PIK3R2/Pik3r2 Activating Mutations Result in Brain Overgrowth and EEG Changes.

OBJECTIVE: Mutations in phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) complex have been associated with a broad spectrum of brain and organ overgrowth syndromes. For example, mutations in phosphatidylinositol-3-kinase regulatory subunit 2 (PIK3R2) have been identified in human patients with megalencephaly polymicrogyria polydactyly hydrocephalus (MPPH) syndrome, which includes brain overgrowth. To better understand the pathogenesis of PIK3R2-related mutations, we have developed and characterized a murine model. METHODS: We generated a knock-in mouse model for the most common human PIK3R2 mutation, p.G373R (p.G367R in mice) using CRISPR/Cas9. The mouse phenotypes, including brain size, seizure activity, cortical lamination, cell proliferation/size/density, interneuron migration, and PI3K pathway activation, were analyzed using standard methodologies. For human patients with PIK3R2 mutations, clinical data (occipitofrontal circumference [OFC] and epilepsy) were retrospectively obtained from our clinical records (published / unpublished). RESULTS: The PI3K-AKT pathway was hyperactivated in these mice, confirming the p.G367R mutation is an activating mutation in vivo. Similar to human patients with PIK3R2 mutations, these mice have enlarged brains. We found cell size to be increased but not cell numbers. The embryonic brain showed mild defects in cortical lamination, although not observed in the mature brain. Furthermore, electroencephalogram (EEG) recordings from mutant mice showed background slowing and rare seizures, again similar to our observations in human patients. INTERPRETATION: We have generated a PIK3R2 mouse model that exhibits megalencephaly and EEG changes, both of which overlap with human patients. Our data provide novel insight into the pathogenesis of the human disease caused by PIK3R2 p.G373R mutation. We anticipate this model will be valuable in testing therapeutic options for human patients with MPPH. ANN NEUROL 2020;88:1077-1094.

Imaging bioluminescence by detecting localized haemodynamic contrast from photosensitized vasculature.

Bioluminescent probes are widely used to monitor biomedically relevant processes and cellular targets in living animals. However, the absorption and scattering of visible light by tissue drastically limit the depth and resolution of the detection of luminescence. Here we show that bioluminescent sources can be detected with magnetic resonance imaging by leveraging the light-mediated activation of vascular cells expressing a photosensitive bacterial enzyme that causes the conversion of bioluminescent emission into local changes in haemodynamic contrast. In the brains of rats with photosensitized vasculature, we used magnetic resonance imaging to volumetrically map bioluminescent xenografts and cell populations virally transduced to express luciferase. Detecting bioluminescence-induced haemodynamic signals from photosensitized vasculature will extend the applications of bioluminescent probes.

Considering the rates of growth in two taxa of coral across Pacific islands.

Reef-building coral taxa demonstrate considerable flexibility and diversity in reproduction and growth mechanisms. Corals take advantage of this flexibility to increase or decrease size through clonal expansion and loss of live tissue area (i.e. via reproduction and mortality of constituent polyps). The biological lability of reef-building corals may be expected to map onto varying patterns of demography across environmental contexts which can contribute to geographic variation in population dynamics. Here we explore the patterns of growth of two common coral taxa, corymbose Pocillopora and massive Porites, across seven islands in the central and south Pacific. The islands span a natural gradient of environmental conditions, including a range of pelagic primary production, a metric linked to the relative availability of inorganic nutrients and heterotrophic resources for mixotrophic corals, and sea surface temperature and thermal histories. Over a multi-year sampling interval, most coral colonies experienced positive growth (greater planar area of live tissue in second relative to first time point), though the distributions of growth varied across islands. Island-level median growth did not relate simply to estimated pelagic primary productivity or temperature. However, at locations that experienced an extreme warm-water event during the sampling interval, most Porites colonies experienced net losses of live tissue and nearly all Pocillopora colonies experienced complete mortality. While descriptive statistics of demographics offer valuable insights into trends and variability in colony change through time, simplified models predicting growth patterns based on summarized oceanographic metrics appear inadequate for robust demographic prediction. We propose that the complexity of life history strategies among colonial reef-building corals introduces unique demographic flexibility for colonies to respond to a wide breadth of environmental conditions.