Neurodevelopmental functions of CHD8: new insights and questions

This is the final version. Available on open access from Portland Press via the DOI in this recordHeterozygous, de novo, loss-of-function variants of the CHD8 gene are associated with a high penetrance of autism and other neurodevelopmental phenotypes. Identifying the neurodevelopmental functions of high-confidence autism risk genes like CHD8 may improve our understanding of the neurodevelopmental mechanisms that underlie autism spectrum disorders. Over the last decade, a complex picture of pleiotropic CHD8 functions and mechanisms of action has emerged. Multiple brain and non-brain cell types and progenitors appear to be affected by CHD8 haploinsufficiency. Behavioural, cellular and synaptic phenotypes are dependent on the nature of the gene mutation and are modified by sex and genetic background. Here, I review some of the CHD8-interacting proteins and molecular mechanisms identified to date, as well as the impacts of CHD8 deficiency on cellular processes relevant to neurodevelopment. I endeavour to highlight some of the critical questions that still require careful and concerted attention over the next decade to bring us closer to the goal of understanding the salient mechanisms whereby CHD8 deficiency causes neurodevelopmental disorders.Medical Research Council (MRC

Male-Dominant Effects of Chd8 Haploinsufficiency on Synaptic Phenotypes during Development in Mouse Prefrontal Cortex

This is the final version. Available on open access from the American Chemical Society via the DOI in this recordCHD8 is a high penetrance, high confidence risk gene for autism spectrum disorder (ASD), a neurodevelopmental disorder that is substantially more prevalent among males than among females. Recent studies have demonstrated variable sex differences in the behaviors and synaptic phenotypes of mice carrying different heterozygous ASD-associated mutations in Chd8. We examined functional and structural cellular phenotypes linked to synaptic transmission in deep layer pyramidal neurons of the prefrontal cortex in male and female mice carrying a heterozygous, loss-of-function Chd8 mutation in the C57BL/6J strain across development from postnatal day 2 to adulthood. Notably, excitatory neurotransmission was decreased only in Chd8+/- males with no differences in Chd8+/- females, and the majority of alterations in inhibitory transmission were found in males. Similarly, analysis of cellular morphology showed male-specific effects of reduced Chd8 expression. Both functional and structural phenotypes were most prominent at postnatal days 14-20, a stage approximately corresponding to childhood. Our findings suggest that the effects of Chd8 mutation are predominantly seen in males and are maximal during childhood.Simons FoundationBiotechnology and Biological Sciences Research Council (BBSRC)KHP Challenge FundBrain & Behavior Research FoundationKing’s Bioscience InstituteSt Thomas’ CharityWellcome Trus

Effects of Low-Dose Gestational TCDD Exposure on Behavior and on Hippocampal Neuron Morphology and Gene Expression in Mice.

BACKGROUND: 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a persistent and toxic environmental pollutant. Gestational exposure to TCDD has been linked to cognitive and motor deficits, and increased incidence of autism spectrum disorder (ASD) traits in children. Most animal studies of these neurodevelopmental effects involve acute TCDD exposure, which does not model typical exposure in humans. OBJECTIVES: The aim of the study was to establish a dietary low-dose gestational TCDD exposure protocol and performed an initial characterization of the effects on offspring behavior, neurodevelopmental phenotypes, and gene expression. METHODS: Throughout gestation, pregnant C57BL/6J mice were fed a diet containing a low dose of TCDD (9 ng TCDD/kg body weight per day) or a control diet. The offspring were tested in a battery of behavioral tests, and structural brain alterations were investigated by magnetic resonance imaging. The dendritic morphology of pyramidal neurons in the hippocampal Cornu Ammonis (CA)1 area was analyzed. RNA sequencing was performed on hippocampi of postnatal day 14 TCDD-exposed and control offspring. RESULTS: TCDD-exposed females displayed subtle deficits in motor coordination and reversal learning. Volumetric difference between diet groups were observed in regions of the hippocampal formation, mammillary bodies, and cerebellum, alongside higher dendritic arborization of pyramidal neurons in the hippocampal CA1 region of TCDD-exposed females. RNA-seq analysis identified 405 differentially expressed genes in the hippocampus, enriched for genes with functions in regulation of microtubules, axon guidance, extracellular matrix, and genes regulated by SMAD3. DISCUSSION: Exposure to 9 ng TCDD/kg body weight per day throughout gestation was sufficient to cause specific behavioral and structural brain phenotypes in offspring. Our data suggest that alterations in SMAD3-regulated microtubule polymerization in the developing postnatal hippocampus may lead to an abnormal morphology of neuronal dendrites that persists into adulthood. These findings show that environmental low-dose gestational exposure to TCDD can have significant, long-term impacts on brain development and function. https://doi.org/10.1289/EHP7352

Antimicrobial activity of two South African honeys produced from indigenous Leucospermum cordifolium and Erica species on selected micro-organisms

<p>Abstract</p> <p>Background</p> <p>Honey has been shown to have wound healing properties which can be ascribed to its antimicrobial activity. The antimicrobial activity can be effective against a broad spectrum of bacterial species especially those of medical importance. It has also been shown that there is considerable variation in the antimicrobial potency of different types of honey, which is impossible to predict. With this in mind we tested the antimicrobial activity of honeys produced from plants grown in South Africa for their antibacterial properties on selected standard strains of oral micro-organisms.</p> <p>Methods</p> <p>The honeys used were produced from the blossoms of <it>Eucalyptus cladocalyx </it>(Bluegum) trees, an indigenous South African plant <it>Leucospermum cordifolium </it>(Pincushion), a mixture of wild heather shrubs, mainly <it>Erica </it>species (Fynbos) and a <it>Leptospermum scoparium </it>(Manuka) honey. Only pure honey which had not been heated was used. The honeys were tested for their antimicrobial properties with a broth dilution method.</p> <p>Results</p> <p>Although the honeys produced some inhibitory effect on the growth of the micro-organisms, no exceptionally high activity occurred in the South African honeys. The carbohydrate concentration plays a key role in the antimicrobial activity of the honeys above 25%. However, these honeys do contain other antimicrobial properties that are effective against certain bacterial species at concentrations well below the hypertonic sugar concentration. The yeast <it>C. albicans </it>was more resistant to the honeys than the bacteria. The species <it>S. anginosus </it>and <it>S. oralis </it>were more sensitive to the honeys than the other test bacteria.</p> <p>Conclusion</p> <p>The honeys produced from indigenous wild flowers from South Africa had no exceptionally high activity that could afford medical grade status.</p

Inositol treatment inhibits medulloblastoma through suppression of epigenetic-driven metabolic adaptation.

Deregulation of chromatin modifiers plays an essential role in the pathogenesis of medulloblastoma, the most common paediatric malignant brain tumour. Here, we identify a BMI1-dependent sensitivity to deregulation of inositol metabolism in a proportion of medulloblastoma. We demonstrate mTOR pathway activation and metabolic adaptation specifically in medulloblastoma of the molecular subgroup G4 characterised by a BMI1High;CHD7Low signature and show this can be counteracted by IP6 treatment. Finally, we demonstrate that IP6 synergises with cisplatin to enhance its cytotoxicity in vitro and extends survival in a pre-clinical BMI1High;CHD7Low xenograft model

Sprouty2 mediated tuning of signalling is essential for somite myogenesis

Background: Negative regulators of signal transduction cascades play critical roles in controlling different aspects of normal embryonic development. Sprouty2 (Spry2) negatively regulates receptor tyrosine kinases (RTK) and FGF signalling and is important in differentiation, cell migration and proliferation. In vertebrate embryos, Spry2 is expressed in paraxial mesoderm and in forming somites. Expression is maintained in the myotome until late stages of somite differentiation. However, its role and mode of action during somite myogenesis is still unclear. Results: Here, we analysed chick Spry2 expression and showed that it overlaps with that of myogenic regulatory factors MyoD and Mgn. Targeted mis-expression of Spry2 led to inhibition of myogenesis, whilst its C-terminal domain led to an increased number of myogenic cells by stimulating cell proliferation. Conclusions: Spry2 is expressed in somite myotomes and its expression overlaps with myogenic regulatory factors. Overexpression and dominant-negative interference showed that Spry2 plays a crucial role in regulating chick myogenesis by fine tuning of FGF signaling through a negative feedback loop. We also propose that mir-23, mir-27 and mir-128 could be part of the negative feedback loop mechanism. Our analysis is the first to shed some light on in vivo Spry2 function during chick somite myogenesis

Determinants of female sexual function in inflammatory bowel disease: a survey based cross-sectional analysis

<p>Abstract</p> <p>Background</p> <p>Sexual function is impaired in women with inflammatory bowel disease (IBD) as compared to normal controls. We examined disease specific determinants of different aspects of low sexual function.</p> <p>Methods</p> <p>Women with IBD aged 18 to 65 presenting to the university departments of internal medicine and surgery were included. In addition, a random sample from the national patients organization was used (separate analyses). Sexual function was assessed by the Brief Index of Sexual Function in Women, comprising seven different domains of sexuality. Function was considered impaired if subscores were < -1 on a z-normalized scale. Results are presented as age adjusted odds ratios with 95% CI based on multiple logistic regression.</p> <p>Results</p> <p>336 questionnaires were included (219 Crohn's disease, 117 ulcerative colitis). Most women reported low sexual activity (63%; 17% none at all, 20% moderate or high activity). Partnership satisfaction was high in spite of low sexual interest in this group. Depressed mood was the strongest predictor of low sexual function scores in all domains. Urban residency and higher socioecomic status had a protective effect. Disease activity was moderately associated with low desire (OR 1.8, 95% CI 1.0 to 3.2). Severity of the disease course impacted most on intercourse frequency (OR 2.3, 95% CI 1.4 to 4.7). Lubrication problems were more common in smokers (OR 2.5, 95% CI 1.3 to 5.1).</p> <p>Conclusion</p> <p>Mood disturbances and social environment impacted more on sexual function in women with IBD than disease specific factors. Smoking is associated with lubrication problems.</p

Genetics of kidney development: pathogenesis of renal anomalies

Congenital anomalies of the kidney and urinary tract (CAKUT) account for more than 50% of abdominal masses found in neonates and involve about 0.5% of all pregnancies. CAKUT has a major role in renal failure, and increasing evidence suggests that certain abnormalities predispose to the development of hypertension and cardiovascular disease in adulthood. To understand the pathogenesis of human renal anomalies, understanding the development of kidney is important. Diverse anomalies of the kidney corresponding to defects at a particular stage of development have been documented recently; however, more research is required to understand the molecular networks underlying kidney development, and such an investigation will provide a clue to the therapeutic intervention for CAKUT

Genetics of kidney development: pathogenesis of renal anomalies

Congenital anomalies of the kidney and urinary tract (CAKUT) account for more than 50% of abdominal masses found in neonates and involve about 0.5% of all pregnancies. CAKUT has a major role in renal failure, and increasing evidence suggests that certain abnormalities predispose to the development of hypertension and cardiovascular disease in adulthood. To understand the pathogenesis of human renal anomalies, understanding the development of kidney is important. Diverse anomalies of the kidney corresponding to defects at a particular stage of development have been documented recently; however, more research is required to understand the molecular networks underlying kidney development, and such an investigation will provide a clue to the therapeutic intervention for CAKUT

Kidney Development in the Absence of Gdnf and Spry1 Requires Fgf10

GDNF signaling through the Ret receptor tyrosine kinase (RTK) is required for ureteric bud (UB) branching morphogenesis during kidney development in mice and humans. Furthermore, many other mutant genes that cause renal agenesis exert their effects via the GDNF/RET pathway. Therefore, RET signaling is believed to play a central role in renal organogenesis. Here, we re-examine the extent to which the functions of Gdnf and Ret are unique, by seeking conditions in which a kidney can develop in their absence. We find that in the absence of the negative regulator Spry1, Gdnf, and Ret are no longer required for extensive kidney development. Gdnf−/−;Spry1−/− or Ret−/−;Spry1−/− double mutants develop large kidneys with normal ureters, highly branched collecting ducts, extensive nephrogenesis, and normal histoarchitecture. However, despite extensive branching, the UB displays alterations in branch spacing, angle, and frequency. UB branching in the absence of Gdnf and Spry1 requires Fgf10 (which normally plays a minor role), as removal of even one copy of Fgf10 in Gdnf−/−;Spry1−/− mutants causes a complete failure of ureter and kidney development. In contrast to Gdnf or Ret mutations, renal agenesis caused by concomitant lack of the transcription factors ETV4 and ETV5 is not rescued by removing Spry1, consistent with their role downstream of both RET and FGFRs. This shows that, for many aspects of renal development, the balance between positive signaling by RTKs and negative regulation of this signaling by SPRY1 is more critical than the specific role of GDNF. Other signals, including FGF10, can perform many of the functions of GDNF, when SPRY1 is absent. But GDNF/RET signaling has an apparently unique function in determining normal branching pattern. In contrast to GDNF or FGF10, Etv4 and Etv5 represent a critical node in the RTK signaling network that cannot by bypassed by reducing the negative regulation of upstream signals