The objective of this study was to identify gene expression differences in blood differences in children with autism (AU) and autism spectrum disorder (ASD) compared to general population controls. Transcriptional profiles were compared with age- and gender-matched, typically developing children from the general population (GP). The AU group was subdivided based on a history of developmental regression (A-R) or a history of early onset (A-E without regression). Total RNA from blood was processed on human Affymetrix microarrays. Thirty-five children with AU (17 with early onset autism and 18 with autism with regression) and 14 ASD children (who did not meet criteria for AU) were compared to 12 GP children. Unpaired t tests (corrected for multiple comparisons with a false discovery rate of 0.05) detected a number of genes that were regulated more than 1.5-fold for AU versus GP (n=55 genes), for A-E versus GP (n=140 genes), for A-R versus GP (n=20 genes), and for A-R versus A-E (n=494 genes). No genes were significantly regulated for ASD versus GP. There were 11 genes shared between the comparisons of all autism subgroups to GP (AU, A-E, and A-R versus GP) and these genes were all expressed in natural killer cells and many belonged to the KEGG natural killer cytotoxicity pathway (p=0.02). A subset of these genes (n=7) was tested with qRT-PCR and all genes were found to be differentially expressed (p<0.05). We conclude that the gene expression data support emerging evidence for abnormalities in peripheral blood leukocytes in autism that could represent a genetic and/or environmental predisposition to the disorder.

Dysregulation of ErbB receptor tyrosine kinases is thought to promote mammary tumor progression by stimulating tumor cell growth and invasion. Overexpression and aberrant activation of ErbB2/HER2 confer aggressive and malignant characteristics to breast cancer cells, and patients displaying ErbB2-amplified breast cancer face a worsened prognosis. Recent studies have established that ErbB2 and ErbB3 are commonly co-overexpressed in breast tumor cell lines and in patient samples. ErbB2 heterodimerizes with and activates the ErbB3 receptor, and the two receptors synergize in promoting growth factor-induced cell proliferation, transformation, and invasiveness. Our previous studies have shown that the neuregulin receptor degradation protein-1 (Nrdp1) E3 ubiquitin ligase specifically suppresses cellular ErbB3 levels by marking the receptor for proteolytic degradation. Here, we show that overexpression of Nrdp1 in human breast cancer cells results in the suppression of ErbB3 levels, accompanied by the inhibition of cell growth and motility and the attenuation of signal transduction pathways. In contrast, either Nrdp1 knockdown or the overexpression of a dominantnegative form enhances ErbB3 levels and cellular proliferation. Additionally, Nrdp1 expression levels inversely correlate with ErbB3 levels in primary human breast cancer tissue and in a mouse model of ErbB2 mammary tumorigenesis. Our observations suggest that Nrdp1-mediated ErbB3 degradation suppresses cellular growth and motility, and that Nrdp1 loss in breast tumors may promote tumor progression by augmenting ErbB2/ErbB3 signaling. (Cancer Res 2006; 66(23): 11279-86)

Autism is a complex neurodevelopmental disorder having both genetic and epigenetic etiological elements. Isodicentric chromosome 15 (Idic15), characterized by duplications of the multi-disorder critical region of 15q11-q14, is a relatively common cytogenetic event. When the duplication involves maternally derived content, this abnormality is strongly correlated with autism disorder. However, the mechanistic links between Idic15 and autism are ill-defined. To gain insight into the potential role of these duplications, we performed a comprehensive, genomics-based characterization of an in vitro model system consisting of lymphoblast cell lines derived from individuals with both autism and Idic15. Array-based comparative genomic hybridization using commercial single nucleotide polymorphism arrays was conducted and found to be capable of sub-classifying Idic15 samples by virtue of the lengths of the duplicated chromosomal region. In further analysis, whole-genome expression profiling revealed that 112 transcripts were significantly dysregulated in samples harboring duplications. Paramount among changing genes was ubiquitin protein ligase E3A (UBE3A; 15q11-q13), which was found to be nearly 1.5-2.0-fold up-regulated in duplicated samples at both the RNA and protein levels. Other key findings from gene expression analysis included two down-regulated genes, APP and SUMO1, with well-characterized roles in the process of apoptosis. We further demonstrate in this lymphoblast model that the gene-dosage directed increases in UBE3A levels can lead to dysregulation of the process of ubiquitination in response to genotoxic insult. This study provides insight into the direct and indirect effects of copy number gains in chromosome 15 and provides a framework for the study of these effects in neuronal systems.

In order to provide an alternative approach for understanding the biology and genetics of autism, we performed statistical analysis of gene expression profiles of lymphoblastoid cell lines derived from children with autism and their families. The goal was to assess the feasibility of using this model in identifying autism-associated genes. Replicate microarray experiments demonstrated that expression data from the cell lines were consistent and highly reproducible. Further analyses identified differentially expressed genes between cell lines derived from children with autism and those derived from their normally developing siblings. These genes were then used to identify biochemical pathways potentially involved in autism. This study suggests that lymphoblastoid cell lines may be a viable tool for identifying genes associated with autism.

Dendritic cells (DC) are essential for the initiation of primary adaptive immune responses, and their functionality is strongly down-modulated by IL-10. Both innate and adaptive immune signals trigger the up-regulation of antiapoptotic Bcl-2 family members to facilitate the survival of DCs after maturation. However, whether IL-10 alters the expression of apoptotic-related genes in maturing DCs has not been determined. In this study, we demonstrate that spontaneous apoptosis rapidly occurred in myeloid DCs exposed to exogenous IL-10 upon maturation. Microarray analysis indicates that IL-10 suppressed the induction of three antiapoptotic genes, bcl-2, bcl-x, and bfl-1, which was coincident with the increased sensitivity of mature DCs to spontaneous apoptosis. IL-10 markedly inhibited the accumulation of steady state Bcl-2 message and protein in myeloid DCs activated through TLRs or TNFR family members, whereas exogenous IL-10 affected Bcl-xL expression in a moderate manner. In contrast, bcl-2 expression of plasmacytoid DCs was less sensitive to the effects of IL-10. We further show that autocrine IL-10 significantly limited the longevity of myeloid DCs and altered the expression kinetics of Bcl-2 but not Bcl-xL in maturing DCs. We conclude that the degree of IL-10 exposure and/or the level of endogenous IL-10 production upon myeloid DC maturation play a critical role in determining DC longevity. This regulatory mechanism of IL-10 is associated with the dynamic control of antiapoptotic Bcl-2 proteins.