Behavioral responses to sociosexual signals often depend on gonadal steroid hormones, which are thought to modulate behavior by acting on motivational systems in the brain. There is mounting evidence that sex steroids may also modulate perception of sociosexual signals by affecting sensory processing. In seasonally breeding songbirds such as the white-throated sparrow (Zonotrichia albicollis), the female's behavioral response to hearing male song depends on her plasma levels of estradiol (E2). Here, we examined whether plasma E2 also affects the selectivity of the song-induced zenk (egr-1) response in the auditory forebrain, which is known to vary according to the behavioral relevance of song stimuli. Non-breeding females were held on a winter-like photoperiod and implanted with silastic capsules containing either no hormone or E2. E2-treated birds hearing 42 min of conspecific song had more cells immunoreactive for the protein product of zenk in the auditory forebrain than did those hearing frequency-matched synthetic tones. In birds not treated with E2, however, the zenk response to song did not differ from that to tones. We found similar effects in the avian homolog of the inferior colliculus, indicating that E2 may affect the processing of auditory information upstream of the forebrain. Our data suggest that in females, zenk induction in the auditory system is selective for song only when plasma E2 exceeds non-breeding levels. E2-dependent plasticity of auditory pathways and processing centres may promote recognition of and attention to conspecific song during the breeding season.

BackgroundThe chemopreventive effects of resveratrol (RSV) on prostate cancer have been well established; the androgen receptor (AR) plays pivotal roles in prostatic tumorigenesis. However, the exact underlying molecular mechanisms about the effects of RSV on AR have not been fully elucidated. A model system is needed to determine whether and how RSV represses AR transcriptional activity.MethodologyThe AR cDNA was first cloned into the retroviral vector pOZ-N and then integrated into the genome of AR-negative HeLa cells to generate the AR(+) cells. The constitutively expressed AR was characterized by monitoring hormone-stimulated nuclear translocation, DNA binding, and transcriptional activation, with the AR(-) cells serving as controls. AR(+) cells were treated with RSV, and both AR protein levels and AR transcriptional activity were measured simultaneously. Chromatin immunoprecipitation (ChIP) assays were used to detect the effects of RSV on the recruitment of AR to its cognate element (ARE).ResultsAR in the AR (+) stable cell line functions in a manner similar to that of endogenously expressed AR. Using this model system we clearly demonstrated that RSV represses AR transcriptional activity independently of any effects on AR protein levels. However, neither the hormone-mediated nucleus translocation nor the AR/ARE interaction was affected by RSV treatment.ConclusionWe demonstrated unambiguously that RSV regulates AR target gene expression, at least in part, by repressing AR transcriptional activity. Repressive effects of RSV on AR activity result from mechanisms other than the affects of AR nuclear translocation or DNA binding.

Senataxin, encoded by the SETX gene, contributes to multiple aspects of gene expression, including transcription and RNA processing. Mutations in SETX cause the recessive disorder ataxia with oculomotor apraxia type 2 (AOA2) and a dominant juvenile form of amyotrophic lateral sclerosis (ALS4). To assess the functional role of senataxin in disease, we examined differential gene expression in AOA2 patient fibroblasts, identifying a core set of genes showing altered expression by microarray and RNA-sequencing. To determine whether AOA2 and ALS4 mutations differentially affect gene expression, we overexpressed disease-specific SETX mutations in senataxin-haploinsufficient fibroblasts and observed changes in distinct sets of genes. This implicates mutation-specific alterations of senataxin function in disease pathogenesis and provides a novel example of allelic neurogenetic disorders with differing gene expression profiles. Weighted gene co-expression network analysis (WGCNA) demonstrated these senataxin-associated genes to be involved in both mutation-specific and shared functional gene networks. To assess this in vivo, we performed gene expression analysis on peripheral blood from members of 12 different AOA2 families and identified an AOA2-specific transcriptional signature. WGCNA identified two gene modules highly enriched for this transcriptional signature in the peripheral blood of all AOA2 patients studied. These modules were disease-specific and preserved in patient fibroblasts and in the cerebellum of Setx knockout mice demonstrating conservation across species and cell types, including neurons. These results identify novel genes and cellular pathways related to senataxin function in normal and disease states, and implicate alterations in gene expression as underlying the phenotypic differences between AOA2 and ALS4.

OBJECTIVE Identification of a novel missense mutation in the SPTBN2 gene of a family with a clinical diagnosis of spinocerebellar ataxia type 5 (SCA5). METHODS A family with late-onset autosomal dominant pure cerebellar ataxia, consistent with SCA5 but lacking previously reported SPTBN2 mutations, was identified. DNA was collected from seven individuals across two generations and the SPTBN2 gene on chromosome 11 was sequenced. RESULTS A nonsynonymous heterozygous substitution in exon 12 was detected in individuals diagnosed with SCA5 while unaffected family members did not possess this variant. The identified c.1415C>T variant results in a p.T472M substitution in the second SPEC domain of the beta-III spectrin protein. The threonine at position 472 is not in close proximity to the characteristic residues that define the SPEC domain and is variable across diverse SPEC domains, yet is highly conserved in SPTBN2. Consistent with these observations, bioinformatic analysis of the p.T472M variant suggests it to be pathological. CONCLUSION Two deletions within the SPTBN2 SPEC domains (E532_M544del and L629_R634delinsW) have been previously reported to cause SCA5, but this is the first missense mutation in this region of the protein shown to likely be pathogenic.

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