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.     

Prox1 function controls progenitor cell proliferation and horizontal cell genesis in the mammalian retina

Retinal progenitor cells regulate their proliferation during development so that the correct number of each cell type is made at the appropriate time. We found that the homeodomain protein Prox1 regulates the exit of progenitor cells from the cell cycle in the embryonic mouse retina. Cells lacking Prox1 are less likely to stop dividing, and ectopic expression of Prox1 forces progenitor cells to exit the cell cycle. During retinogenesis, Prox1 can be detected in differentiating horizontal, bipolar and AII amacrine cells. Horizontal cells are absent in retinae of Prox1-/- mice and misexpression of Prox1 in postnatal progenitor cells promotes horizontal-cell formation. Thus, Prox1 activity is both necessary and sufficient for progenitor-cell proliferation and cell-fate determination in the vertebrate retina.     

Water transport in plants obeys Murray's law

The optimal water transport system in plants should maximize hydraulic conductance (which is proportional to photosynthesis) for a given investment in transport tissue. To investigate how this optimum may be achieved, we have performed computer simulations of the hydraulic conductance of a branched transport system. Here we show that the optimum network is not achieved by the commonly assumed pipe model of plant form, or its antecedent, da Vinci's rule. In these representations, the number and area of xylem conduits is constant at every branch rank. Instead, the optimum network has a minimum number of wide conduits at the base that feed an increasing number of narrower conduits distally. This follows from the application of Murray's law, which predicts the optimal taper of blood vessels in the cardiovascular system. Our measurements of plant xylem indicate that these conduits conform to the Murray's law optimum as long as they do not function additionally as supports for the plant body.     

Dental microwear texture analysis shows within-species diet variability in fossil hominins

Reconstructing the diets of extinct hominins is essential to understanding the paleobiology and evolutionary history of our lineage. Dental microwear, the study of microscopic tooth-wear resulting from use, provides direct evidence of what an individual ate in the past. Unfortunately, established methods of studying microwear are plagued with low repeatability and high observer error. Here we apply an objective, repeatable approach for studying three-dimensional microwear surface texture to extinct South African hominins. Scanning confocal microscopy together with scale-sensitive fractal analysis are used to characterize the complexity and anisotropy of microwear. Results for living primates show that this approach can distinguish among diets characterized by different fracture properties. When applied to hominins, microwear texture analysis indicates that Australopithecus africanus microwear is more anisotropic, but also more variable in anisotropy than Paranthropus robustus. This latter species has more complex microwear textures, but is also more variable in complexity than A. africanus. This suggests that A. africanus ate more tough foods and P. robustus consumed more hard and brittle items, but that both had variable and overlapping diets.     

Predictive models of molecular machines involved in Caenorhabditis elegans early embryogenesis

Although numerous fundamental aspects of development have been uncovered through the study of individual genes and proteins, system-level models are still missing for most developmental processes. The first two cell divisions of Caenorhabditis elegans embryogenesis constitute an ideal test bed for a system-level approach. Early embryogenesis, including processes such as cell division and establishment of cellular polarity, is readily amenable to large-scale functional analysis. A first step toward a system-level understanding is to provide 'first-draft' models both of the molecular assemblies involved and of the functional connections between them. Here we show that such models can be derived from an integrated gene/protein network generated from three different types of functional relationship: protein interaction, expression profiling similarity and phenotypic profiling similarity, as estimated from detailed early embryonic RNA interference phenotypes systematically recorded for hundreds of early embryogenesis genes. The topology of the integrated network suggests that C. elegans early embryogenesis is achieved through coordination of a limited set of molecular machines. We assessed the overall predictive value of such molecular machine models by dynamic localization of ten previously uncharacterized proteins within the living embryo.     

Mediation of pathogen resistance by exudation of antimicrobials from roots

Most plant species are resistant to most potential pathogens. It is not known why most plant-microbe interactions do not lead to disease, although recent work indicates that this basic disease resistance is multi-factorial. Here we show that the exudation of root-derived antimicrobial metabolites by Arabidopsis thaliana confers tissue-specific resistance to a wide range of bacterial pathogens. However, a Pseudomonas syringae strain that is both at least partly resistant to these compounds and capable of blocking their synthesis/exudation is able to infect the roots and cause disease. We also show that the ability of this P. syringae strain to block antimicrobial exudation is dependent on the type III secretory system.     

Phospholipase C gamma 1 is a physiological guanine nucleotide exchange factor for the nuclear GTPase PIKE

Phospholipase C gamma 1 (PLC-gamma 1) hydrolyses phosphatidylinositol-4,5-bisphosphate to the second messengers inositol-1,4,5-trisphosphate and diacylglycerol. PLC-gamma 1 also has mitogenic activity upon growth-factor-dependent tyrosine phosphorylation; however, this activity is not dependent on the phospholipase activity of PLC-gamma 1, but requires an SH3 domain. Here, we demonstrate that PLC-gamma 1 acts as a guanine nucleotide exchange factor (GEF) for PIKE (phosphatidylinositol-3-OH kinase (PI(3)K) enhancer). PIKE is a nuclear GTPase that activates nuclear PI(3)K activity, and mediates the physiological activation by nerve growth factor (NGF) of nuclear PI(3)K activity. This enzymatic activity accounts for the mitogenic properties of PLC-gamma 1.