Nck adaptor proteins link nephrin to the actin cytoskeleton of kidney podocytes

The glomerular filtration barrier in the kidney is formed in part by a specialized intercellular junction known as the slit diaphragm, which connects adjacent actin-based foot processes of kidney epithelial cells (podocytes). Mutations affecting a number of slit diaphragm proteins, including nephrin (encoded by NPHS1), lead to renal disease owing to disruption of the filtration barrier and rearrangement of the actin cytoskeleton, although the molecular basis for this is unclear. Here we show that nephrin selectively binds the Src homology 2 (SH2)/SH3 domain-containing Nck adaptor proteins, which in turn control the podocyte cytoskeleton in vivo. The cytoplasmic tail of nephrin has multiple YDxV sites that form preferred binding motifs for the Nck SH2 domain once phosphorylated by Src-family kinases. We show that this Nck-nephrin interaction is required for nephrin-dependent actin reorganization. Selective deletion of Nck from podocytes of transgenic mice results in defects in the formation of foot processes and in congenital nephrotic syndrome. Together, these findings identify a physiological signalling pathway in which nephrin is linked through phosphotyrosine-based interactions to Nck adaptors, and thus to the underlying actin cytoskeleton in podocytes. Simple and widely expressed SH2/SH3 adaptor proteins can therefore direct the formation of a specialized cellular morphology in vivo.     

Multi-model ensembles in climate science: Mathematical structures and expert judgements

Projections of future climate change cannot rely on a single model. It has become common to rely on multiple simulations generated by Multi-Model Ensembles (MMEs), especially to quantify the uncertainty about what would constitute an adequate model structure. But, as Parker points out (2018), one of the remaining philosophically interesting questions is: “How can ensemble studies be designed so that they probe uncertainty in desired ways?” This paper offers two interpretations of what General Circulation Models (GCMs) are and how MMEs made of GCMs should be designed. In the first interpretation, models are combinations of modules and parameterisations; an MME is obtained by “plugging and playing” with interchangeable modules and parameterisations. In the second interpretation, models are aggregations of expert judgements that result from a history of epistemic decisions made by scientists about the choice of representations; an MME is a sampling of expert judgements from modelling teams. We argue that, while the two interpretations involve distinct domains from philosophy of science and social epistemology, they both could be used in a complementary manner in order to explore ways of designing better MMEs.     

Subtypes of medulloblastoma have distinct developmental origins

Medulloblastoma encompasses a collection of clinically and molecularly diverse tumour subtypes that together comprise the most common malignant childhood brain tumour. These tumours are thought to arise within the cerebellum, with approximately 25% originating from granule neuron precursor cells (GNPCs) after aberrant activation of the Sonic Hedgehog pathway (hereafter, SHH subtype). The pathological processes that drive heterogeneity among the other medulloblastoma subtypes are not known, hindering the development of much needed new therapies. Here we provide evidence that a discrete subtype of medulloblastoma that contains activating mutations in the WNT pathway effector CTNNB1 (hereafter, WNT subtype) arises outside the cerebellum from cells of the dorsal brainstem. We found that genes marking human WNT-subtype medulloblastomas are more frequently expressed in the lower rhombic lip (LRL) and embryonic dorsal brainstem than in the upper rhombic lip (URL) and developing cerebellum. Magnetic resonance imaging (MRI) and intra-operative reports showed that human WNT-subtype tumours infiltrate the dorsal brainstem, whereas SHH-subtype tumours are located within the cerebellar hemispheres. Activating mutations in Ctnnb1 had little impact on progenitor cell populations in the cerebellum, but caused the abnormal accumulation of cells on the embryonic dorsal brainstem which included aberrantly proliferating Zic1(+) precursor cells. These lesions persisted in all mutant adult mice; moreover, in 15% of cases in which Tp53 was concurrently deleted, they progressed to form medulloblastomas that recapitulated the anatomy and gene expression profiles of human WNT-subtype medulloblastoma. We provide the first evidence, to our knowledge, that subtypes of medulloblastoma have distinct cellular origins. Our data provide an explanation for the marked molecular and clinical differences between SHH- and WNT-subtype medulloblastomas and have profound implications for future research and treatment of this important childhood cancer.     

Regulatory networks define phenotypic classes of human stem cell lines

Stem cells are defined as self-renewing cell populations that can differentiate into multiple distinct cell types. However, hundreds of different human cell lines from embryonic, fetal and adult sources have been called stem cells, even though they range from pluripotent cells-typified by embryonic stem cells, which are capable of virtually unlimited proliferation and differentiation-to adult stem cell lines, which can generate a far more limited repertoire of differentiated cell types. The rapid increase in reports of new sources of stem cells and their anticipated value to regenerative medicine has highlighted the need for a general, reproducible method for classification of these cells. We report here the creation and analysis of a database of global gene expression profiles (which we call the 'stem cell matrix') that enables the classification of cultured human stem cells in the context of a wide variety of pluripotent, multipotent and differentiated cell types. Using an unsupervised clustering method to categorize a collection of approximately 150 cell samples, we discovered that pluripotent stem cell lines group together, whereas other cell types, including brain-derived neural stem cell lines, are very diverse. Using further bioinformatic analysis we uncovered a protein-protein network (PluriNet) that is shared by the pluripotent cells (embryonic stem cells, embryonal carcinomas and induced pluripotent cells). Analysis of published data showed that the PluriNet seems to be a common characteristic of pluripotent cells, including mouse embryonic stem and induced pluripotent cells and human oocytes. Our results offer a new strategy for classifying stem cells and support the idea that pluripotency and self-renewal are under tight control by specific molecular networks.     

From Cars to Bicycles: an Ecosystem View of Montreal Traffic as a Wicked Problem

Systemic Practice and Action Research - In this paper, we share our reflections based on a process consultation project in collaboration with the Montreal Bicycle Advisory Committee. We put forward...     

Lake geochemistry reveals marked environmental change in Southwest China during the Mid Miocene Climatic Optimum

Science Bulletin - The Mid-Miocene Climatic Optimum (MMCO; ~15–17 Ma) was one of the short-term climatic warm events that punctuated the Cenozoic long-term cooling trend. Because...     

Alkyltransferase-like proteins: molecular switches between DNA repair pathways

Alkyltransferase-like proteins (ATLs) play a role in the protection of cells from the biological effects of DNA alkylation damage. Although ATLs share functional motifs with the DNA repair protein and cancer chemotherapy target O ⁶-alkylguanine-DNA alkyltransferase, they lack the reactive cysteine residue required for alkyltransferase activity, so its mechanism for cell protection was previously unknown. Here we review recent advances in unraveling the enigmatic cellular protection provided by ATLs against the deleterious effects of DNA alkylation damage. We discuss exciting new evidence that ATLs aid in the repair of DNA O ⁶-alkylguanine lesions through a novel repair cross-talk between DNA-alkylation base damage responses and the DNA nucleotide excision repair pathway.     

Genetic analysis of the rare species Salix arizonica (Salicacea) and associated willows in Arizona and Utah

Management decisions affecting the rare plant Arizona willow ( Salix arizonica ) will be aided by understanding genetic similarities among populations of this species. Random Amplified Polymorphic DNA (RAPD) analysis was conducted on 20 populations of S. arizonica , 12 populations of 5 congeners, and 2 samples of outgroup, Populus tremuloides . A phenogram based on DNA markers shows clear separation of populations of S. arizonica from those of co-occurring willow species, but similarity is low (～ 37%) between Utah and Arizona populations of S. arizonica . Evaluation of the relationship of habitat characteristics and geographic distance to genetic similarity reveals that environment and genetic similarity are poorly correlated. Considering Arizona versus Utah populations, we found a significant negative relationship between geographic distance and genetic similarity ( r = 0.936), but no significant relationship between interpopulation distance and genetic similarity within Arizona or Utah. The wide geographic disjunction of S. arizonica populations in Utah and Arizona appears to have existed for a long period during which genetic drift, random mutations, and selection for somewhat different habitats have pushed the 2 regional complexes along separate evolutionary trajectories. Preservation of genetic variation within S. arizonica will require protection of multiple populations in Arizona and Utah.