Impaired amino acid transport at the blood brain barrier is a cause of autism spectrum disorder

Autism spectrum disorders (ASD) are a group of genetic disorders often overlapping with other neurological conditions. We previously described abnormalities in the branched-chain amino acid (BCAA) catabolic pathway as a cause of ASD. Here, we show that the solute carrier transporter 7a5 (SLC7A5), a large neutral amino acid transporter localized at the blood brain barrier (BBB), has an essential role in maintaining normal levels of brain BCAAs. In mice, deletion of Slc7a5 from the endothelial cells of the BBB leads to atypical brain amino acid profile, abnormal mRNA translation, and severe neurological abnormalities. Furthermore, we identified several patients with autistic traits and motor delay carrying deleterious homozygous mutations in the SLC7A5 gene. Finally, we demonstrate that BCAA intracerebroventricular administration ameliorates abnormal behaviors in adult mutant mice. Our data elucidate a neurological syndrome defined by SLC7A5 mutations and support an essential role for the BCAA in human brain function

Recurrent somatic mutations in POLR2A define a distinct subset of meningiomas

RNA polymerase II mediates the transcription of all protein-coding genes in eukaryotic cells, a process that is fundamental to life. Genomic mutations altering this enzyme have not previously been linked to any pathology in humans, which is a testament to its indispensable role in cell biology. On the basis of a combination of next-generation genomic analyses of 775 meningiomas, we report that recurrent somatic p.Gln403Lys or p.Leu438_His439del mutations in POLR2A, which encodes the catalytic subunit of RNA polymerase II (ref. 1), hijack this essential enzyme and drive neoplasia. POLR2A mutant tumors show dysregulation of key meningeal identity genes including WNT6 and ZIC1/ZIC4. In addition to mutations in POLR2A, NF2, SMARCB1, TRAF7, KLF4, AKT1, PIK3CA, and SMO4 we also report somatic mutations in AKT3, PIK3R1, PRKAR1A, and SUFU in meningiomas. Our results identify a role for essential transcriptional machinery in driving tumorigenesis and define mutually exclusive meningioma subgroups with distinct clinical and pathological features

Functional Synergy between Cholecystokinin Receptors CCKAR and CCKBR in Mammalian Brain Development

<div><p>Cholecystokinin (CCK), a peptide hormone and one of the most abundant neuropeptides in vertebrate brain, mediates its actions via two G-protein coupled receptors, CCKAR and CCKBR, respectively active in peripheral organs and the central nervous system. Here, we demonstrate that the CCK receptors have a dynamic and largely reciprocal expression in embryonic and postnatal brain. Using compound homozygous mutant mice lacking the activity of both CCK receptors, we uncover their additive, functionally synergistic effects in brain development and demonstrate that CCK receptor loss leads to abnormalities of cortical development, including defects in the formation of the midline and corpus callosum, and cortical interneuron migration. Using comparative transcriptome analysis of embryonic neocortex, we define the molecular mechanisms underlying these defects. Thus we demonstrate a developmental, hitherto unappreciated, role of the two CCK receptors in mammalian neocortical development.</p></div

Defects in cortical development in <i>Cckar/br</i> mutant mice.

<p>(A and B) Nissl staining of coronal sections of control and <i>Cckar/br</i> mutant brains at postnatal day 14 (P14) reveals thickening of the cingulate cortex, agenesis of the corpus callosum, and lateral displacement of the hippocampus. (C and D) In situ hybridization with <i>claudin 11</i>, which is expressed in myelinated oligodentrocytes thus highlighting white matter tracts, shows that the commissural axons of the corpus callosum do not cross to the contralateral hemisphere in <i>Cckar/br</i> mutants (D) compared to control (C). Of a total of 16 brains from <i>Cckar/br</i> mutants that were fully sectioned and analyzed for callosal development, 13 had complete and 3 had partial agenesis of the corpus callosum. Scale bar, 100 μm. (E and F) Labeling of callosal projections with DiI shows that colossal axons fail to cross the midline in <i>Cckar/br</i> double mutants (F). Green lines (in E,F) and asterisk (in F) indicate the midline and Probst bundles, respectively. Scale bar, 200 μm.</p

Pathway analysis (Ingenuity.com) of RNA-Seq data.

<p>Pathway analysis (Ingenuity.com) of RNA-Seq data.</p

Abnormal differentiation of the midline in <i>Cckar/br</i> mutant embryos.

<p>(A-F) In situ hybridization with <i>Gfap</i>, a marker of midline glia at perinatal stages, reveals that two midline cell populations, the induseum griseum (IG) and midline zipper glia (mzg), are reduced in <i>Cckar/br</i> double mutants (D-F) compared even with <i>Cckar^+/-;Cckbr^+/-</i> double heterozygous embryos (A-C) at E17.5. Expression of <i>Gfap</i> at the glial wedge (gw) does not appear to be affected to the same extent, suggesting defective differentiation of the midline. Scale bar, 200 μm. (G and H) In situ hybridization with <i>Tag1</i>, a marker of commissural neurons, which also marks the subcallosal sling (scs), demonstrates that a continuous sling is present in control <i>Cckbr^+/-</i> pups (G) at P0, but it fails to transverse the gap between the two hemispheres in <i>Cckar/br</i> mutants (H). Scale bar, 200 μm. (I-N) In situ hybridization demonstrates a modest increase in <i>Cckbr</i> transcripts in the ventral hypothalamus of <i>Cckar</i> single mutants (J,L,N) compared with wild type (I,K,M) at P14. The sections shown are at three different rostro-caudal levels. Scale bar, 0.5 mm.</p

Defects in tangentially migrating interneurons in <i>Cckar/br</i> mutants.

<p>(A,B,E,F) Interneuron progenitors are generated normally in <i>Cckar/br</i> mutant embryos compared to controls, as demonstrated by in situ hybridization with <i>Gad1</i> (A,B) and <i>Lhx6</i> (E,F). However their tangential migration appears delayed in the mutants. Arrows in (A,B) indicate the onset of tangential routes employed by migrating interneurons. Note a delay/reduction in tangential migration in <i>Cckar/br</i> mutants. Red marks in (E,F) indicate the extent of tangential migration (deep route) in the neocortex. Scale bar (B,D), 200 μm. (C,D,G,H) In situ hybridization with <i>Gad1</i> and <i>Lhx6</i> at birth (P0, C,D) or late embryogenesis (E17.5, G,H) demonstrates that despite the delay in migration, a majority of interneurons settle into the neocortex. Scale bar (F,H), 200 μm.</p