We isolated a Dictyostelium cytokinesis mutant with a defect in a novel locus called large volume sphere A (lvsA). lvsA mutants exhibit an unusual phenotype when attempting to undergo cytokinesis in suspension culture. Early in cytokinesis, they initiate furrow formation with concomitant myosin II localization at the cleavage furrow. However, the furrow is later disrupted by a bulge that forms in the middle of the cell. This bulge is bounded by furrows on both sides, which are often enriched in myosin II. The bulge can increase and decrease in size multiple times as the cell attempts to divide. Interestingly, this phenotype is similar to the cytokinesis failure of Dictyosteliumclathrin heavy-chain mutants. Furthermore, both cell lines cap ConA receptors but form only a C-shaped loose cap. Unlike clathrin mutants,lvsA mutants are not defective in endocytosis or development. The LvsA protein shares several domains in common with the molecules beige and Chediak–Higashi syndrome proteins that are important for lysosomal membrane traffic. Thus, on the basis of the sequence analysis of the LvsA protein and the phenotype of thelvsA mutants, we postulate that LvsA plays an important role in a membrane-processing pathway that is essential for cytokinesis.
We present a multifactorial, multistep approach called genomic convergence that combines gene expression with genomic linkage analysis to identify and prioritize candidate susceptibility genes for Parkinson's disease (PD). To initiate this process, we used serial analysis of gene expression (SAGE) to identify genes expressed in two normal substantia nigras (SN) and adjacent midbrain tissue. This identified over 3700 transcripts, including the three most abundant SAGE tags, which did not correspond to any known genes or ESTs. We developed high-throughput bioinformatics methods to map the genes corresponding to these tags and identified 402 SN genes that lay within five large genomic linkage regions, previously identified in 174 multiplex PD families. These genes represent excellent candidates for PD susceptibility alleles and further genomic convergence and analyses.
During perinatal development, avian and mammalian skeletal muscles express a novel set of troponin T (TnT) isoforms with higher M(r)s and more acidic pIs than their adult counterparts. In mammals, these TnTs result from the incorporation of a developmentally regulated 5'-fetal exon into fast TnT mRNAs. To determine whether chicken perinatal TnTs are generated by a similar mechanism, we sequenced 40 chicken TnT 5'-cDNAs from perinatal and adult pectoralis. Evidence for five 5'-exons not present in the mammalian gene was found, including one, y, whose splicing is developmentally regulated. Although none of these new exons are homologous with the mammalian fetal exon, their alternative splicing, superimposed on three conserved splicing patterns of the phylogenetically shared 5'-exons, generates the chicken perinatal TnT isoforms. These observations indicate that chicken, and most likely other avian species, evolved an independent 5'-alternative splicing mechanism to generate perinatal TnTs that have the same biophysical, and presumably functional, properties as their mammalian homologs.
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