comprised largely of crystallin proteins assembled into a highly ordered, interactive macro-structure essential for lens transparency and refractive index. Any disruption of intra- or inter-protein interactions will alter this delicate structure, exposing hydrophobic surfaces, with consequent protein aggregation and cataract formation. Cataracts are the most common cause of blindness worldwide, affecting tens of millions of people 1 , and currently the only treatment is surgical removal of cataractous lenses. The precise mechanisms by which lens proteins both prevent aggregation and maintain lens transparency are largely unknown. Lanosterol is an amphipathic molecule enriched in the lens. It is synthesized by lanosterol synthase (LSS) in a key cyclization reaction of a cholesterol synthesis pathway. Here we identify two distinct homozygous LSS missense mutations (W581R and G588S) in two families with extensive congenital cataracts. Both of these mutations affect highly conserved amino acid residues and impair key catalytic functions of LSS. Engineered expression of wild-type, but not mutant, LSS prevents intracellular protein aggregation of various cataract-causing mutant crystallins. Treatment by lanosterol, but not cholesterol, significantly decreased preformed protein aggregates both in vitro and in cell-transfection experiments. We further show that lanosterol treatment could reduce cataract severity and increase transparency in dissected rabbit cataractous lenses in vitro and cataract severity in vivo in dogs. Our study identifies lanosterol as a key molecule in the prevention of lens protein aggregation and points to a novel strategy for cataract prevention and treatment.

The repair and regeneration of tissues using endogenous stem cells represents an ultimate goal in regenerative medicine. To our knowledge, human lens regeneration has not yet been demonstrated. Currently, the only treatment for cataracts, the leading cause of blindness worldwide, is to extract the cataractous lens and implant an artificial intraocular lens. However, this procedure poses notable risks of complications. Here we isolate lens epithelial stem/progenitor cells (LECs) in mammals and show that Pax6 and Bmi1 are required for LEC renewal. We design a surgical method of cataract removal that preserves endogenous LECs and achieves functional lens regeneration in rabbits and macaques, as well as in human infants with cataracts. Our method differs conceptually from current practice, as it preserves endogenous LECs and their natural environment maximally, and regenerates lenses with visual function. Our approach demonstrates a novel treatment strategy for cataracts and provides a new paradigm for tissue regeneration using endogenous stem cells. A new procedure for cataract removal that preserves lens epithelial progenitor cells in mammals, which require Pax6 and Bmi1 for their self-renewal, achieves lens regeneration in rabbits, macaques and in infants with cataracts. Sight restoration through cellular regeneration The only current treatment for cataracts, the leading cause of blindness, is to extract the damaged lens surgically and implant an artificial intraocular lens. The technique has its limitations, so there is great interest in the possibility of a regenerative medicine approach. Two papers published in this issue of Nature report advances that could bring that prospect a little closer. Kang Zhang and colleagues isolate mammalian lens epithelial stem/progenitor cells and show that Pax6 and Bmi1 are required for their renewal. They have also developed a removal procedure for cataract-affected tissue that preserves these cells, and achieved lens regeneration in rabbits, macaques and in human infants with cataracts. In the second paper, Kohji Nishida and colleagues describe a protocol for in vitro generation of a self-formed ectodermal autonomous multi-zone (SEAM) from human induced pluripotent stem cells. The SEAM includes distinct cell lineages from the ocular surface ectoderm, lens, neuro-retina, and retinal pigment epithelium. Previous experiments had focused mainly on obtaining one cell type. These authors show that cells from the SEAM can be expanded to form a functional corneal epithelium when transplanted to an animal model of blindness.

Nature 531, 323–328 (2016); doi:10.1038/nature17181 In this Article, errors in the length of the scale bars were inadvertently introduced into Fig. 3e and Extended Data Fig. 7b. The corrected Fig. 3e is shown as Fig. 1 of this Corrigendum and the corrected Extended Data Fig. 7b is shown in the Supplementary Information to this Corrigendum (both of the corrected scale bars are now shorter).

Nature 523, 607–611 (2015); doi:10.1038/nature14650 In this Letter, author Yong-Bin Yan was incorrectly associated with affiliation number 5 (Department of Ophthalmology, Xijing Hospital) instead of affiliation number 4 (State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China).

In spite of its immutable susceptibility to penicillin, Treponema pallidum ( T . pallidum ) subsp. pallidum continues to cause millions of cases of syphilis each year worldwide, resulting in significant morbidity and mortality and underscoring the urgency of developing an effective vaccine to curtail the spread of the infection. Several technical challenges, including absence of an in vitro culture system until very recently, have hampered efforts to catalog the diversity of strains collected worldwide. Here, we provide near-complete genomes from 196 T . pallidum strains–including 191 T . pallidum subsp. pallidum –sequenced directly from patient samples collected from 8 countries and 6 continents. Maximum likelihood phylogeny revealed that samples from most sites were predominantly SS14 clade. However, 99% (84/85) of the samples from Madagascar formed two of the five distinct Nichols subclades. Although recombination was uncommon in the evolution of modern circulating strains, we found multiple putative recombination events between T . pallidum subsp. pallidum and subsp. endemicum , shaping the genomes of several subclades. Temporal analysis dated the most recent common ancestor of Nichols and SS14 clades to 1717 (95% HPD: 1543–1869), in agreement with other recent studies. Rates of SNP accumulation varied significantly among subclades, particularly among different Nichols subclades, and was associated in the Nichols A subclade with a C394F substitution in TP0380, a ERCC3-like DNA repair helicase. Our data highlight the role played by variation in genes encoding putative surface-exposed outer membrane proteins in defining separate lineages, and provide a critical resource for the design of broadly protective syphilis vaccines targeting surface antigens.

Hantavirus nucleocapsid protein (NP) inhibits protein kinase R (PKR) dimerization by an unknown mechanism to counteract its antiviral responses during virus infection. Here we demonstrate that NP exploits an endogenous PKR inhibitor P58 IPK to inhibit PKR. The activity of P58 IPK is normally restricted in cells by the formation of an inactive complex with its negative regulator Hsp40. On the other hand, PKR remains associated with the 40S ribosomal subunit, a unique strategic location that facilitates its free access to the downstream target eIF2α. Although both NP and Hsp40 bind to P58 IPK , the binding affinity of NP is much stronger compared to Hsp40. P58 IPK harbors an NP binding site, spanning to N-terminal TPR subdomains I and II. The Hsp40 binding site on P58 IPK was mapped to the TPR subdomain II. The high affinity binding of NP to P58 IPK and the overlap between NP and Hsp40 binding sites releases the P58 IPK from its negative regulator by competitive inhibition. The NP-P58 IPK complex is selectively recruited to the 40S ribosomal subunit by direct interaction between NP and the ribosomal protein S19 (RPS19), a structural component of the 40S ribosomal subunit. NP has distinct binding sites for P58 IPK and RPS19, enabling it to serve as bridge between P58 IPK and the 40S ribosomal subunit. NP mutants deficient in binding to either P58 IPK or RPS19 fail to inhibit PKR, demonstrating that selective engagement of P58 IPK to the 40S ribosomal subunit is required for PKR inhibition. Cells deficient in P58 IPK mount a rapid PKR antiviral response and establish an antiviral state, observed by global translational shutdown and rapid decline in viral load. These studies reveal a novel viral strategy in which NP releases P58 IPK from its negative regulator and selectively engages it on the 40S ribosomal subunit to promptly combat the PKR antiviral responses.