Monitoring and robust induction of nephrogenic intermediate mesoderm from human pluripotent stem cells

A method for stimulating the differentiation of human pluripotent stem cells into kidney lineages remains to be developed. Most cells in kidney are derived from an embryonic germ layer known as intermediate mesoderm. Here we show the establishment of an efficient system of homologous recombination in human pluripotent stem cells by means of bacterial artificial chromosome-based vectors and single-nucleotide polymorphism array-based detection. This system allowed us to generate human-induced pluripotent stem cell lines containing green fluorescence protein knocked into OSR1, a specific intermediate mesoderm marker. We have also established a robust induction protocol for intermediate mesoderm, which produces up to 90% OSR1(+) cells. These human intermediate mesoderm cells can differentiate into multiple cell types of intermediate mesoderm-derived organs in vitro and in vivo, thereby supplying a useful system to elucidate the mechanisms of intermediate mesoderm development and potentially providing a cell source for regenerative therapies of the kidney.

Desmoglein 1 deficiency results in severe dermatitis, multiple allergies and metabolic wasting

The relative contribution of immunological dysregulation and impaired epithelial barrier function to allergic diseases is still a matter of debate. Here we describe a new syndrome featuring severe dermatitis, multiple allergies and metabolic wasting (SAM syndrome) caused by homozygous mutations in DSG1. DSG1 encodes desmoglein 1, a major constituent of desmosomes, which connect the cell surface to the keratin cytoskeleton and have a crucial role in maintaining epidermal integrity and barrier function. Mutations causing SAM syndrome resulted in lack of membrane expression of DSG1, leading to loss of cell-cell adhesion. In addition, DSG1 deficiency was associated with increased expression of a number of genes encoding allergy-related cytokines. Our deciphering of the pathogenesis of SAM syndrome substantiates the notion that allergy may result from a primary structural epidermal defect.

Harnessing the Stem Cell Potential: The path to prevent mitochondrial disease

Bessel beams beyond the limit

A back door to the neuron

An enhanced view of the brain

Magnetic signaling control

Focus on Mapping the Brain

We are entering a new era in neuroscience in which technological development will allow us to obtain full anatomical, high-resolution renderings of entire brain circuits and to map the activity of ever larger cellular populations as an animal performs specific behaviors. Assembling anatomical, molecular and functional maps has the potential to greatly advance our understanding of how brains work. In this Focus, experts outline the technologies needed to obtain these maps and discuss what will be needed beyond them to understand brain function. In a Historical Perspective, Cornelia Bargmann and Eve Marder discuss what has been learned from invertebrate circuits whose connectivity patterns are known and what will be needed beyond anatomical maps to understand brain function in other organisms. In a Commentary, Jeff Lichtman and Joshua Morgan express their views about why obtaining detailed, high-resolution structural maps should be an essential part of this endeavor. To understand the deluge of data these maps will engender once generated, Olaf Sporns argues in another Commentary that data representation and modeling will be critical. Other experts discuss the newest technologies available for obtaining brain maps. Moritz Helmstaedter presents the state of the art and current challenges of electron microscopy–based circuit reconstruction. In three papers, the potential of using light to unveil the function and anatomy of brain circuits is presented. Karl Deisseroth and Kwanghun Chung discuss their newly developed method named CLARITY for rendering mammalian brains permeable to visible photons and molecules. Pavel Osten and Troy Margrie review light-microscopy methods available for large-scale anatomical tracing and discuss ways to integrate molecular identity, activity recording and anatomical information. In a Resource, Josh Sanes and colleagues present improved tools for mapping the mouse brain using the Brainbow technology. Finally, Michael Milham, Stan Colcombe and their colleagues review methods for functional and anatomical analysis of human brains at the macroscale. We are pleased to acknowledge the financial support of Carl Zeiss Microscopy, Hamamatsu Corporation, LaVision BioTec, TissueVision, Inc. and Chroma Technology Corp. Nature Methods carries sole responsibility for all editorial content and peer review.

Fly walk

Light on genome function