Eva Chmielnicki

Autism spectrum disorders: Mutual mutation mechanisms

The epidermal growth factor receptor (EGFR) is altered in 50% of glioblastomas (GBMs), but EGFR inhibitors have yielded disappointing results in clinical assays. A new study may allow improved targeting of EGFR-dependent GBMs by identifying a key regulator of EGFR in GBMs (J. Clin. Invest. http://dx.doi.org/ 10.1172/JCI63623). Natividad Pozo et al. examined the effect of DYRK1A, a kinase important in central nervous system development, on EGFR in established GBM cell lines. They found that silencing of DYRK1A led to a reduction in the amounts of EGFR and inhibited self-renewal of the cells. Downregulation of DYRK1A also decreased tumor growth in nude mice after injection of GBM cells. Similarly, the authors found that pharmacological inhibition of DYRK1A reduced self-renewal of GBM cells and decreased tumor growth in nude mice injected with GBM cells. The researchers then turned their attention to human glioma samples, finding that DYRK1A was more highly expressed in gliomas compared with normal brain tissue. They also identified a positive correlation between EGFR and DYRK1A expression in GBM samples. Notably, the authors’ data indicate that DYRK1A acts at the level of regulating EGFR stability rather than its kinase activity. They suggest that targeting DYRK1A, either alone or in combination with EGFR inhibitors, could have therapeutic benefit in EGFR-dependent GBMs. —MS

Neuronal development: Environmental brain protection

inducing this gene expression program and in maintaining these macrophages at this location, which helped ameliorate inflammation. Functionally, activation of GATA6 by retinoic acid in these macrophages regulated the production of IgA by peritoneal B-1 immune cells. Looking at other downstream effects of GATA6, Marcela Rosas and her colleagues found that mice lacking Gata6 had altered proliferation of tissue macrophages during homeostasis. In a mouse model of acute peritonitis, the absence of this factor inhibited recovery of macrophages and resulted in delayed resolution of inflammation. Although the authors did not pinpoint what induces GATA6 in peritoneal macrophages, ex vivo cultures confirmed that a local tissue signal was needed.—CP

Amyotrophic lateral sclerosis: Mayhem-making microglia

Tebas et al. enrolled 12 patients with HIV infections that were undetectable in the blood during highly active antiretroviral treatment in a trial in which the patients received one dose of CD4-enriched T cells, consisting of 11–28% T cells with CCR5 disrupted by zinc finger nuclease modification. The infusion increased the overall number of circulating CD4+ T cells. These cells, however, declined in number upon withdrawal of antiretroviral therapy, though the decline was smaller in the CCR5-engineered cells, and the overall CD4+ T cell number was still higher than before infusion. There was also a decrease in viral RNA in four patients who were able to finish the 12-week withdrawal, and only one individual had an adverse effect due to the infusion. Although the number of patients enrolled in the study is too small to make any strong conclusions regarding safety and efficacy, it seems that gene editing to create immune cells resistant to HIV infection might be safe and shows promise for the treatment of HIV. —HS

Schizophrenia: Going retro

Retrotransposons are movable genetic elements that are found throughout the genome. Insertion of new retrotransposon copies in or near genes could be involved in disease pathogenesis. Now, Miki Bundo and colleagues have identified a high copy number of the retrotransposon L1 specifically in neurons within the postmortem prefrontal cortex from individuals with schizophrenia compared to normal controls and other psychiatric diseases (Neuron doi:10.1016/j.neuron.2013.10.053, 2 January 2014). Using whole-genome sequencing of brain DNA from the patients with schizophrenia versus control subjects, the authors found that L1 insertions sites in individuals with schizophrenia often occur in or near genes linked to neuronal and synaptic function. Mechanistically, maternal immune activation in pregnant mice with the immunostimulant poly-I:C led to increased L1 copy number in the offspring. The findings suggest how early environmental risk factors, which have been previously linked to increased disease risk, could drive genetic changes that contribute to the pathogenesis of schizophrenia or other illnesses.—EC

Adult neurogenesis: Making new neurons

Innate lymphoid cells (ILCs) are found in the spleen, where they promote antibody production by marginal zone B cells, according to a recent study in Nature Immunology (15, 354–364, 2014). ILCs are commonly found at barrier surfaces where, in response to environmental stimuli, they provide an important source of cytokines that prime the development and function of immune cells. Although ILCs have been shown to support antibody production at mucosal surfaces, whether these cells also function in the spleen is not clear. Andrea Cerutti and his colleagues now report that in humans, ILCs are found within the marginal zone of the spleen and exhibit a phenotype similar to mucosal ILCs. These ILCs interact with and receive survival signals from stromal cells within the spleen that help promote their function. ILCs are positioned near B cells and promote the survival and differentiation of marginal zone B cells and plasma cells via B cell–activating factor (BAFF), CD40 ligand and the Notch ligand delta-like ligand 1 (DLL1). In addition, ILCs help recruit neutrophils to the spleen, which, in turn, promotes antibody production. In the absence of splenic ILCs, T cell–independent antigen antibody production is impaired. These findings suggest ILCs provide crosstalk between stromal cells and different arms of the immune system to support antibody production. —KDS

Neurodegeneration: Arresting aggregation

Frontotemporal dementia and amyotrophic lateral sclerosis (ALS) are neurodegenerative diseases that have been linked to a repeat expansion of the hexanucleotide sequence GGGGCC in C9ORF72. RNA transcribed from this repeat forms aggregates in the nucleus of neurons that can sequester key RNAbinding proteins. Non-ATG translation from the hexanucleotide sequence also occurs, leading to the formation of potentially toxic peptide aggregates within neurons. Both of these mechanisms could contribute to disease pathogenesis. Zhaoming Su et al. now report their development of small molecules that bind to RNA transcribed from this sequence, which could protect vulnerable neuronal populations (Neuron 83, 1043– 1050, 2014). By studying the structure that the hexanucleotide RNA adopts, the researchers generated small molecules that bind the transcript. These compounds reduce formation of RNA aggregates and peptides in neurons derived from fibroblasts of human carriers of the repeat expansion. In addition, Su et al. developed an immunoassay that enabled detection of these peptides in the cerebrospinal fluid (CSF) of individuals with ALS carrying the repeat expansion. This suggests that peptide levels in the CSF could serve as a biomarker for therapeutic response to the compounds they identified. —EC

Neuroscience: Bringing back neuronal inhibition

A recent study in humans has identified the first genetic link between body mass index (BMI) and carbohydrate metabolism (Nat. Genet. doi:10.1038/ng.2939). Mario Falchi and his colleagues analyzed DNA arrays for common copy number variants (CNVs) in 651 subjects from 149 Swedish families that had pairs of siblings where one was obese and one was not. By linking the identified CNVs with gene expression data from adipose tissue (to ensure a phenotypic effect of the CNV) and BMI, the authors identified an inverse association between BMI and copy number of the region encoding the salivary amylase gene cluster (AMY1). This cluster encodes a protein called salivary amylase, which initiates carbohydrate digestion in the oral cavity. Quantitative PCR analyses of DNA copy number confirmed this association in another 3,600 European subjects, in which AMY1 copy number could account for 2.47% to 19.86% of the total genetic variation in obesity. Similar results were seen in 2,400 subjects from a Singaporean Chinese case control study, indicating that AMY1 copy number is not a European population– specific genetic risk factor for obesity. Amounts of plasma salivary amylase in 468 morbidly obese French subjects were linked to copy number and inversely associated with BMI. How these genetic alterations in AMY1 lead to obesity and how to therapeutically exploit this new link between digestive enzyme levels and obesity remain to be explored. —HS

Neurodevelopmental disorders: Synaptic supervision

restricting hiV from macrophages In addition to HIV-1–infected CD4+ T cells, macrophages may also be a key source of the viral reservoir in HIV-1–infected people. A recent study reveals details of how HIV-1 is restricted from macrophages, which might inform the design of new strategies for eradicating the HIV reservoir (J. Exp. Med. 210, 517–534). The Imamichi laboratory previously showed that interleukin-27 (IL-27) inhibits HIV-1 replication in monocyte-derived macrophages. In their new study, this group sought to identify how IL-27 exerts its anti–HIV-1 effects. They found no evidence that IL-27 blocks entry of HIV-1 into macrophages but showed that macrophages induced with IL-27 produced less proviral cDNA of late HIV-1 gene products than control macrophages, suggesting that IL-27 interferes with HIV-1 replication between viral entry and reverse transcription. Dai et al. then found that spectrin b nonerythrocyte 1 (SPTBN1) was downregulated in IL-27–treated macrophages compared with control macrophages. Knockdown of SPTBN1 in control macrophages prevented their infection by HIV-1, and overexpression of SPTBN1 in IL-27–induced macrophages rendered them susceptible to HIV-1 infection. The authors found that SPTBN1 associates with HIV-1 Gag proteins in macrophages and suggest that this interaction may be important for reverse transcription of the HIV-1 genome, but the functional relevance of the SPTBN1-Gag association still remains to be investigated in more detail. In addition, the effects of IL-27 need to be assessed in an in vivo model of HIV-1 infection. —MS

Neurodegeneration: A repeat offense

implicates the receptor tyrosine kinase EphA3 in GBM progression and highlights a new potential therapeutic approach (Cancer Cell 23, 238–248). Brian W. Day and his colleagues showed that EphA3 was significantly overexpressed in about 40% of human glioma samples they studied. They associated elevated EphA3 expression with poor survival of patients afflicted with the mesenchymal subtype of GBM, an undifferentiated and particularly aggressive form of the cancer.

Diseases of the nervous system: Neurons on the move

The intellectual disability and seizure disorder Börjeson-Forssman-Lehmann syndrome (BFLS) is linked to abnormal neuronal migration, according to a recent study (Neuron 78, 986–993). BFLS is caused by mutations in the gene that encodes the nuclear protein PHF6. When Chi Zhang et al. knocked down the expression of PHF6 in developing mouse brains using RNAi in utero, they observed reduced neuron migration to the outer layers of the cortex, leading the neurons to reside in an abnormal cortical location and become hyperexcitable. The expression of mutant versions of PHF6 that are found in individuals with BFLS could not rescue the abnormal migration phenotype, suggesting that dysfunctional neuronal migration causes the disorder in humans. Zhang et al. found that PHF6 binds the transcription factor PAF1 and that knocking down PAF1 in developing mice also induces abnormal neuronal migration. In micro array experiments, the researchers found that expression of the transmembrane protein neuroglycan C was decreased in neurons with reduced expression of PHF6 compared with wild-type neurons and that reexpression of neuroglycan C could rescue cortical neuron migration in mice with PHF6 knockdown. Whether restoring neuronal migration via this mechanism could improve cognition in BFLS remains an open question. —EC