Failure of human rhombic lip differentiation underlies medulloblastoma formation

Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to early development of the hindbrain 1–4. Mutations that activate Sonic hedgehog signalling lead to Sonic hedgehog MB in the upper rhombic lip (RL) granule cell lineage 5–8. By contrast, mutations that activate WNT signalling lead to WNT MB in the lower RL 9,10. However, little is known about the more commonly occurring group 4 (G4) MB, which is thought to arise in the unipolar brush cell lineage 3,4. Here we demonstrate that somatic mutations that cause G4 MB converge on the core binding factor alpha (CBFA) complex and mutually exclusive alterations that affect CBFA2T2, CBFA2T3, PRDM6, UTX and OTX2. CBFA2T2 is expressed early in the progenitor cells of the cerebellar RL subventricular zone in Homo sapiens, and G4 MB transcriptionally resembles these progenitors but are stalled in developmental time. Knockdown of OTX2 in model systems relieves this differentiation blockade, which allows MB cells to spontaneously proceed along normal developmental differentiation trajectories. The specific nature of the split human RL, which is destined to generate most of the neurons in the human brain, and its high level of susceptible EOMES +KI67 + unipolar brush cell progenitor cells probably predisposes our species to the development of G4 MB

Data from: Signatures of human impact: size distributions and spatial organization of wetlands in the prairie pothole landscape

More than 50% of global wetland area has been lost over the last 200 years, resulting in losses of habitat and species diversity as well as decreased hydrologic and biogeochemical functionality. Recognition of the magnitude of wetland loss as well as the wide variety of ecosystem services provided by wetlands has in recent decades led to an increased focus on wetland restoration. Restoration activities, however, often proceed in an ad-hoc manner, with a focus on maximizing the total restored area rather than on other spatial attributes of the wetland network, which are less well understood. In this study, we have addressed the question of how human activities have altered the size distribution and spatial organization of wetlands over the Prairie Pothole Region of the Des Moines Lobe using high-resolution LIDAR data. Our results show that as well as the generally accepted 90% loss of depressional wetland area, there has been a disproportionate loss of both smaller and larger wetlands, with a marked alteration of the historical power-law relationship observed between wetland size and frequency and a resulting homogenization of the wetland size distribution. In addition, our results show significant decreases in perimeter-to-area ratios, increased mean distances between wetlands, particularly between smaller wetlands, and a reduced likelihood that current wetlands will be located in upland areas. Such patterns of loss can lead to disproportionate losses of ecosystem services, as smaller wetlands with larger perimeter-to-area ratios have been found to provide higher rates of biogeochemical processing and groundwater recharge, while increased mean distances between wetlands hinder species migration and thus negatively impact biodiversity. These results suggest the need to gear restoration efforts towards understanding and recreating the size distribution and spatial organization of historical wetlands, rather than focusing primarily on an increase in overall area

Normalized concentration reduction trajectories under different patterns of land-use change.

<p>(a) Normalized concentration trajectories at the catchment outlet plotted as a function of time (years) after land-use change for the frontal, random and distal patterns of conversion; fractional land-use conversion p = 0.5; (b) Concentration reduction fraction at infinite time as a function of land use conversion fraction p. In both figures, k = 0.18 ± 0.12, which corresponds to a range of “moderate” denitrification rates (Tesoriero et al. 2011). Other parameters used are lambda = 0.23 y^-1 and μ = 21.6 y. A 1:1 relationship between CR_inf and p, with no dependence on the k values is apparent for the random truncation.</p

Model Parameters for the Walnut Creek Watershed.

<p>Model Parameters for the Walnut Creek Watershed.</p

Normalized concentration reduction contours at t = 5 years (CR₅) plotted as a function of the fractional land-use conversion p and mean watershed travel time <i>μ</i>.

<p>Contours are plotted for the (a) frontal, (b) random and (c) distal truncation scenarios (k = 0.06 y^-1, <i>λ</i> = 0.16 y^-1).</p

Des Moines Lobe Wetland Data

This geodatabase contains lidar data and NWI wetland data for the Des Moines Lobe of the North American Prairie Pothole region

Conceptual framework for predicting catchment scale time lags as a function of hydrologic and biogeochemical legacies in the landscape.

<p>The left frame represents depletion of biogeochemical legacy in the source zone. The source zone depletion function is then convoluted with the groundwater travel time distribution (middle frame) to ultimately describe concentrations at the catchment outlet (right frame).</p