The Muller F element (4.2 Mb, ~80 protein-coding genes) is an unusual autosome of Drosophila melanogaster; it is mostly heterochromatic with a low recombination rate. To investigate how these properties impact the evolution of repeats and genes, we manually improved the sequence and annotated the genes on the D. erecta, D. mojavensis, and D. grimshawi F elements and euchromatic domains from the Muller D element. We find that F elements have greater transposon density (25–50%) than euchromatic reference regions (3–11%). Among the F elements, D. grimshawi has the lowest transposon density (particularly DINE-1: 2% vs. 11–27%). F element genes have larger coding spans, more coding exons, larger introns, and lower codon bias. Comparison of the Effective Number of Codons with the Codon Adaptation Index shows that, in contrast to the other species, codon bias in D. grimshawi F element genes can be attributed primarily to selection instead of mutational biases, suggesting that density and types of transposons affect the degree of local heterochromatin formation. F element genes have lower estimated DNA melting temperatures than D element genes, potentially facilitating transcription through heterochromatin. Most F element genes (~90%) have remained on that element, but the F element has smaller syntenic blocks than genome averages (3.4–3.6 vs. 8.4–8.8 genes per block), indicating greater rates of inversion despite lower rates of recombination. Overall, the F element has maintained characteristics that are distinct from other autosomes in the Drosophila lineage, illuminating the constraints imposed by a heterochromatic milieu.

Tauopathies are defined by assembly of the microtubule associated protein tau into filamentous tangles and classified by the predominant tau isoform within these aggregates. The major isoforms are determined by alternative mRNA splicing of exon 10 generating tau with three (3R) or four (4R) ∼32 amino acid imperfect repeats in the microtubule binding domain. In normal adult brains there is an approximately equimolar ratio of 3R and 4R tau which is altered by several disease-causing mutations in the tau gene. We hypothesized that when 4R and 3R tau isoforms are not at equimolar ratios aggregation is favored. Here we provide evidence for the first time that the combination of 3R and 4R tau isoforms results in less in vitro heparin induced polymerization than with 4R preparations alone. This effect was independent of reducing conditions and the presence of alternatively spliced exons 2 and 3 N-terminal inserts. The addition of even small amounts of 3R to 4R tau assembly reactions significantly decreased 4R assembly. Together these findings suggest that co-expression of 3R and 4R tau isoforms reduce tau filament assembly and that 3R tau isoforms inhibit 4R tau assembly. Expression of equimolar amounts of 3R and 4R tau in adult humans may be necessary to maintain proper neuronal microtubule dynamics and to prevent abnormal tau filament assembly. Importantly, these findings indicate that disruption of the normal equimolar 3R to 4R ratio may be sufficient to drive tau aggregation and that restoration of the tau isoform balance may have important therapeutic implications in tauopathies.

Here, we describe the generation and characterization of a novel tau transgenic mouse model (mTau) that overexpresses wild-type murine tau protein by twofold compared with endogenous levels. Transgenic tau expression was driven by a BAC transgene containing the entire wild-type mouse tau locus, including the endogenous promoter and the regulatory elements associated with the tau gene. The mTau model therefore differs from other tau models in that regulation of the genomic mouse transgene mimics that of the endogenous gene, including normal exon splicing regulation. Biochemical data from the mTau mice demonstrated that modest elevation of mouse tau leads to tau hyperphosphorylation at multiple pathologically relevant epitopes and accumulation of sarkosyl-insoluble tau. The mTau mice show a progressive increase in hyperphosphorylated tau pathology with age up to 15 to 18 months, which is accompanied by gliosis and vacuolization. In contrast, older mice show a decrease in tau pathology levels, which may represent hippocampal neuronal loss occurring in this wild-type model. Collectively, these results describe a novel model of tauopathy that develops pathological changes reminiscent of early stage Alzheimer's disease and other related neurodegenerative diseases, achieved without overexpression of a mutant human tau transgene. This model will provide an important tool for understanding the early events leading to the development of tau pathology and a model for analysis of potential therapeutic targets for sporadic tauopathies. Abnormal accumulation of the microtubule-associated protein tau, in the form of neurofibrillary tangles (NFTs), is the defining pathological feature of neurodegenerative diseases termed tauopathies. Six major tau protein isoforms are generated in adult human brain by alternative splicing of the tau (MAPT) gene, 1,2 and studies of mutations within this gene have provided insight into potential mechanisms for the pathological aggregation of tau proteins.3,4 With use of a single isoform of mutant human tau, transgenic mice have been generated (reviewed in 5 ) that recapitulate many features of human tauopathy; however, most tauopathies are not associated with specific MAPT mutations. Because normal and mutant tau proteins appear to have functional differences, 6 -8 the mechanism of tau pathology development, neuronal loss, and interactions with other proteins may also differ between sporadic tauopathies and cases linked to specific mutations. Previous attempts to create a wild-type tauopathy model through overexpression of a single wild-type human tau isoform have generally led to minimal pathological changes. Although these models have been useful in studying early aspects of tauopathy, they do not mimic normal gene regulation or tau isoform profiles in the brain. Development of a mouse model overexpressing the entire human tau transgene (8c mice) was expected to overcome this limitation. However, these mice failed to elicit notable tau pathology, but did result in a significant shift in exon 10...