The adult hippocampal formation (HF) is functionally, connectionally, and transcriptionally differentiated along the dorsal-ventral axis. At birth, the hippocampus appears shortened along its dorsal-ventral axis. We therefore questioned at what postnatal age the differentiated dorsal-ventral hippocampus is present. We first established that the ventral tissue in the short postnatal hippocampus remains ventral in the adult-like hippocampus. Second, using anatomical tracing techniques we report that, within the first postnatal week, the main input from the entorhinal cortex (EC) to HF is topographically organized. The terminal distribution of this input along the dorsal-ventral axis of HF was related to a dorsolateral-to-ventromedial axis of origin in EC, thus reflecting adult topography. Finally, we examined gene expression along the dorsal-ventral axis in the developing hippocampus. We found that several genes that were differentially enriched in the adult dorsal and ventral hippocampus were similarly enriched in the dorsal and ventral hippocampal poles at birth. The differentially expressed genes relate to different molecular pathways and biomarkers of disease. Taken together, these data lead us to conclude that the entire dorsal-ventral axis of HF is present at birth showing adult-like functional differentiation. Moreover, our findings indicate that the neonatal ventral hippocampus is enriched with biomarkers associated with mental illnesses. These include schizophrenia, affective and anxiety disorders, disorders previously deemed as ventral hippocampal associated disorders, as well as alcoholism. Our results thus suggest an early developmental susceptibility of the ventral HF to mental illness.

Human immunodeficiency virus type 1 (HIV-1) integrase (IN) catalyzes the integration of viral DNA into the host chromosome, an essential step in retroviral replication. As a tool to study the structure and function of this enzyme, monoclonal antibodies (MAbs) against HIV-1 IN were produced. Epitope mapping demonstrated that the 17 MAbs obtained could be divided into seven different groups, and a selection of MAbs representing these groups were tested for their effect on in vitro activities of IN. Four groups of MAbs recognized epitopes within the region of amino acids (aa) 1 to 16, 17 to 38, or 42 to 55 in and around the conserved HHCC motif near the N terminus of IN. MAbs binding to these epitopes inhibited end processing and DNA joining and either stimulated or had little effect on disintegration and reintegration activities of IN. Two MAbs binding to epitopes within the region of aa 56 to 102 in the central core or aa 186 to 250 in the C-terminal half of the protein showed only minor effects on the in vitro activities of IN. Three MAbs which recognized an epitope within the region of aa 262 to 271 of HIV-1 IN cross-reacted with HIV-2 IN. MAbs binding to this epitope clearly inhibited end processing and DNA joining and stimulated or had little effect on disintegration. In contrast to the N-terminal-specific MAbs, these C-terminal-specific MAbs abolished reintegration activity of IN.

Base excision repair (BER) initiated by alkyladenine DNA glycosylase (AAG) is essential for removal of aberrantly methylated DNA bases. Genome instability and accumulation of aberrant bases accompany multiple diseases, including cancer and neurological disorders. While BER is well studied on naked DNA, it remains unclear how BER efficiently operates on chromatin. Here, we show that AAG binds to chromatin and forms complex with RNA polymerase (pol) II. This occurs through direct interaction with Elongator and results in transcriptional co-regulation. Importantly, at co-regulated genes, aberrantly methylated bases accumulate towards the 3′end in regions enriched for BER enzymes AAG and APE1, Elongator and active RNA pol II. Active transcription and functional Elongator are further crucial to ensure efficient BER, by promoting AAG and APE1 chromatin recruitment. Our findings provide insights into genome stability maintenance in actively transcribing chromatin and reveal roles of aberrantly methylated bases in regulation of gene expression.

S ary The semiautomated fluorimetric microculture cytotoxicity assay (FMCA)

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